Genetic improvement of leaf photosynthesis and intrinsic water use efficiency in C3 plants: Why so much little success?

PubMed

Flexas, J

2016-10-01

There is an urgent need for simultaneously increasing photosynthesis/yields and water use efficiency (WUE) in C3 crops. Potentially, this can be achieved by genetic manipulation of the key traits involved. However, despite significant efforts in the past two decades very limited success has been achieved. Here I argue that this is mostly due to the fact that single gene/single trait approaches have been used thus far. Photosynthesis models demonstrate that only limited improving of photosynthesis can be expected by large improvements of any of its single limiting factors, i.e. stomatal conductance, mesophyll conductance, and the biochemical capacity for photosynthesis, the latter co-limited by Rubisco and the orchestrated activity of thylakoid electron transport and the Calvin cycle enzymes. Accordingly, only limited improvements of photosynthesis have been obtained by genetic manipulation of any of these single factors. In addition, improving photosynthesis by genetic manipulation in general reduced WUE, and vice-versa, and in many cases pleiotropic effects appear that cancel out some of the expected benefits. I propose that success in genetic manipulation for simultaneous improvement of photosynthesis and WUE efficiency may take longer than suggested in previous reports, and that it can be achieved only by joint projects addressing multi-gene manipulation for simultaneous alterations of all the limiting factors of photosynthesis, including the often neglected phloem capacity for loading and transport the expected surplus of carbohydrates in plants with improved photosynthesis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Genetic Risk Score of NOS Gene Variants Associated with Myocardial Infarction Correlates with Coronary Incidence across Europe

PubMed Central

Carreras-Torres, Robert; Kundu, Suman; Zanetti, Daniela; Esteban, Esther

2014-01-01

Coronary artery disease (CAD) mortality and morbidity is present in the European continent in a four-fold gradient across populations, from the South (Spain and France) with the lowest CAD mortality, towards the North (Finland and UK). This observed gradient has not been fully explained by classical or single genetic risk factors, resulting in some cases in the so called Southern European or Mediterranean paradox. Here we approached population genetic risk estimates using genetic risk scores (GRS) constructed with single nucleotide polymorphisms (SNP) from nitric oxide synthases (NOS) genes. These SNPs appeared to be associated with myocardial infarction (MI) in 2165 cases and 2153 controls. The GRSs were computed in 34 general European populations. Although the contribution of these GRS was lower than 1% between cases and controls, the mean GRS per population was positively correlated with coronary incidence explaining 65–85% of the variation among populations (67% in women and 86% in men). This large contribution to CAD incidence variation among populations might be a result of colinearity with several other common genetic and environmental factors. These results are not consistent with the cardiovascular Mediterranean paradox for genetics and support a CAD genetic architecture mainly based on combinations of common genetic polymorphisms. Population genetic risk scores is a promising approach in public health interventions to develop lifestyle programs and prevent intermediate risk factors in certain subpopulations with specific genetic predisposition. PMID:24806096

Genetics or environment in drug transport: the case of organic anion transporting polypeptides and adverse drug reactions.

PubMed

Clarke, John D; Cherrington, Nathan J

2012-03-01

Organic anion transporting polypeptide (OATP) uptake transporters are important for the disposition of many drugs and perturbed OATP activity can contribute to adverse drug reactions (ADRs). It is well documented that both genetic and environmental factors can alter OATP expression and activity. Genetic factors include single nucleotide polymorphisms (SNPs) that change OATP activity and epigenetic regulation that modify OATP expression levels. SNPs in OATPs contribute to ADRs. Environmental factors include the pharmacological context of drug-drug interactions and the physiological context of liver diseases. Liver diseases such as non-alcoholic fatty liver disease, cholestasis and hepatocellular carcinoma change the expression of multiple OATP isoforms. The role of liver diseases in the occurrence of ADRs is unknown. This article covers the roles OATPs play in ADRs when considered in the context of genetic or environmental factors. The reader will gain a greater appreciation for the current evidence regarding the salience and importance of each factor in OATP-mediated ADRs. A SNP in a single OATP transporter can cause changes in drug pharmacokinetics and contribute to ADRs but, because of overlap in substrate specificities, there is potential for compensatory transport by other OATP isoforms. By contrast, the expression of multiple OATP isoforms is decreased in liver diseases, reducing compensatory transport and thereby increasing the probability of ADRs. To date, most research has focused on the genetic factors in OATP-mediated ADRs while the impact of environmental factors has largely been ignored.

Genetic and Environmental Architecture of Changes in Episodic Memory from Middle to Late Middle Age

PubMed Central

Panizzon, Matthew S.; Neale, Michael C.; Docherty, Anna R.; Franz, Carol E.; Jacobson, Kristen C.; Toomey, Rosemary; Xian, Hong; Vasilopoulos, Terrie; Rana, Brinda K.; McKenzie, Ruth M.; Lyons, Michael J.; Kremen, William S.

2015-01-01

Episodic memory is a complex construct at both the phenotypic and genetic level. Ample evidence supports age-related cognitive stability and change being accounted for by general and domain-specific factors. We hypothesized that general and specific factors would underlie change even within this single cognitive domain. We examined six measures from three episodic memory tests in a narrow age cohort at middle and late middle age. The factor structure was invariant across occasions. At both timepoints two of three test-specific factors (story recall, design recall) had significant genetic influences independent of the general memory factor. Phenotypic stability was moderate to high, and primarily accounted for by genetic influences, except for one test-specific factor (list learning). Mean change over time was nonsignificant for one test-level factor; one declined; one improved. The results highlight the phenotypic and genetic complexity of memory and memory change, and shed light on an understudied period of life. PMID:25938244

Genetic and environmental architecture of changes in episodic memory from middle to late middle age.

PubMed

Panizzon, Matthew S; Neale, Michael C; Docherty, Anna R; Franz, Carol E; Jacobson, Kristen C; Toomey, Rosemary; Xian, Hong; Vasilopoulos, Terrie; Rana, Brinda K; McKenzie, Ruth; Lyons, Michael J; Kremen, William S

2015-06-01

Episodic memory is a complex construct at both the phenotypic and genetic level. Ample evidence supports age-related cognitive stability and change being accounted for by general and domain-specific factors. We hypothesized that general and specific factors would underlie change even within this single cognitive domain. We examined 6 measures from 3 episodic memory tests in a narrow age cohort at middle and late middle age. The factor structure was invariant across occasions. At both timepoints 2 of 3 test-specific factors (story recall, design recall) had significant genetic influences independent of the general memory factor. Phenotypic stability was moderate to high, and primarily accounted for by genetic influences, except for 1 test-specific factor (list learning). Mean change over time was nonsignificant for 1 test-level factor; 1 declined; 1 improved. The results highlight the phenotypic and genetic complexity of memory and memory change, and shed light on an understudied period of life. (c) 2015 APA, all rights reserved.

Specificity of genetic and environmental risk factors for symptoms of cannabis, cocaine, alcohol, caffeine, and nicotine dependence.

PubMed

Kendler, Kenneth S; Myers, John; Prescott, Carol A

2007-11-01

Although genetic risk factors have been found to contribute to dependence on both licit and illicit psychoactive substances, we know little of how these risk factors interrelate. To clarify the structure of genetic and environmental risk factors for symptoms of dependence on cannabis, cocaine, alcohol, caffeine, and nicotine in males and females. Lifetime history by structured clinical interview. General community. Four thousand eight hundred sixty-five members of male-male and female-female pairs from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. Main Outcome Measure Lifetime symptoms of abuse of and dependence on cannabis, cocaine, alcohol, caffeine, and nicotine. Controlling for greater symptom prevalence in males, genetic and environmental parameters could be equated across sexes. Two models explained the data well. The best-fit exploratory model contained 2 genetic factors and 1 individual environmental factor contributing to all substances. The first genetic factor loaded strongly on cocaine and cannabis dependence; the second, on alcohol and nicotine dependence. Nicotine and caffeine had high substance-specific genetic effects. A confirmatory model, which also fit well, contained 1 illicit drug genetic factor--loading only on cannabis and cocaine--and 1 licit drug genetic factor loading on alcohol, caffeine, and nicotine. However, these factors were highly intercorrelated (r = + 0.82). Large substance-specific genetic effects remained for nicotine and caffeine. The pattern of genetic and environmental risk factors for psychoactive substance dependence was similar in males and females. Genetic risk factors for dependence on common psychoactive substances cannot be explained by a single factor. Rather, 2 genetic factors-one predisposing largely to illicit drug dependence, the other primarily to licit drug dependence-are needed. Furthermore, a large proportion of the genetic influences on nicotine and particularly caffeine dependence appear to be specific to those substances.

Genetic diversity revealed by single nucleotide polymorphism markers in a worldwide germplasm collection of durum wheat.

PubMed

Ren, Jing; Sun, Daokun; Chen, Liang; You, Frank M; Wang, Jirui; Peng, Yunliang; Nevo, Eviatar; Sun, Dongfa; Luo, Ming-Cheng; Peng, Junhua

2013-03-28

Evaluation of genetic diversity and genetic structure in crops has important implications for plant breeding programs and the conservation of genetic resources. Newly developed single nucleotide polymorphism (SNP) markers are effective in detecting genetic diversity. In the present study, a worldwide durum wheat collection consisting of 150 accessions was used. Genetic diversity and genetic structure were investigated using 946 polymorphic SNP markers covering the whole genome of tetraploid wheat. Genetic structure was greatly impacted by multiple factors, such as environmental conditions, breeding methods reflected by release periods of varieties, and gene flows via human activities. A loss of genetic diversity was observed from landraces and old cultivars to the modern cultivars released during periods of the Early Green Revolution, but an increase in cultivars released during the Post Green Revolution. Furthermore, a comparative analysis of genetic diversity among the 10 mega ecogeographical regions indicated that South America, North America, and Europe possessed the richest genetic variability, while the Middle East showed moderate levels of genetic diversity.

The Effect and Relative Importance of Neutral Genetic Diversity for Predicting Parasitism Varies across Parasite Taxa

PubMed Central

Ruiz-López, María José; Monello, Ryan J.; Gompper, Matthew E.; Eggert, Lori S.

2012-01-01

Understanding factors that determine heterogeneity in levels of parasitism across individuals is a major challenge in disease ecology. It is known that genetic makeup plays an important role in infection likelihood, but the mechanism remains unclear as does its relative importance when compared to other factors. We analyzed relationships between genetic diversity and macroparasites in outbred, free-ranging populations of raccoons (Procyon lotor). We measured heterozygosity at 14 microsatellite loci and modeled the effects of both multi-locus and single-locus heterozygosity on parasitism using an information theoretic approach and including non-genetic factors that are known to influence the likelihood of parasitism. The association of genetic diversity and parasitism, as well as the relative importance of genetic diversity, differed by parasitic group. Endoparasite species richness was better predicted by a model that included genetic diversity, with the more heterozygous hosts harboring fewer endoparasite species. Genetic diversity was also important in predicting abundance of replete ticks (Dermacentor variabilis). This association fit a curvilinear trend, with hosts that had either high or low levels of heterozygosity harboring fewer parasites than those with intermediate levels. In contrast, genetic diversity was not important in predicting abundance of non-replete ticks and lice (Trichodectes octomaculatus). No strong single-locus effects were observed for either endoparasites or replete ticks. Our results suggest that in outbred populations multi-locus diversity might be important for coping with parasitism. The differences in the relationships between heterozygosity and parasitism for the different parasites suggest that the role of genetic diversity varies with parasite-mediated selective pressures. PMID:23049796

Mismatch repair factor MSH2-MSH3 binds and alters the conformation of branched DNA structures predicted to form during genetic recombination.

PubMed

Surtees, Jennifer A; Alani, Eric

2006-07-14

Genetic studies in Saccharomyces cerevisiae predict that the mismatch repair (MMR) factor MSH2-MSH3 binds and stabilizes branched recombination intermediates that form during single strand annealing and gene conversion. To test this model, we constructed a series of DNA substrates that are predicted to form during these recombination events. We show in an electrophoretic mobility shift assay that S. cerevisiae MSH2-MSH3 specifically binds branched DNA substrates containing 3' single-stranded DNA and that ATP stimulates its release from these substrates. Chemical footprinting analyses indicate that MSH2-MSH3 specifically binds at the double-strand/single-strand junction of branched substrates, alters its conformation and opens up the junction. Therefore, MSH2-MSH3 binding to its substrates creates a unique nucleoprotein structure that may signal downstream steps in repair that include interactions with MMR and nucleotide excision repair factors.

Cardiovascular Disease, Psychosocial Factors, and Genetics: The Case of Depression

PubMed Central

Mulle, Jennifer Gladys; Vaccarino, Viola

2013-01-01

Psychosocial factors are associated with cardiovascular disease, but little is known about the role of genetics in this relationship. Focusing on the well-studied phenotype of depression, current data show that there are shared genetic factors that may give rise to both depression and CVD, and these genetic risks appear to be modified by gender. This pleiotropic effect suggests that a single pathway, when perturbed, gives rise to the dual phenotypes of CVD and depression. The data also suggest that women contribute disproportionately to the depression-CVD comorbidity, and this unbalanced contribution is attributable, in part, to genetic factors. While the underlying biology behind this relationship is unclear, recent data support contributions from inflammatory or serotonergic pathways toward the comorbidity between CVD and depression. Even without knowledge of a specific mechanism, epidemiological observations offer new directions to explain the relationship between depression and CVD that have both research and clinical applications. PMID:23621965

Genetic Determinants of Parkinson's Disease: Can They Help to Stratify the Patients Based on the Underlying Molecular Defect?

PubMed Central

Redenšek, Sara; Trošt, Maja; Dolžan, Vita

2017-01-01

Parkinson's disease (PD) is a sporadic progressive neurodegenerative brain disorder with a relatively strong genetic background. We have reviewed the current literature about the genetic factors that could be indicative of pathophysiological pathways of PD and their applications in everyday clinical practice. Information on novel risk genes is coming from several genome-wide association studies (GWASs) and their meta-analyses. GWASs that have been performed so far enabled the identification of 24 loci as PD risk factors. These loci take part in numerous cellular processes that may contribute to PD pathology: protein aggregation, protein, and membrane trafficking, lysosomal autophagy, immune response, synaptic function, endocytosis, inflammation, and metabolic pathways are among the most important ones. The identified single nucleotide polymorphisms are usually located in the non-coding regions and their functionality remains to be determined, although they presumably influence gene expression. It is important to be aware of a very low contribution of a single genetic risk factor to PD development; therefore, novel prognostic indices need to account for the cumulative nature of genetic risk factors. A better understanding of PD pathophysiology and its genetic background will help to elucidate the underlying pathological processes. Such knowledge may help physicians to recognize subjects with the highest risk for the development of PD, and provide an opportunity for the identification of novel potential targets for neuroprotective treatment. Moreover, it may enable stratification of the PD patients according to their genetic fingerprint to properly personalize their treatment as well as supportive measures. PMID:28239348

[Genetic testing in polygenic diseases : Atrial fibrillation, arterial hypertension and coronary artery disease].

PubMed

Trenkwalder, T; Kessler, T; Schunkert, H

2017-08-01

Genetic testing plays an increasing role in cardiovascular medicine. Advances in technology and the development of novel and more affordable (high throughput) methods have led to the identification of genetic risk factors in research and clinical practice. Also, this progress has simplified the screening of patients and individuals at risk. In case of rare monogenic diseases, diagnostics, risk stratification, and, in some cases, treatment decisions have become easier. For common, polygenic cardiovascular diseases, the situation is more complex due to interaction of modifiable external risk factors and nonmodifiable factors like genetic predisposition. Over the last few years, it has been shown that multiple genes are involved in the pathophysiology of these cardiovascular diseases rather than one single gene. In the following article, we give an overview of the genetic risk factors in polygenic cardiovascular diseases as atrial fibrillation, arterial hypertension and coronary artery disease. Furthermore, we aim to illustrate in which cases genetic testing is recommended in these diseases.

A Multivariate Twin Study of the DSM-IV Criteria for Antisocial Personality Disorder

PubMed Central

Kendler, Kenneth S.; Aggen, Steven H.; Patrick, Christopher J.

2012-01-01

BACKGROUND Many assessment instruments for psychopathy are multidimensional, suggesting that distinguishable factors are needed to effectively capture variation in this personality domain. However, no prior study has examined the factor structure of the DSM-IV criteria for antisocial personality disorder (ASPD). METHODS Self-report questionnaire items reflecting all A criteria for DSM-IV ASPD were available from 4,291 twins (including both members of 1,647 pairs) from the Virginia Adult Study of Psychiatric and Substance Use Disorders. Exploratory factor analysis and twin model fitting were performed using, respectively, Mplus and Mx. RESULTS Phenotypic factor analysis produced evidence for 2 correlated factors: aggressive-disregard and disinhibition. The best-fitting multivariate twin model included two genetic and one unique environmental common factor, along with criteria-specific genetic and environmental effects. The two genetic factors closely resembled the phenotypic factors and varied in their prediction of a range of relevant criterion variables. Scores on the genetic aggressive-disregard factor score were more strongly associated with risk for conduct disorder, early and heavy alcohol use, and low educational status, whereas scores on the genetic disinhibition factor score were more strongly associated with younger age, novelty seeking, and major depression. CONCLUSION From a genetic perspective, the DSM-IV criteria for ASPD do not reflect a single dimension of liability but rather are influenced by two dimensions of genetic risk reflecting aggressive-disregard and disinhibition. The phenotypic structure of the ASPD criteria results largely from genetic and not from environmental influences. PMID:21762879

Genetics of schizophrenia in the context of integrative psychiatry.

PubMed

Sagud, Marina; Mihaljević-Peles, Alma; Pivac, Nela; Muck-Seler, Dorotea; Simunović, Ivona; Jakovljević, Miro

2008-09-01

Epidemiological studies suggest a strong heritability in schizophrenia. Positive family history is the greatest risk factor for developing schizophrenia. However, regarding the genetic factors in schizophrenia, there is a lot of the inconsistency (i.e. non-replication) in the literature of the associations of different genes with schizophrenia. The presence of a single gene is neither sufficient, nor necessary to cause schizophrenia. The understanding of the genetic basis of schizophrenia is complex. Besides different gene polymorphisms, numerous environmental factors, interacting with genes, contribute to susceptibility to schizophrenia. Such factors include the use of street drugs, childhood head injury, maternal infection during pregnancy, paternal age at conception, stressful life events and urban upbringing. While knowing genetic risks, integrative psychiatry may have a role in reducing other modifiable risk factors, including reduction of stress level, stress management strategies, family consultation/education, education against street drugs use, treatment of prodromal symptoms and development of social skills.

Can data science inform environmental justice and community risk screening for type 2 diabetes?

PubMed

Davis, J Allen; Burgoon, Lyle D

2015-01-01

Having the ability to scan the entire country for potential "hotspots" with increased risk of developing chronic diseases due to various environmental, demographic, and genetic susceptibility factors may inform risk management decisions and enable better environmental public health policies. Develop an approach for community-level risk screening focused on identifying potential genetic susceptibility hotpots. Our approach combines analyses of phenotype-genotype data, genetic prevalence of single nucleotide polymorphisms, and census/geographic information to estimate census tract-level population attributable risks among various ethnicities and total population for the state of California. We estimate that the rs13266634 single nucleotide polymorphism, a type 2 diabetes susceptibility genotype, has a genetic prevalence of 56.3%, 47.4% and 37.0% in Mexican Mestizo, Caucasian, and Asian populations. Looking at the top quintile for total population attributable risk, 16 California counties have greater than 25% of their population living in hotspots of genetic susceptibility for developing type 2 diabetes due to this single genotypic susceptibility factor. This study identified counties in California where large portions of the population may bear additional type 2 diabetes risk due to increased genetic prevalence of a susceptibility genotype. This type of screening can easily be extended to include information on environmental contaminants of interest and other related diseases, and potentially enables the rapid identification of potential environmental justice communities. Other potential uses of this approach include problem formulation in support of risk assessments, land use planning, and prioritization of site cleanup and remediation actions.

Gambling, disordered gambling and their association with major depression and substance use: a web-based cohort and twin-sibling study.

PubMed

Blanco, C; Myers, J; Kendler, K S

2012-03-01

Relatively little is known about the environmental and genetic contributions to gambling frequency and disordered gambling (DG), the full continuum of gambling-related problems that includes pathological gambling (PG). A web-based sample (n=43,799 including both members of 609 twin and 303 sibling pairs) completed assessments of number of lifetime gambling episodes, DSM-IV criteria for PG, alcohol, nicotine and caffeine intake, and nicotine dependence (ND) and DSM-III-R criteria for lifetime major depression (MD). Twin modeling was performed using Mx. In the entire cohort, symptoms of DG indexed a single dimension of liability. Symptoms of DG were weakly related to caffeine intake and moderately related to MD, consumption of cigarettes and alcohol, and ND. In twin and sibling pairs, familial resemblance for number of times gambled resulted from both familial-environmental (c²=42%) and genetic factors (a²=32%). For symptoms of DG, resemblance resulted solely from genetic factors (a²=83%). Bivariate analyses indicated a low genetic correlation between symptoms of DG and MD (r(a)=+0.14) whereas genetic correlations with DG symptoms were substantially higher with use of alcohol, caffeine and nicotine, and ND (ranging from +0.29 to +0.80). The results were invariant across genders. Whereas gambling participation is determined by shared environmental and genetic factors, DG constitutes a single latent dimension that is largely genetically determined and more closely related to externalizing than internalizing behaviors. Because these findings are invariant across genders, they suggest that the etiological factors of DG are likely to be similar in men and women.

Genetic Testing for Autism Spectrum Disorders

ERIC Educational Resources Information Center

Bauer, Sarah C.; Msall, Michael E.

2011-01-01

Children with autism spectrum disorders (ASD) have unique developmental and behavioral phenotypes, and they have specific challenges with communication, social skills, and repetitive behaviors. At this time, no single etiology for ASD has been identified. However, evidence from family studies and linkage analyses suggests that genetic factors play…

Genetic and environmental influences on female sexual orientation, childhood gender typicality and adult gender identity.

PubMed

Burri, Andrea; Cherkas, Lynn; Spector, Timothy; Rahman, Qazi

2011-01-01

Human sexual orientation is influenced by genetic and non-shared environmental factors as are two important psychological correlates--childhood gender typicality (CGT) and adult gender identity (AGI). However, researchers have been unable to resolve the genetic and non-genetic components that contribute to the covariation between these traits, particularly in women. Here we performed a multivariate genetic analysis in a large sample of British female twins (N = 4,426) who completed a questionnaire assessing sexual attraction, CGT and AGI. Univariate genetic models indicated modest genetic influences on sexual attraction (25%), AGI (11%) and CGT (31%). For the multivariate analyses, a common pathway model best fitted the data. This indicated that a single latent variable influenced by a genetic component and common non-shared environmental component explained the association between the three traits but there was substantial measurement error. These findings highlight common developmental factors affecting differences in sexual orientation.

A multivariate twin study of the DSM-IV criteria for antisocial personality disorder.

PubMed

Kendler, Kenneth S; Aggen, Steven H; Patrick, Christopher J

2012-02-01

Many assessment instruments for psychopathy are multidimensional, suggesting that distinguishable factors are needed to effectively capture variation in this personality domain. However, no prior study has examined the factor structure of the DSM-IV criteria for antisocial personality disorder (ASPD). Self-report questionnaire items reflecting all A criteria for DSM-IV ASPD were available from 4291 twins (including both members of 1647 pairs) from the Virginia Adult Study of Psychiatric and Substance Use Disorders. Exploratory factor analysis and twin model fitting were performed using, respectively, Mplus and Mx. Phenotypic factor analysis produced evidence for two correlated factors: aggressive-disregard and disinhibition. The best-fitting multivariate twin model included two genetic and one unique environmental common factor, along with criteria-specific genetic and environmental effects. The two genetic factors closely resembled the phenotypic factors and varied in their prediction of a range of relevant criterion variables. Scores on the genetic aggressive-disregard factor score were more strongly associated with risk for conduct disorder, early and heavy alcohol use, and low educational status, whereas scores on the genetic disinhibition factor score were more strongly associated with younger age, novelty seeking, and major depression. From a genetic perspective, the DSM-IV criteria for ASPD do not reflect a single dimension of liability but rather are influenced by two dimensions of genetic risk reflecting aggressive-disregard and disinhibition. The phenotypic structure of the ASPD criteria results largely from genetic and not from environmental influences. Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Prediction of Adult Dyslipidemia Using Genetic and Childhood Clinical Risk Factors: The Cardiovascular Risk in Young Finns Study.

PubMed

Nuotio, Joel; Pitkänen, Niina; Magnussen, Costan G; Buscot, Marie-Jeanne; Venäläinen, Mikko S; Elo, Laura L; Jokinen, Eero; Laitinen, Tomi; Taittonen, Leena; Hutri-Kähönen, Nina; Lyytikäinen, Leo-Pekka; Lehtimäki, Terho; Viikari, Jorma S; Juonala, Markus; Raitakari, Olli T

2017-06-01

Dyslipidemia is a major modifiable risk factor for cardiovascular disease. We examined whether the addition of novel single-nucleotide polymorphisms for blood lipid levels enhances the prediction of adult dyslipidemia in comparison to childhood lipid measures. Two thousand four hundred and twenty-two participants of the Cardiovascular Risk in Young Finns Study who had participated in 2 surveys held during childhood (in 1980 when aged 3-18 years and in 1986) and at least once in a follow-up study in adulthood (2001, 2007, and 2011) were included. We examined whether inclusion of a lipid-specific weighted genetic risk score based on 58 single-nucleotide polymorphisms for low-density lipoprotein cholesterol, 71 single-nucleotide polymorphisms for high-density lipoprotein cholesterol, and 40 single-nucleotide polymorphisms for triglycerides improved the prediction of adult dyslipidemia compared with clinical childhood risk factors. Adjusting for age, sex, body mass index, physical activity, and smoking in childhood, childhood lipid levels, and weighted genetic risk scores were associated with an increased risk of adult dyslipidemia for all lipids. Risk assessment based on 2 childhood lipid measures and the lipid-specific weighted genetic risk scores improved the accuracy of predicting adult dyslipidemia compared with the approach using only childhood lipid measures for low-density lipoprotein cholesterol (area under the receiver-operating characteristic curve 0.806 versus 0.811; P =0.01) and triglycerides (area under the receiver-operating characteristic curve 0.740 versus area under the receiver-operating characteristic curve 0.758; P <0.01). The overall net reclassification improvement and integrated discrimination improvement were significant for all outcomes. The inclusion of weighted genetic risk scores to lipid-screening programs in childhood could modestly improve the identification of those at highest risk of dyslipidemia in adulthood. © 2017 American Heart Association, Inc.

The clinical content of preconception care: genetics and genomics.

PubMed

Solomon, Benjamin D; Jack, Brian W; Feero, W Gregory

2008-12-01

The prevalence of paternal and maternal genetic conditions that affect pregnancy varies according to many factors that include parental age, medical history, and family history. Although some genetic conditions that affect pregnancy are identified easily early in life, other conditions are not and may require additional diagnostic testing. A complete 3-generation family medical history that includes ethnicity information about both sides of the family is arguably the single best genetic "test" that is applicable to preconception care. Assessment of genetic risk by an experienced professional has been shown to improve the detection rate of identifiable risk factors. Learning about possible genetic issues in the preconception period is ideal, because knowledge permits patients to make informed reproductive decisions. Options that are available to couples before conception include adoption, surrogacy, use of donor sperm, in vitro fertilization after preimplantation genetic diagnosis, and avoidance of pregnancy. Future technologic advances will increase the choices that are available to couples.

The Clinical Content of Preconception Care: Genetics and Genomics

PubMed Central

SOLOMON, Benjamin D.; JACK, Brian; FEERO, W. Gregory

2008-01-01

The prevalence of paternal and maternal genetic conditions that affect pregnancy varies according to many factors, including parental age, medical history, and family history. While some genetic conditions that affect pregnancy are easily identified early in life, others are not and may require additional diagnostic testing. A complete three-generation family medical history that includes ethnicity information about both sides of the family is arguably the single best genetic “test” applicable to preconception care. Assessment of genetic risk by an experienced professional has been shown to improve the detection rate of identifiable risk factors. Learning about possible genetic issues in the pre-conception period is ideal, as knowledge permits patients to make informed reproductive decisions. Options available to couples before conception include adoption, surrogacy, use of donor sperm, in vitro fertilization after pre-implantation genetic diagnosis, and avoidance of pregnancy. Future technological advances will increase the choices available to couples. PMID:19081428

Recent genetic discoveries in osteoporosis, sarcopenia and obesity.

PubMed

Urano, Tomohiko; Inoue, Satoshi

2015-01-01

Osteoporosis is a skeletal disorder characterized by low bone mineral density (BMD) and an increased susceptibility to fractures. Evidence from genetic studies indicates that BMD, a complex quantitative trait with a normal distribution, is genetically controlled. Genome-wide association studies (GWAS) as well as studies using candidate gene approaches have identified single-nucleotide polymorphisms (SNPs) that are associated with BMD, osteoporosis and osteoporotic fractures. These SNPs have been mapped close to or within genes including those encoding WNT/β-catenin signaling proteins. Understanding the genetics of osteoporosis will help to identify novel candidates for diagnostic and therapeutic targets. Genetic factors are also important for the development of sarcopenia, which is characterized by a loss of lean body mass, and obesity, which is characterized by high fat mass. Hence, in this review, we discuss the genetic factors, identified by genetic studies, which regulate the body components related to osteoporosis, sarcopenia, and obesity.

Prediction of Adulthood Obesity Using Genetic and Childhood Clinical Risk Factors in the Cardiovascular Risk in Young Finns Study.

PubMed

Seyednasrollah, Fatemeh; Mäkelä, Johanna; Pitkänen, Niina; Juonala, Markus; Hutri-Kähönen, Nina; Lehtimäki, Terho; Viikari, Jorma; Kelly, Tanika; Li, Changwei; Bazzano, Lydia; Elo, Laura L; Raitakari, Olli T

2017-06-01

Obesity is a known risk factor for cardiovascular disease. Early prediction of obesity is essential for prevention. The aim of this study is to assess the use of childhood clinical factors and the genetic risk factors in predicting adulthood obesity using machine learning methods. A total of 2262 participants from the Cardiovascular Risk in YFS (Young Finns Study) were followed up from childhood (age 3-18 years) to adulthood for 31 years. The data were divided into training (n=1625) and validation (n=637) set. The effect of known genetic risk factors (97 single-nucleotide polymorphisms) was investigated as a weighted genetic risk score of all 97 single-nucleotide polymorphisms (WGRS97) or a subset of 19 most significant single-nucleotide polymorphisms (WGRS19) using boosting machine learning technique. WGRS97 and WGRS19 were validated using external data (n=369) from BHS (Bogalusa Heart Study). WGRS19 improved the accuracy of predicting adulthood obesity in training (area under the curve [AUC=0.787 versus AUC=0.744, P <0.0001) and validation data (AUC=0.769 versus AUC=0.747, P =0.026). WGRS97 improved the accuracy in training (AUC=0.782 versus AUC=0.744, P <0.0001) but not in validation data (AUC=0.749 versus AUC=0.747, P =0.785). Higher WGRS19 associated with higher body mass index at 9 years and WGRS97 at 6 years. Replication in BHS confirmed our findings that WGRS19 and WGRS97 are associated with body mass index. WGRS19 improves prediction of adulthood obesity. Predictive accuracy is highest among young children (3-6 years), whereas among older children (9-18 years) the risk can be identified using childhood clinical factors. The model is helpful in screening children with high risk of developing obesity. © 2017 American Heart Association, Inc.

Single cells from human primary colorectal tumors exhibit polyfunctional heterogeneity in secretions of ELR+ CXC chemokines.

PubMed

Adalsteinsson, Viktor A; Tahirova, Narmin; Tallapragada, Naren; Yao, Xiaosai; Campion, Liam; Angelini, Alessandro; Douce, Thomas B; Huang, Cindy; Bowman, Brittany; Williamson, Christina A; Kwon, Douglas S; Wittrup, K Dane; Love, J Christopher

2013-10-01

Cancer is an inflammatory disease of tissue that is largely influenced by the interactions between multiple cell types, secreted factors, and signal transduction pathways. While single-cell sequencing continues to refine our understanding of the clonotypic heterogeneity within tumors, the complex interplay between genetic variations and non-genetic factors ultimately affects therapeutic outcome. Much has been learned through bulk studies of secreted factors in the tumor microenvironment, but the secretory behavior of single cells has been largely uncharacterized. Here we directly profiled the secretions of ELR+ CXC chemokines from thousands of single colorectal tumor and stromal cells, using an array of subnanoliter wells and a technique called microengraving to characterize both the rates of secretion of several factors at once and the numbers of cells secreting each chemokine. The ELR+ CXC chemokines are highly redundant, pro-angiogenic cytokines that signal via the CXCR1 and CXCR2 receptors, influencing tumor growth and progression. We find that human primary colorectal tumor and stromal cells exhibit polyfunctional heterogeneity in the combinations and magnitudes of secretions for these chemokines. In cell lines, we observe similar variance: phenotypes observed in bulk can be largely absent among the majority of single cells, and discordances exist between secretory states measured and gene expression for these chemokines among single cells. Together, these measures suggest secretory states among tumor cells are complex and can evolve dynamically. Most importantly, this study reveals new insight into the intratumoral phenotypic heterogeneity of human primary tumors.

Different neurodevelopmental symptoms have a common genetic etiology.

PubMed

Pettersson, Erik; Anckarsäter, Henrik; Gillberg, Christopher; Lichtenstein, Paul

2013-12-01

Although neurodevelopmental disorders are demarcated as discrete entities in the Diagnostic Statistical Manual of mental disorders, empirical evidence indicates that there is a high degree of overlap among them. The first aim of this investigation was to explore if a single general factor could account for the large degree of observed overlap among neurodevelopmental problems, and explore whether this potential factor was primarily genetic or environmental in origin. The second aim was to explore whether there was systematic covariation, either genetic or environmental, over and above that contributed by the potential general factor, unique to each syndrome. Parents of all Swedish 9- and 12-year-old twin pairs born between 1992 and 2002 were targeted for interview regarding problems typical of autism spectrum disorders, ADHD and other neurodevelopmental conditions (response rate: 80 percent). Structural equation modeling was conducted on 6,595 pairs to examine the genetic and environmental structure of 53 neurodevelopmental problems. One general genetic factor accounted for a large proportion of the phenotypic covariation among the 53 symptoms. Three specific genetic subfactors identified 'impulsivity,' 'learning problems,' and 'tics and autism,' respectively. Three unique environment factors identified 'autism,' 'hyperactivity and impulsivity,' and 'inattention and learning problems,' respectively. One general genetic factor was responsible for the wide-spread phenotypic overlap among all neurodevelopmental symptoms, highlighting the importance of addressing broad patient needs rather than specific diagnoses. The unique genetic factors may help guide diagnostic nomenclature, whereas the unique environmental factors may highlight that neurodevelopmental symptoms are responsive to change at the individual level and may provide clues into different mechanisms and treatments. Future research would benefit from assessing the general factor separately from specific factors to better understand observed overlap among neurodevelopmental problems. © 2013 The Authors. Journal of Child Psychology and Psychiatry © 2013 Association for Child and Adolescent Mental Health.

Nutrigenomics in cardiovascular disease: implications for the future.

PubMed

Engler, Mary B

2009-12-01

Cardiovascular disease (CVD), the leading cause of morbidity and mortality worldwide, is a complex multifactorial disease which is influenced by environmental and genetic factors. There is substantial evidence on the relationship between diet and CVD risk. An understanding of how genetic variation interacts with the diet to influence CVD risk is a rapidly evolving area of research. Since diet is the mainstay of risk factor modification, it is important to consider potential genetic influences on CVD risk. Nutrigenomics is the study of the interaction between diet and an individual's genetic makeup. Single nucleotide polymorphisms are the key factors in human genetic variation and provide a molecular basis for phenotypic differences between individuals. Whole genome and candidate gene association studies are two main approaches used in cardiovascular genetics to identify disease-causing genes. Recent nutrigenomics studies show the influence of genotype on the responsiveness to dietary factors or nutrients that may reduce CVD risk. Nutrigenomics research is expected to provide the scientific evidence for genotype-based personalized nutrition to promote health and prevent chronic disease, including CVD. It is imperative that healthcare providers, including cardiovascular nurses, are trained in genetics to foster delivery of competent genetic- and genomic-focused care and to facilitate incorporation of this new knowledge into current clinical practice, education, and research.

Innovative Tools and Technology for Analysis of Single Cells and Cell-Cell Interaction.

PubMed

Konry, Tania; Sarkar, Saheli; Sabhachandani, Pooja; Cohen, Noa

2016-07-11

Heterogeneity in single-cell responses and intercellular interactions results from complex regulation of cell-intrinsic and environmental factors. Single-cell analysis allows not only detection of individual cellular characteristics but also correlation of genetic content with phenotypic traits in the same cell. Technological advances in micro- and nanofabrication have benefited single-cell analysis by allowing precise control of the localized microenvironment, cell manipulation, and sensitive detection capabilities. Additionally, microscale techniques permit rapid, high-throughput, multiparametric screening that has become essential for -omics research. This review highlights innovative applications of microscale platforms in genetic, proteomic, and metabolic detection in single cells; cell sorting strategies; and heterotypic cell-cell interaction. We discuss key design aspects of single-cell localization and isolation in microfluidic systems, dynamic and endpoint analyses, and approaches that integrate highly multiplexed detection of various intracellular species.

Linking genetic and environmental factors in amphibian disease risk

PubMed Central

Savage, Anna E; Becker, Carlos G; Zamudio, Kelly R

2015-01-01

A central question in evolutionary biology is how interactions between organisms and the environment shape genetic differentiation. The pathogen Batrachochytrium dendrobatidis (Bd) has caused variable population declines in the lowland leopard frog (Lithobates yavapaiensis); thus, disease has potentially shaped, or been shaped by, host genetic diversity. Environmental factors can also influence both amphibian immunity and Bd virulence, confounding our ability to assess the genetic effects on disease dynamics. Here, we used genetics, pathogen dynamics, and environmental data to characterize L. yavapaiensis populations, estimate migration, and determine relative contributions of genetic and environmental factors in predicting Bd dynamics. We found that the two uninfected populations belonged to a single genetic deme, whereas each infected population was genetically unique. We detected an outlier locus that deviated from neutral expectations and was significantly correlated with mortality within populations. Across populations, only environmental variables predicted infection intensity, whereas environment and genetics predicted infection prevalence, and genetic diversity alone predicted mortality. At one locality with geothermally elevated water temperatures, migration estimates revealed source–sink dynamics that have likely prevented local adaptation. We conclude that integrating genetic and environmental variation among populations provides a better understanding of Bd spatial epidemiology, generating more effective conservation management strategies for mitigating amphibian declines. PMID:26136822

Trans-Ethnic Meta-Analysis Identifies Common and Rare Variants Associated with Hepatocyte Growth Factor Levels in the Multi-Ethnic Study of Atherosclerosis (MESA)

PubMed Central

Larson, Nicholas B.; Berardi, Cecilia; Decker, Paul A.; Wassel, Christina L.; Kirsch, Phillip S.; Pankow, James S.; Sale, Michele M.; de Andrade, Mariza; Sicotte, Hugues; Tang, Weihong; Hanson, Naomi Q.; Tsai, Michael Y.; Taylor, Kent D.; Bielinski, Suzette J.

2015-01-01

Summary Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic factor that regulates cell growth, motility, mitogenesis, and morphogenesis in a variety of cells, and increased serum levels of HGF have been linked to a number of clinical and subclinical cardiovascular disease phenotypes. However, little is currently known regarding what genetic factors influence HGF levels, despite evidence of substantial genetic contributions to HGF variation. Based upon ethnicity-stratified single-variant association analysis and trans-ethnic meta-analysis of 6201 participants of the Multi-Ethnic Study of Atherosclerosis (MESA), we discovered five statistically significant common and low-frequency variants: HGF missense polymorphism rs5745687 (p.E299K) as well as four variants (rs16844364, rs4690098, rs114303452, rs3748034) within or in proximity to HGFAC. We also identified two significant ethnicity-specific gene-level associations (A1BG in African Americans; FASN in Chinese Americans) based upon low-frequency/rare variants, while meta-analysis of gene-level results identified a significant association for HGFAC. However, identified single-variant associations explained modest proportions of the total trait variation and were not significantly associated with coronary artery calcium or coronary heart disease. Our findings indicate genetic factors influencing circulating HGF levels may be complex and ethnically diverse. PMID:25998175

Single nucleotide polymorphisms in multiple sclerosis: disease susceptibility and treatment response biomarkers.

PubMed

Pravica, Vera; Popadic, Dusan; Savic, Emina; Markovic, Milos; Drulovic, Jelena; Mostarica-Stojkovic, Marija

2012-04-01

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system characterized by unpredictable and variable clinical course. Etiology of MS involves both genetic and environmental factors. New technologies identified genetic polymorphisms associated with MS susceptibility among which immunologically relevant genes are significantly overrepresented. Although individual genes contribute only a small part to MS susceptibility, they might be used as biomarkers, thus helping to identify accurate diagnosis, predict clinical disease course and response to therapy. This review focuses on recent progress in research on MS genetics with special emphasis on the possibility to use single nucleotide polymorphism of candidate genes as biomarkers of susceptibility to disease and response to therapy.

Genetic and Environmental Influences on Female Sexual Orientation, Childhood Gender Typicality and Adult Gender Identity

PubMed Central

Burri, Andrea; Cherkas, Lynn; Spector, Timothy; Rahman, Qazi

2011-01-01

Background Human sexual orientation is influenced by genetic and non-shared environmental factors as are two important psychological correlates – childhood gender typicality (CGT) and adult gender identity (AGI). However, researchers have been unable to resolve the genetic and non-genetic components that contribute to the covariation between these traits, particularly in women. Methodology/Principal Findings Here we performed a multivariate genetic analysis in a large sample of British female twins (N = 4,426) who completed a questionnaire assessing sexual attraction, CGT and AGI. Univariate genetic models indicated modest genetic influences on sexual attraction (25%), AGI (11%) and CGT (31%). For the multivariate analyses, a common pathway model best fitted the data. Conclusions/Significance This indicated that a single latent variable influenced by a genetic component and common non-shared environmental component explained the association between the three traits but there was substantial measurement error. These findings highlight common developmental factors affecting differences in sexual orientation. PMID:21760939

The Genetic Basis of Peyronie Disease: A Review.

PubMed

Herati, Amin S; Pastuszak, Alexander W

2016-01-01

Peyronie disease (PD) is a progressive fibrotic disorder of the penile tunica albuginea that results in fibrotic penile plaques and can lead to penile deformity. Characterized by aberrant fibrosis resulting in part from the persistence of myofibroblasts and altered gene expression, the molecular factors underpinning PD and other related fibrotic diatheses are just being elucidated. A genetic link to PD was first identified three decades ago using pedigree analyses. However, the specific genetic factors that predispose patients to aberrant fibrosis remain unknown, and the relations between these fibrotic conditions and other heritable diseases, including malignancy, are uncharacterized. To review the current landscape linking molecular and genetic factors to aberrant fibrosis in PD and related fibrotic diatheses, including Dupuytren disease. Review and evaluation of the literature from 1970 to the present for genetic factors associated with PD were performed. Data describing the genetic factors associated with PD were obtained. We describe the known structural chromosomal abnormalities and single-nucleotide polymorphisms associated with fibrotic diatheses and discuss the spectrum of differential gene expression data comparing normal tissues with those derived from men with PD or Dupuytren disease. We discuss epigenetic mechanisms that might regulate gene expression and alter predisposition to fibrosis. Although the current understanding of the genetic factors associated with PD is limited, significant advances have been made during the past three decades. Further research is necessary to provide a more comprehensive understanding of the landscape of genetic factors responsible for the development of PD. Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Organizational Benchmarks for Test Utilization Performance: An Example Based on Positivity Rates for Genetic Tests.

PubMed

Rudolf, Joseph; Jackson, Brian R; Wilson, Andrew R; Smock, Kristi J; Schmidt, Robert L

2017-04-01

Health care organizations are under increasing pressure to deliver value by improving test utilization management. Many factors, including organizational factors, could affect utilization performance. Past research has focused on the impact of specific interventions in single organizations. The impact of organizational factors is unknown. The objective of this study is to determine whether testing patterns are subject to organizational effects, ie, are utilization patterns for individual tests correlated within organizations. Comparative analysis of ordering patterns (positivity rates for three genetic tests) across 659 organizations. Hierarchical regression was used to assess the impact of organizational factors after controlling for test-level factors (mutation prevalence) and hospital bed size. Test positivity rates were correlated within organizations. Organizations have a statistically significant impact on the positivity rate of three genetic tests. © American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Single nucleotide polymorphisms associated with coronary heart disease predict incident ischemic stroke in the atherosclerosis risk in communities study.

PubMed

Morrison, Alanna C; Bare, Lance A; Luke, May M; Pankow, James S; Mosley, Thomas H; Devlin, James J; Willerson, James T; Boerwinkle, Eric

2008-01-01

Ischemic stroke and coronary heart disease (CHD) may share genetic factors contributing to a common etiology. This study investigates whether 51 single nucleotide polymorphisms (SNPs) associated with CHD in multiple antecedent studies are associated with incident ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study. From the multiethnic ARIC cohort of 14,215 individuals, 495 validated ischemic strokes were identified. Cox proportional hazards models, adjusted for age and gender, identified three SNPs in Whites and two SNPs in Blacks associated with incident stroke (p

Women-specific risk factors for heart failure: A genetic approach.

PubMed

van der Kemp, Jet; van der Schouw, Yvonne T; Asselbergs, Folkert W; Onland-Moret, N Charlotte

2018-03-01

Heart failure is a complex disease, which is presented differently by men and women. Several studies have shown that reproductive factors, such as age at natural menopause, parity and polycystic ovarian syndrome (PCOS), may play a role in the development of heart failure. Shared genetics may provide clues to underlying mechanisms; however, this has never been examined. Therefore, the aim of the current study was to explore whether any reproductive factor is potentially related to heart failure in women, based on genetic similarities. Conducting a systematic literature review, single nucleotide polymorphisms (SNPs) associated with reproductive factors, heart failure and its risk factors were extracted from recent genome-wide association studies. We tested whether there was any overlap between the SNPs and their proxies of reproductive risk factors with those known for heart failure or its risk factors. In total, 520 genetic variants were found that are associated with reproductive factors, namely age at menarche, age at natural menopause, menstrual cycle length, PCOS, preeclampsia, preterm delivery and spontaneous dizygotic twinning. For heart failure and associated phenotypes, 25 variants were found. Genetic variants for reproductive factors did not overlap with those for heart failure. However, age at menarche, gestational diabetes and PCOS were found to be genetically linked to risk factors for heart failure, such as atrial fibrillation, diabetes and smoking. Corresponding implicated genes, such as TNNI3K, ErbB3, MKL2, MTNR1B and PRKD1, may explain the associations between reproductive factors and heart failure. Exact effector mechanisms of these genes remain to be investigated further. Copyright © 2017. Published by Elsevier B.V.

Genetic diversity promotes homeostasis in insect colonies.

PubMed

Oldroyd, Benjamin P; Fewell, Jennifer H

2007-08-01

Although most insect colonies are headed by a singly mated queen, some ant, wasp and bee taxa have evolved high levels of multiple mating or 'polyandry'. We argue here that a contributing factor towards the evolution of polyandry is that the resulting genetic diversity within colonies provides them with a system of genetically based task specialization, enabling them to respond resiliently to environmental perturbation. An alternate view is that genetic contributions to task specialization are a side effect of multiple mating, which evolved through other causes, and that genetically based task specialization now makes little or no contribution to colony fitness.

Dynamics of Biomarkers in Relation to Aging and Mortality

PubMed Central

Arbeev, Konstantin G.; Ukraintseva, Svetlana V.; Yashin, Anatoliy I.

2016-01-01

Contemporary longitudinal studies collect repeated measurements of biomarkers allowing one to analyze their dynamics in relation to mortality, morbidity, or other health-related outcomes. Rich and diverse data collected in such studies provide opportunities to investigate how various socioeconomic, demographic, behavioral and other variables can interact with biological and genetic factors to produce differential rates of aging in individuals. In this paper, we review some recent publications investigating dynamics of biomarkers in relation to mortality, which use single biomarkers as well as cumulative measures combining information from multiple biomarkers. We also discuss the analytical approach, the stochastic process models, which conceptualizes several aging-related mechanisms in the structure of the model and allows evaluating “hidden” characteristics of aging-related changes indirectly from available longitudinal data on biomarkers and follow-up on mortality or onset of diseases taking into account other relevant factors (both genetic and non-genetic). We also discuss an extension of the approach, which considers ranges of “optimal values” of biomarkers rather than a single optimal value as in the original model. We discuss practical applications of the approach to single biomarkers and cumulative measures highlighting that the potential of applications to cumulative measures is still largely underused. PMID:27138087

Association of genetic variations in the serotonin and dopamine systems with aggressive behavior in the Chinese adolescent population: Single- and multiple-risk genetic variants.

PubMed

Chang, Hongjuan; Yan, Qiuge; Tang, Lina; Huang, Juan; Ma, Yuqiao; Ye, Xiaozhou; Wu, Chunxia; Wu, Linguo; Yu, Yizhen

2018-01-01

Genetic predisposition is an important factor leading to aggressive behavior. However, the relationship between genetic polymorphisms and aggressive behavior has not been elucidated. We identified candidate genes located in the dopaminergic and serotonin system (DRD3, DRD4, and FEV) that had been previously reported to be associated with aggressive behavior. We investigated 14 tag single-nucleotide polymorphisms (SNPs) using a multi-analytic strategy combining logistic regression (LR) and classification and regression tree (CART) to explore higher-order interactions between these SNPs and aggressive behavior in 318 patients and 558 controls. Both LR and CART analyses suggested that the rs16859448 polymorphism is the strongest individual factor associated with aggressive behavior risk. In CART analysis, individuals carrying the combined genotypes of rs16859448TT/GT-rs11246228CT/TT-rs3773679TT had the highest risk, while rs16859448GG-rs2134655CT had the lowest risk (OR = 5.25, 95% CI: 2.53-10.86). This study adds to the growing evidence on the association of single- and multiple-risk variants in DRD3, DRD4, and FEV with aggressive behavior in Chinese adolescents. However, the aggressive behavior scale used to diagnose aggression in this study did not account for comorbid conditions; therefore, further studies are needed to confirm our observations. Copyright © 2017 Elsevier B.V. All rights reserved.

A Single IGF1 Allele Is a Major Determinant of Small Size in Dogs

PubMed Central

Sutter, Nathan B.; Bustamante, Carlos D.; Chase, Kevin; Gray, Melissa M.; Zhao, Keyan; Zhu, Lan; Padhukasahasram, Badri; Karlins, Eric; Davis, Sean; Jones, Paul G.; Quignon, Pascale; Johnson, Gary S.; Parker, Heidi G.; Fretwell, Neale; Mosher, Dana S.; Lawler, Dennis F.; Satyaraj, Ebenezer; Nordborg, Magnus; Lark, K. Gordon; Wayne, Robert K.; Ostrander, Elaine A.

2009-01-01

The domestic dog exhibits greater diversity in body size than any other terrestrial vertebrate. We used a strategy that exploits the breed structure of dogs to investigate the genetic basis of size. First, through a genome-wide scan, we identified a major quantitative trait locus (QTL) on chromosome 15 influencing size variation within a single breed. Second, we examined genetic variation in the 15-megabase interval surrounding the QTL in small and giant breeds and found marked evidence for a selective sweep spanning a single gene (IGF1), encoding insulin-like growth factor 1. A single IGF1 single-nucleotide polymorphism haplotype is common to all small breeds and nearly absent from giant breeds, suggesting that the same causal sequence variant is a major contributor to body size in all small dogs. PMID:17412960

A single IGF1 allele is a major determinant of small size in dogs.

PubMed

Sutter, Nathan B; Bustamante, Carlos D; Chase, Kevin; Gray, Melissa M; Zhao, Keyan; Zhu, Lan; Padhukasahasram, Badri; Karlins, Eric; Davis, Sean; Jones, Paul G; Quignon, Pascale; Johnson, Gary S; Parker, Heidi G; Fretwell, Neale; Mosher, Dana S; Lawler, Dennis F; Satyaraj, Ebenezer; Nordborg, Magnus; Lark, K Gordon; Wayne, Robert K; Ostrander, Elaine A

2007-04-06

The domestic dog exhibits greater diversity in body size than any other terrestrial vertebrate. We used a strategy that exploits the breed structure of dogs to investigate the genetic basis of size. First, through a genome-wide scan, we identified a major quantitative trait locus (QTL) on chromosome 15 influencing size variation within a single breed. Second, we examined genetic variation in the 15-megabase interval surrounding the QTL in small and giant breeds and found marked evidence for a selective sweep spanning a single gene (IGF1), encoding insulin-like growth factor 1. A single IGF1 single-nucleotide polymorphism haplotype is common to all small breeds and nearly absent from giant breeds, suggesting that the same causal sequence variant is a major contributor to body size in all small dogs.

Gene-environment interplay in the etiology of psychosis.

PubMed

Zwicker, Alyson; Denovan-Wright, Eileen M; Uher, Rudolf

2018-01-15

Schizophrenia and other types of psychosis incur suffering, high health care costs and loss of human potential, due to the combination of early onset and poor response to treatment. Our ability to prevent or cure psychosis depends on knowledge of causal mechanisms. Molecular genetic studies show that thousands of common and rare variants contribute to the genetic risk for psychosis. Epidemiological studies have identified many environmental factors associated with increased risk of psychosis. However, no single genetic or environmental factor is sufficient to cause psychosis on its own. The risk of developing psychosis increases with the accumulation of many genetic risk variants and exposures to multiple adverse environmental factors. Additionally, the impact of environmental exposures likely depends on genetic factors, through gene-environment interactions. Only a few specific gene-environment combinations that lead to increased risk of psychosis have been identified to date. An example of replicable gene-environment interaction is a common polymorphism in the AKT1 gene that makes its carriers sensitive to developing psychosis with regular cannabis use. A synthesis of results from twin studies, molecular genetics, and epidemiological research outlines the many genetic and environmental factors contributing to psychosis. The interplay between these factors needs to be considered to draw a complete picture of etiology. To reach a more complete explanation of psychosis that can inform preventive strategies, future research should focus on longitudinal assessments of multiple environmental exposures within large, genotyped cohorts beginning early in life.

[Progress in genetic research of human height].

PubMed

Chen, Kaixu; Wang, Weilan; Zhang, Fuchun; Zheng, Xiufen

2015-08-01

It is well known that both environmental and genetic factors contribute to adult height variation in general population. However, heritability studies have shown that the variation in height is more affected by genetic factors. Height is a typical polygenic trait which has been studied by traditional linkage analysis and association analysis to identify common DNA sequence variation associated with height, but progress has been slow. More recently, with the development of genotyping and DNA sequencing technologies, tremendous achievements have been made in genetic research of human height. Hundreds of single nucleotide polymorphisms (SNPs) associated with human height have been identified and validated with the application of genome-wide association studies (GWAS) methodology, which deepens our understanding of the genetics of human growth and development and also provides theoretic basis and reference for studying other complex human traits. In this review, we summarize recent progress in genetic research of human height and discuss problems and prospects in this research area which may provide some insights into future genetic studies of human height.

Gene × Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms

PubMed Central

Tordjman, Sylvie; Somogyi, Eszter; Coulon, Nathalie; Kermarrec, Solenn; Cohen, David; Bronsard, Guillaume; Bonnot, Olivier; Weismann-Arcache, Catherine; Botbol, Michel; Lauth, Bertrand; Ginchat, Vincent; Roubertoux, Pierre; Barburoth, Marianne; Kovess, Viviane; Geoffray, Marie-Maude; Xavier, Jean

2014-01-01

Several studies support currently the hypothesis that autism etiology is based on a polygenic and epistatic model. However, despite advances in epidemiological, molecular and clinical genetics, the genetic risk factors remain difficult to identify, with the exception of a few chromosomal disorders and several single gene disorders associated with an increased risk for autism. Furthermore, several studies suggest a role of environmental factors in autism spectrum disorders (ASD). First, arguments for a genetic contribution to autism, based on updated family and twin studies, are examined. Second, a review of possible prenatal, perinatal, and postnatal environmental risk factors for ASD are presented. Then, the hypotheses are discussed concerning the underlying mechanisms related to a role of environmental factors in the development of ASD in association with genetic factors. In particular, epigenetics as a candidate biological mechanism for gene × environment interactions is considered and the possible role of epigenetic mechanisms reported in genetic disorders associated with ASD is discussed. Furthermore, the example of in utero exposure to valproate provides a good illustration of epigenetic mechanisms involved in ASD and innovative therapeutic strategies. Epigenetic remodeling by environmental factors opens new perspectives for a better understanding, prevention, and early therapeutic intervention of ASD. PMID:25136320

Evolving hard problems: Generating human genetics datasets with a complex etiology.

PubMed

Himmelstein, Daniel S; Greene, Casey S; Moore, Jason H

2011-07-07

A goal of human genetics is to discover genetic factors that influence individuals' susceptibility to common diseases. Most common diseases are thought to result from the joint failure of two or more interacting components instead of single component failures. This greatly complicates both the task of selecting informative genetic variants and the task of modeling interactions between them. We and others have previously developed algorithms to detect and model the relationships between these genetic factors and disease. Previously these methods have been evaluated with datasets simulated according to pre-defined genetic models. Here we develop and evaluate a model free evolution strategy to generate datasets which display a complex relationship between individual genotype and disease susceptibility. We show that this model free approach is capable of generating a diverse array of datasets with distinct gene-disease relationships for an arbitrary interaction order and sample size. We specifically generate eight-hundred Pareto fronts; one for each independent run of our algorithm. In each run the predictiveness of single genetic variation and pairs of genetic variants have been minimized, while the predictiveness of third, fourth, or fifth-order combinations is maximized. Two hundred runs of the algorithm are further dedicated to creating datasets with predictive four or five order interactions and minimized lower-level effects. This method and the resulting datasets will allow the capabilities of novel methods to be tested without pre-specified genetic models. This allows researchers to evaluate which methods will succeed on human genetics problems where the model is not known in advance. We further make freely available to the community the entire Pareto-optimal front of datasets from each run so that novel methods may be rigorously evaluated. These 76,600 datasets are available from http://discovery.dartmouth.edu/model_free_data/.

Cognitive Impairments Are Different in Single-Incidence and Multi-Incidence ADHD Families

ERIC Educational Resources Information Center

Oerlemans, Anoek M.; Hartman, Catharina A.; Bruijn, Yvette G. E.; Franke, Barbara; Buitelaar, Jan K.; Rommelse, Nanda N. J.

2015-01-01

Background: We may improve our understanding of the role of common versus unique risk factors in attention-deficit/hyperactivity disorder (ADHD) by examining ADHD-related cognitive deficits in single- (SPX), and multi-incidence (MPX) families. Given that individuals from multiplex (MPX) families are likely to share genetic vulnerability for the…

Gene-environment interaction study for BMI reveals interactions between genetic factors and physical activity, alcohol consumption and socioeconomic status

PubMed Central

Karlsson, Torgny; Ek, Weronica E.

2017-01-01

Previous genome-wide association studies (GWAS) have identified hundreds of genetic loci to be associated with body mass index (BMI) and risk of obesity. Genetic effects can differ between individuals depending on lifestyle or environmental factors due to gene-environment interactions. In this study, we examine gene-environment interactions in 362,496 unrelated participants with Caucasian ancestry from the UK Biobank resource. A total of 94 BMI-associated SNPs, selected from a previous GWAS on BMI, were used to construct weighted genetic scores for BMI (GSBMI). Linear regression modeling was used to estimate the effect of gene-environment interactions on BMI for 131 lifestyle factors related to: dietary habits, smoking and alcohol consumption, physical activity, socioeconomic status, mental health, sleeping patterns, as well as female-specific factors such as menopause and childbirth. In total, 15 lifestyle factors were observed to interact with GSBMI, of which alcohol intake frequency, usual walking pace, and Townsend deprivation index, a measure of socioeconomic status, were all highly significant (p = 1.45*10−29, p = 3.83*10−26, p = 4.66*10−11, respectively). Interestingly, the frequency of alcohol consumption, rather than the total weekly amount resulted in a significant interaction. The FTO locus was the strongest single locus interacting with any of the lifestyle factors. However, 13 significant interactions were also observed after omitting the FTO locus from the genetic score. Our analyses indicate that many lifestyle factors modify the genetic effects on BMI with some groups of individuals having more than double the effect of the genetic score. However, the underlying causal mechanisms of gene-environmental interactions are difficult to deduce from cross-sectional data alone and controlled experiments are required to fully characterise the causal factors. PMID:28873402

Genetic Associations With White Matter Hyperintensities Confer Risk of Lacunar Stroke

PubMed Central

Rutten-Jacobs, Loes C.A.; Thijs, Vincent; Holliday, Elizabeth G.; Levi, Chris; Bevan, Steve; Malik, Rainer; Boncoraglio, Giorgio; Sudlow, Cathie; Rothwell, Peter M.; Dichgans, Martin; Markus, Hugh S.

2016-01-01

Background and Purpose— White matter hyperintensities (WMH) are increased in patients with lacunar stroke. Whether this is because of shared pathogenesis remains unknown. Using genetic data, we evaluated whether WMH-associated genetic susceptibility factors confer risk of lacunar stroke, and therefore whether they share pathogenesis. Methods— We used a genetic risk score approach to test whether single nucleotide polymorphisms associated with WMH in community populations were associated with magnetic resonance imaging–confirmed lacunar stroke (n=1,373), as well as cardioembolic (n=1,331) and large vessel (n=1,472) Trial of Org 10172 in Acute Stroke Treatment subtypes, against 9,053 controls. Second, we separated lacunar strokes into those with WMH (n=568) and those without (n=787) and tested for association with the risk score in these 2 groups. In addition, we evaluated whether WMH-associated single nucleotide polymorphisms are associated with lacunar stroke, or in the 2 groups. Results— The WMH genetic risk score was associated with lacunar stroke (odds ratio [OR; 95% confidence interval [CI

Heritability and genetic covariation of sensitivity to PROP, SOA, quinine HCl, and caffeine.

PubMed

Hansen, Jonathan L; Reed, Danielle R; Wright, Margaret J; Martin, Nicholas G; Breslin, Paul A S

2006-06-01

The perceived bitterness intensity for bitter solutions of propylthiouracil (PROP), sucrose octa-acetate (SOA), quinine HCl and caffeine were examined in a genetically informative sample of 392 females and 313 males (mean age of 17.8 +/- 3.1 years), including 62 monozygotic and 131 dizygotic twin pairs and 237 sib pairs. Broad-sense heritabilities were estimated at 0.72, 0.28, 0.34, and 0.30 for PROP, SOA, quinine, and caffeine, respectively, for perceived intensity measures. Modeling showed 1) a group factor which explained a large amount of the genetic variation in SOA, quinine, and caffeine (22-28% phenotypic variation), 2) a factor responsible for all the genetic variation in PROP (72% phenotypic variation), which only accounted for 1% and 2% of the phenotypic variation in SOA and caffeine, respectively, and 3) a modest specific genetic factor for quinine (12% phenotypic variation). Unique environmental influences for all four compounds were due to a single factor responsible for 7-22% of phenotypic variation. The results suggest that the perception of PROP and the perception of SOA, quinine, and caffeine are influenced by two distinct sets of genes.

Heritability and Genetic Covariation of Sensitivity to PROP, SOA, Quinine HCl, and Caffeine

PubMed Central

Hansen, Jonathan L.; Reed, Danielle R.; Wright, Margaret J.; Martin, Nicholas G.; Breslin, Paul A. S.

2006-01-01

The perceived bitterness intensity for bitter solutions of propylthiouracil (PROP), sucrose octa-acetate (SOA), quinine HCl and caffeine were examined in a genetically informative sample of 392 females and 313 males (mean age of 17.8 ± 3.1 years), including 62 MZ and 131 DZ twin pairs and 237 sib pairs. Broad-sense heritabilities were estimated at 0.72, 0.28, 0.34, and 0.30 for PROP, SOA, quinine, and caffeine, respectively, for perceived intensity measures. Modeling showed 1) a group factor which explained a large amount of the genetic variation in SOA, quinine, and caffeine (22–28% phenotypic variation), 2) a factor responsible for all the genetic variation in PROP (72% phenotypic variation), which only accounted for 1% and 2% of the phenotypic variation in SOA and caffeine, respectively, and 3) a modest specific genetic factor for quinine (12% phenotypic variation). Unique environmental influences for all four compounds were due to a single factor responsible for 7–22% of phenotypic variation. The results suggest that the perception of PROP and the perception of SOA, quinine, and caffeine are influenced by two distinct sets of genes. PMID:16527870

Triggers for Autism: Genetic and Environmental Factors

PubMed Central

Matsuzaki, Hideo; Iwata, Keiko; Manabe, Takayuki; Mori, Norio

2012-01-01

This report reviews the research on the factors that cause autism. In several studies, these factors have been verified by reproducing them in autistic animal models. Clinical research has demonstrated that genetic and environmental factors play a major role in the development of autism. However, most cases are idiopathic, and no single factor can explain the trends in the pathology and prevalence of autism. At the time of this writing, autism is viewed more as a multi-factorial disorder. However, the existence of an unknown factor that may be common in all autistic cases cannot be ruled out. It is hoped that future biological studies of autism will help construct a new theory that can interpret the pathology of autism in a coherent manner. To achieve this, large-scale epidemiological research is essential. PMID:23650465

The interplay between environmental and genetic factors in Parkinson's disease susceptibility: the evidence for pesticides.

PubMed

Dardiotis, Efthimios; Xiromerisiou, Georgia; Hadjichristodoulou, Christos; Tsatsakis, Aristidis M; Wilks, Martin F; Hadjigeorgiou, Georgios M

2013-05-10

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by dopaminergic neuron loss in the substantia nigra. Several genetic and environmental factors have been implicated in the pathogenesis of PD. Single risk factors are likely to exert relatively minor effects, whereas their interaction may prove to be sufficient to cause PD. In the present review we summarize current knowledge from human genetic association studies regarding the interaction between gene polymorphisms and pesticide exposure in the risk of PD. A number of genetic association studies have investigated joint effects between genes and pesticides on PD risk. They have provided some evidence that genetic susceptibility either in metabolism, elimination and transport of pesticides or in the extent of mitochondrial dysfunction, oxidative stress and neuronal loss may predispose individuals to PD if they have been exposed to pesticides. These findings confirm the importance of considering pesticide-gene interactions in future studies in order to gain a better understanding of the pathogenic mechanisms of PD. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

[Genetic aspects of the Stroop test].

PubMed

Nánási, Tibor; Katonai, Enikő Rózsa; Sasvári-Székely, Mária; Székely, Anna

2012-12-01

Impairment of executive control functions in depression is well documented, and performance on the Stroop Test is one of the most widely used markers to measure the decline. This tool provides reliable quantitative phenotype data that can be used efficiently in candidate gene studies investigating inherited components of executive control. Aim of the present review is to summarize research on genetic factors of Stroop performance. Interestingly, only a few such candidate gene studies have been carried out to date. Twin studies show a 30-60% heritability estimate for the Stroop test, suggesting a significant genetic component. A single genome-wide association study has been carried out on Stroop performance, and it did not show any significant association with any of the tested polymorphisms after correction for multiple testing. Candidate gene studies to date pointed to the polymorphisms of several neurotransmitter systems (dopamine, serotonin, acetylcholine) and to the role of the APOE ε4 allele. Surprisingly, little is known about the genetic role of neurothrophic factors and survival factors. In conclusion, further studies are needed for clarifying the genetic background of Stroop performance, characterizing attentional functions.

Contribution of genetic background, traditional risk factors, and HIV-related factors to coronary artery disease events in HIV-positive persons.

PubMed

Rotger, Margalida; Glass, Tracy R; Junier, Thomas; Lundgren, Jens; Neaton, James D; Poloni, Estella S; van 't Wout, Angélique B; Lubomirov, Rubin; Colombo, Sara; Martinez, Raquel; Rauch, Andri; Günthard, Huldrych F; Neuhaus, Jacqueline; Wentworth, Deborah; van Manen, Danielle; Gras, Luuk A; Schuitemaker, Hanneke; Albini, Laura; Torti, Carlo; Jacobson, Lisa P; Li, Xiuhong; Kingsley, Lawrence A; Carli, Federica; Guaraldi, Giovanni; Ford, Emily S; Sereti, Irini; Hadigan, Colleen; Martinez, Esteban; Arnedo, Mireia; Egaña-Gorroño, Lander; Gatell, Jose M; Law, Matthew; Bendall, Courtney; Petoumenos, Kathy; Rockstroh, Jürgen; Wasmuth, Jan-Christian; Kabamba, Kabeya; Delforge, Marc; De Wit, Stephane; Berger, Florian; Mauss, Stefan; de Paz Sierra, Mariana; Losso, Marcelo; Belloso, Waldo H; Leyes, Maria; Campins, Antoni; Mondi, Annalisa; De Luca, Andrea; Bernardino, Ignacio; Barriuso-Iglesias, Mónica; Torrecilla-Rodriguez, Ana; Gonzalez-Garcia, Juan; Arribas, José R; Fanti, Iuri; Gel, Silvia; Puig, Jordi; Negredo, Eugenia; Gutierrez, Mar; Domingo, Pere; Fischer, Julia; Fätkenheuer, Gerd; Alonso-Villaverde, Carlos; Macken, Alan; Woo, James; McGinty, Tara; Mallon, Patrick; Mangili, Alexandra; Skinner, Sally; Wanke, Christine A; Reiss, Peter; Weber, Rainer; Bucher, Heiner C; Fellay, Jacques; Telenti, Amalio; Tarr, Philip E

2013-07-01

Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection. In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort. A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9 × 10(-4)). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05-2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06-1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16-1.96), diabetes (OR = 1.66; 95% CI, 1.10-2.49), ≥ 1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06-1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17-2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD. In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD.

Single Nucleotide Polymorphisms Predict Symptom Severity of Autism Spectrum Disorder

ERIC Educational Resources Information Center

Jiao, Yun; Chen, Rong; Ke, Xiaoyan; Cheng, Lu; Chu, Kangkang; Lu, Zuhong; Herskovits, Edward H.

2012-01-01

Autism is widely believed to be a heterogeneous disorder; diagnosis is currently based solely on clinical criteria, although genetic, as well as environmental, influences are thought to be prominent factors in the etiology of most forms of autism. Our goal is to determine whether a predictive model based on single-nucleotide polymorphisms (SNPs)…

Recent Advances in the Genetics of Vocal Learning

PubMed Central

Condro, Michael C.; White, Stephanie A.

2015-01-01

Language is a complex communicative behavior unique to humans, and its genetic basis is poorly understood. Genes associated with human speech and language disorders provide some insights, originating with the FOXP2 transcription factor, a mutation in which is the source of an inherited form of developmental verbal dyspraxia. Subsequently, targets of FOXP2 regulation have been associated with speech and language disorders, along with other genes. Here, we review these recent findings that implicate genetic factors in human speech. Due to the exclusivity of language to humans, no single animal model is sufficient to study the complete behavioral effects of these genes. Fortunately, some animals possess subcomponents of language. One such subcomponent is vocal learning, which though rare in the animal kingdom, is shared with songbirds. We therefore discuss how songbird studies have contributed to the current understanding of genetic factors that impact human speech, and support the continued use of this animal model for such studies in the future. PMID:26052371

Single nucleotide polymorphisms in the growth hormone - insulin like growth factor axis in straight bred and crossbred Angus, Brahman, and Romosinuano heifers: population genetic analyses and association of genotypes

USDA-ARS?s Scientific Manuscript database

The growth endocrine axis influences reproduction. Objectives of this study were to evaluate population genetic characteristics of SNP genotypes within genes of the GH and IGF axis in straightbred and diallel-crossed Angus, Brahman and Romosinuano heifers (n = 650) and to test the associations of th...

Exome Array Analysis of Nuclear Lens Opacity.

PubMed

Loomis, Stephanie J; Klein, Alison P; Lee, Kristine E; Chen, Fei; Bomotti, Samantha; Truitt, Barbara; Iyengar, Sudha K; Klein, Ronald; Klein, Barbara E K; Duggal, Priya

2018-06-01

Nuclear cataract is the most common subtype of age-related cataract, the leading cause of blindness worldwide. It results from advanced nuclear sclerosis, or opacity in the center of the optic lens, and is affected by both genetic and environmental risk factors, including smoking. We sought to understand the genetic factors associated with nuclear sclerosis through interrogation of rare and low frequency coding variants using exome array data. We analyzed Illumina Human Exome Array data for 1,488 participants of European ancestry in the Beaver Dam Eye Study who were without cataract surgery for association with nuclear sclerosis grade, controlling for age and sex. We performed single-variant regression analysis for 32,138 variants with minor allele frequency (MAF) ≥0.003. In addition, gene-based analysis of 11,844 genes containing at least two variants with MAF < 0.05 was performed using a gene-based unified burden and non-burden sequence kernel association test (SKAT-O). Additionally, both single-variant and gene-based analyses were analyzed stratified by smoking status. No single-variant test was statistically significant after Bonferroni correction (p < 1.6 × 10 -6 ; top single nucleotide polymorphism (SNP): rs144458991, p = 2.83 × 10 -5 ). Gene-based tests were suggestively associated with the gene RNF149 overall (p = 8.29 × 10 -6 ) and among never smokers (N = 790, p = 2.67 × 10 -6 ). This study did not find a significant genetic association with nuclear sclerosis, the possible association with the RNF149 gene highlights a potential candidate gene for future studies that aim to understand the genetic architecture of nuclear sclerosis.

Deconstructing vulnerability for psychosis: Meta-analysis of environmental risk factors for psychosis in subjects at ultra high-risk.

PubMed

Fusar-Poli, P; Tantardini, M; De Simone, S; Ramella-Cravaro, V; Oliver, D; Kingdon, J; Kotlicka-Antczak, M; Valmaggia, L; Lee, J; Millan, M J; Galderisi, S; Balottin, U; Ricca, V; McGuire, P

2017-02-01

Subjects at ultra high-risk (UHR) for psychosis have an enhanced vulnerability to develop the disorder but the risk factors accounting for this accrued risk are undetermined. Systematic review of associations between genetic or environmental risk factors for psychosis that are widely established in the literature and UHR state, based on comparisons to controls. Forty-four studies encompassing 170 independent datasets and 54 risk factors were included. There were no studies on association between genetic or epigenetic risk factors and the UHR state that met the inclusion criteria. UHR subjects were more likely to show obstetric complications, tobacco use, physical inactivity, childhood trauma/emotional abuse/physical neglect, high perceived stress, childhood and adolescent low functioning, affective comorbidities, male gender, single status, unemployment and low educational level as compared to controls. The increased vulnerability of UHR subjects can be related to environmental risk factors like childhood trauma, adverse life events and affective dysfunction. The role of genetic and epigenetic risk factors awaits clarification. Copyright © 2016 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

No Major Host Genetic Risk Factor Contributed to A(H1N1)2009 Influenza Severity

PubMed Central

Garcia-Etxebarria, Koldo; Bracho, María Alma; Galán, Juan Carlos; Pumarola, Tomàs; Castilla, Jesús; Ortiz de Lejarazu, Raúl; Rodríguez-Dominguez, Mario; Quintela, Inés; Bonet, Núria; Garcia-Garcerà, Marc; Domínguez, Angela; González-Candelas, Fernando; Calafell, Francesc

2015-01-01

While most patients affected by the influenza A(H1N1) pandemic experienced mild symptoms, a small fraction required hospitalization, often without concomitant factors that could explain such a severe course. We hypothesize that host genetic factors could contribute to aggravate the disease. To test this hypothesis, we compared the allele frequencies of 547,296 genome-wide single nucleotide polymorphisms (SNPs) between 49 severe and 107 mild confirmed influenza A cases, as well as against a general population sample of 549 individuals. When comparing severe vs. mild influenza A cases, only one SNP was close to the conventional p = 5×10−8. This SNP, rs28454025, sits in an intron of the GSK233 gene, which is involved in a neural development, but seems not to have any connections with immunological or inflammatory functions. Indirectly, a previous association reported with CD55 was replicated. Although sample sizes are low, we show that the statistical power in our design was sufficient to detect highly-penetrant, quasi-Mendelian genetic factors. Hence, and assuming that rs28454025 is likely to be a false positive, no major genetic factor was detected that could explain poor influenza A course. PMID:26379185

The structure of genetic and environmental risk factors for phobias in women.

PubMed

Czajkowski, N; Kendler, K S; Tambs, K; Røysamb, E; Reichborn-Kjennerud, T

2011-09-01

To explore the genetic and environmental factors underlying the co-occurrence of lifetime diagnoses of DSM-IV phobia. Female twins (n=1430) from the population-based Norwegian Institute of Public Health Twin Panel were assessed at personal interview for DSM-IV lifetime specific phobia, social phobia and agoraphobia. Comorbidity between the phobias were assessed by odds ratios (ORs) and polychoric correlations and multivariate twin models were fitted in Mx. Phenotypic correlations of lifetime phobia diagnoses ranged from 0.55 (agoraphobia and social phobia, OR 10.95) to 0.06 (animal phobia and social phobia, OR 1.21). In the best fitting twin model, which did not include shared environmental factors, heritability estimates for the phobias ranged from 0.43 to 0.63. Comorbidity between the phobias was accounted for by two common liability factors. The first loaded principally on animal phobia and did not influence the complex phobias (agoraphobia and social phobia). The second liability factor strongly influenced the complex phobias, but also loaded weak to moderate on all the other phobias. Blood phobia was mainly influenced by a specific genetic factor, which accounted for 51% of the total and 81% of the genetic variance. Phobias are highly co-morbid and heritable. Our results suggest that the co-morbidity between phobias is best explained by two distinct liability factors rather than a single factor, as has been assumed in most previous multivariate twin analyses. One of these factors was specific to the simple phobias, while the other was more general. Blood phobia was mainly influenced by disorder specific genetic factors.

The structure of genetic and environmental risk factors for phobias in women

PubMed Central

Czajkowski, N.; Kendler, K. S.; Tambs, K.; Røysamb, E.; Reichborn-Kjennerud, T.

2011-01-01

Background To explore the genetic and environmental factors underlying the co-occurrence of lifetime diagnoses of DSM-IV phobia. Method Female twins (n = 1430) from the population-based Norwegian Institute of Public Health Twin Panel were assessed at personal interview for DSM-IV lifetime specific phobia, social phobia and agoraphobia. Comorbidity between the phobias were assessed by odds ratios (ORs) and polychoric correlations and multivariate twin models were fitted in Mx. Results Phenotypic correlations of lifetime phobia diagnoses ranged from 0.55 (agoraphobia and social phobia, OR 10.95) to 0.06 (animal phobia and social phobia, OR 1.21). In the best fitting twin model, which did not include shared environmental factors, heritability estimates for the phobias ranged from 0.43 to 0.63. Comorbidity between the phobias was accounted for by two common liability factors. The first loaded principally on animal phobia and did not influence the complex phobias (agoraphobia and social phobia). The second liability factor strongly influenced the complex phobias, but also loaded weak to moderate on all the other phobias. Blood phobia was mainly influenced by a specific genetic factor, which accounted for 51% of the total and 81% of the genetic variance. Conclusions Phobias are highly co-morbid and heritable. Our results suggest that the co-morbidity between phobias is best explained by two distinct liability factors rather than a single factor, as has been assumed in most previous multivariate twin analyses. One of these factors was specific to the simple phobias, while the other was more general. Blood phobia was mainly influenced by disorder specific genetic factors. PMID:21211096

Examining the role of common genetic variants on alcohol, tobacco, cannabis, and illicit drug dependence

PubMed Central

Palmer, RHC; Brick, L; Nugent, NR; Bidwell, LC; McGeary, JE; Knopik, VS; Keller, MC

2014-01-01

Background and Aims Twin and family studies suggest that genetic influences are shared across substances of abuse. However, despite evidence of heritability, genome-wide association and candidate gene studies have indicated numerous markers of limited effects, suggesting that much of the heritability remains missing. We estimated (1) the aggregate effect of common single nucleotide polymorphisms (SNPs) on multiple indicators of comorbid drug problems that are typically employed across community and population-based samples, and (2) the genetic covariance across these measures. Participants 2596 unrelated subjects from the “Study of Addiction: Genetics and Environment” provided information on alcohol, tobacco, cocaine, cannabis, and other illicit substance dependence. Phenotypic measures included: (1) a factor score based on DSM-IV drug dependence diagnoses (DD), (2) a factor score based on problem use (PU; i.e., 1+ DSM-IV symptoms), and (3) dependence vulnerability (DV; a ratio of DSM-IV symptoms to the number of substances used). Findings Univariate and bivariate Genome-wide complex trait analyses of this selected sample indicated that common SNPs explained 25-36% of the variance across measures, with DD and DV having the largest effects [h2SNP (CI)=0.36 (0.11-0.62) and 0.33(0.07-0.58), respectively; PU = 0.25 (-0.01-0.51)]. Genetic effects were shared across the three phenotypic measures of comorbid drug problems (rSNP; rDD-PU = 0.92 (0.76-1.00), rDD-DV = 0.97 (0.87-1.00), and rPU-DV = 0.96 (0.82-1.00)). Conclusion At least 20% of the variance in the generalized vulnerability to substance dependence is attributable to common single nucleotide polymorphisms. The additive effect of common single nucleotide polymorphisms is shared across important indicators of comorbid drug problems. PMID:25424661

The genetics of exceptional longevity: Insights from centenarians.

PubMed

Santos-Lozano, Alejandro; Santamarina, Ana; Pareja-Galeano, Helios; Sanchis-Gomar, Fabian; Fiuza-Luces, Carmen; Cristi-Montero, Carlos; Bernal-Pino, Aranzazu; Lucia, Alejandro; Garatachea, Nuria

2016-08-01

As the world population ages, so the prevalence increases of individuals aged 100 years or more, known as centenarians. Reaching this age has been described as exceptional longevity (EL) and is attributed to both genetic and environmental factors. Many genetic variations known to affect life expectancy exist in centenarians. This review of studies conducted on centenarians and supercentenarians (older than 110 years) updates knowledge of the impacts on longevity of the twenty most widely investigated single nucleotide polymorphisms (SNPs). Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

BAT2 and BAT3 polymorphisms as novel genetic risk factors for rejection after HLA-related SCT.

PubMed

Piras, Ignazio Stefano; Angius, Andrea; Andreani, Marco; Testi, Manuela; Lucarelli, Guido; Floris, Matteo; Marktel, Sarah; Ciceri, Fabio; La Nasa, Giorgio; Fleischhauer, Katharina; Roncarolo, Maria Grazia; Bulfone, Alessandro; Gregori, Silvia; Bacchetta, Rosa

2014-11-01

The genetic background of donor and recipient is an important factor determining the outcome of allogeneic hematopoietic SCT (allo-HSCT). We applied whole-genome analysis to investigate genetic variants-other than HLA class I and II-associated with negative outcome after HLA-identical sibling allo-HSCT in a cohort of 110 β-Thalassemic patients. We identified two single-nucleotide polymorphisms (SNPs) in BAT2 (A/G) and BAT3 (T/C) genes, SNP rs11538264 and SNP rs10484558, both located in the HLA class III region, in strong linkage disequilibrium between each other (R(2)=0.92). When considered as single SNP, none of them reached a significant association with graft rejection (nominal P<0.00001 for BAT2 SNP rs11538264, and P<0.0001 for BAT3 SNP rs10484558), whereas the BAT2/BAT3 A/C haplotype was present at significantly higher frequency in patients who rejected as compared to those with functional graft (30.0% vs 2.6%, nominal P=1.15 × 10(-8); and adjusted P=0.0071). The BAT2/BAT3 polymorphisms and specifically the A/C haplotype may represent a novel immunogenetic factor associated with graft rejection in patients undergoing allo-HSCT.

Initial evidence that polymorphisms in neurotransmitter-regulating genes contribute to being born small for gestational age

PubMed Central

Morgan, Angharad R.; Thompson, John M.D.; Waldie, Karen E.; Cornforth, Christine M.; Turic, Darko; Sonuga-Barke, Edmund J.S.; Lam, Wen-Jiun; Ferguson, Lynnette R.; Mitchell, Edwin A.

2012-01-01

Being born small for gestational age (SGA) is a putative risk factor for the development of later cognitive and psychiatric health problems. While the inter-uterine environment has been shown to play an important role in predicting birth weight, little is known about the genetic factors that might be important. Here we test the hypothesis that neurotransmitter-regulating genes implicated in psychiatric disorders previously shown to be associated with SGA (such as attention-deficit hyperactivity disorder) are themselves predictive of SGA. DNA was collected from 227 SGA and 319 appropriate for gestational age children taking part in the Auckland Birthweight Collaborative Study. Candidate single nucleotide polymorphisms in genes regulating activity within dopamine, serotonin, glutamate and gamma-aminobutyric acid pathways were genotyped. Multiple regression analysis, controlling for potentially confounding factors, supported nominally significant associations between SGA and single nucleotide polymorphisms in COMT, HTR2A, SLC1A1 and SLC6A1. This is the first evidence that genes implicated in psychiatric disorders previously linked to SGA status themselves predict SGA. This highlights the possibility that the link between SGA and psychiatric disorders such as attention-deficit hyperactivity disorder may in part be genetically determined – that SGA marks pre-existing genetic risk for later problems. PMID:27625810

BAT2 and BAT3 polymorphisms as novel genetic risk factors for rejection after HLA-related stem cell transplantation

PubMed Central

Piras, Ignazio Stefano; Angius, Andrea; Andreani, Marco; Testi, Manuela; Lucarelli, Guido; Floris, Matteo; Marktel, Sarah; Ciceri, Fabio; La Nasa, Giorgio; Fleischhauer, Katharina; Roncarolo, Maria Grazia; Bulfone, Alessandro

2014-01-01

The genetic background of donor and recipient is an important factor determining the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We applied a whole genome analysis to investigate genetic variants - other than HLA class I and II - associated with negative outcome after HLA-identical sibling allo-HSCT in a cohort of 110 β-Thalassemic patients. We identified two single nucleotide polymorphisms in BAT2 (A/G) and BAT3 (T/C) genes, SNP rs11538264 and SNP rs10484558, both located in the HLA class III region, in strong Linkage Disequilibrium between each other (R2=0.92). When considered as single SNP, none of them reached a significant association with graft rejection (nominal P < 0.00001 for BAT2 SNP rs11538264, and P < 0.0001 for BAT3 SNP rs10484558). Whereas, the BAT2/BAT3 A/C haplotype was present at significantly higher frequency in patients who rejected as compared to those with functional graft (30.0% vs. 2.6%, nominal P = 1.15×10−8; and adjusted P = 0.0071). The BAT2/BAT3 polymorphisms and specifically the A/C haplotype may represent novel immunogenetic factor associated with graft rejection in patients undergoing allo-HSCT. PMID:25111513

Association of "ADAM10" and "CAMK2A" Polymorphisms with Conduct Disorder: Evidence from Family-Based Studies

ERIC Educational Resources Information Center

Jian, Xue-Qiu; Wang, Ke-Sheng; Wu, Tie-Jian; Hillhouse, Joel J.; Mullersman, Jerald E.

2011-01-01

Twin and family studies have shown that genetic factors play a role in the development of conduct disorder (CD). The purpose of this study was to identify genetic variants associated with CD using a family-based association study. We used 4,720 single nucleotide polymorphisms (SNPs) from the Illumina Panel and 11,120 SNPs from the Affymetrix 10K…

A critical analysis of disease-associated DNA polymorphisms in the genes of cattle, goat, sheep, and pig

PubMed Central

Ibeagha-Awemu, Eveline M.; Kgwatalala, Patrick; Ibeagha, Aloysius E.

2008-01-01

Genetic variations through their effects on gene expression and protein function underlie disease susceptibility in farm animal species. The variations are in the form of single nucleotide polymorphisms, deletions/insertions of nucleotides or whole genes, gene or whole chromosomal rearrangements, gene duplications, and copy number polymorphisms or variants. They exert varying degrees of effects on gene action, such as substitution of an amino acid for another, shift in reading frame and premature termination of translation, and complete deletion of entire exon(s) or gene(s) in diseased individuals. These factors influence gene function by affecting mRNA splicing pattern or by altering/eliminating protein function. Elucidating the genetic bases of diseases under the control of many genes is very challenging, and it is compounded by several factors, including host × pathogen × environment interactions. In this review, the genetic variations that underlie several diseases of livestock (under monogenic and polygenic control) are analyzed. Also, factors hampering research efforts toward identification of genetic influences on animal disease identification and control are highlighted. A better understanding of the factors analyzed could be better harnessed to effectively identify and control, genetically, livestock diseases. Finally, genetic control of animal diseases can reduce the costs associated with diseases, improve animal welfare, and provide healthy animal products to consumers, and should be given more attention. PMID:18350334

A Kernel Machine Method for Detecting Effects of Interaction Between Multidimensional Variable Sets: An Imaging Genetics Application

PubMed Central

Ge, Tian; Nichols, Thomas E.; Ghosh, Debashis; Mormino, Elizabeth C.

2015-01-01

Measurements derived from neuroimaging data can serve as markers of disease and/or healthy development, are largely heritable, and have been increasingly utilized as (intermediate) phenotypes in genetic association studies. To date, imaging genetic studies have mostly focused on discovering isolated genetic effects, typically ignoring potential interactions with non-genetic variables such as disease risk factors, environmental exposures, and epigenetic markers. However, identifying significant interaction effects is critical for revealing the true relationship between genetic and phenotypic variables, and shedding light on disease mechanisms. In this paper, we present a general kernel machine based method for detecting effects of interaction between multidimensional variable sets. This method can model the joint and epistatic effect of a collection of single nucleotide polymorphisms (SNPs), accommodate multiple factors that potentially moderate genetic influences, and test for nonlinear interactions between sets of variables in a flexible framework. As a demonstration of application, we applied the method to data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to detect the effects of the interactions between candidate Alzheimer's disease (AD) risk genes and a collection of cardiovascular disease (CVD) risk factors, on hippocampal volume measurements derived from structural brain magnetic resonance imaging (MRI) scans. Our method identified that two genes, CR1 and EPHA1, demonstrate significant interactions with CVD risk factors on hippocampal volume, suggesting that CR1 and EPHA1 may play a role in influencing AD-related neurodegeneration in the presence of CVD risks. PMID:25600633

Genetic and environmental influences on dimensional representations of DSM-IV cluster C personality disorders: a population-based multivariate twin study.

PubMed

Reichborn-Kjennerud, Ted; Czajkowski, Nikolai; Neale, Michael C; Ørstavik, Ragnhild E; Torgersen, Svenn; Tambs, Kristian; Røysamb, Espen; Harris, Jennifer R; Kendler, Kenneth S

2007-05-01

The DSM-IV cluster C Axis II disorders include avoidant (AVPD), dependent (DEPD) and obsessive-compulsive (OCPD) personality disorders. We aimed to estimate the genetic and environmental influences on dimensional representations of these disorders and examine the validity of the cluster C construct by determining to what extent common familial factors influence the individual PDs. PDs were assessed using the Structured Interview for DSM-IV Personality (SIDP-IV) in a sample of 1386 young adult twin pairs from the Norwegian Institute of Public Health Twin Panel (NIPHTP). A single-factor independent pathway multivariate model was applied to the number of endorsed criteria for the three cluster C disorders, using the statistical modeling program Mx. The best-fitting model included genetic and unique environmental factors only, and equated parameters for males and females. Heritability ranged from 27% to 35%. The proportion of genetic variance explained by a common factor was 83, 48 and 15% respectively for AVPD, DEPD and OCPD. Common genetic and environmental factors accounted for 54% and 64% respectively of the variance in AVPD and DEPD but only 11% of the variance in OCPD. Cluster C PDs are moderately heritable. No evidence was found for shared environmental or sex effects. Common genetic and individual environmental factors account for a substantial proportion of the variance in AVPD and DEPD. However, OCPD appears to be largely etiologically distinct from the other two PDs. The results do not support the validity of the DSM-IV cluster C construct in its present form.

Do genetic and individual risk factors moderate the efficacy of motivational enhancement therapy? Drinking outcomes with an emerging adult sample

PubMed Central

Feldstein Ewing, Sarah W.; LaChance, Heather A.; Bryan, Angela; Hutchison, Kent E.

2010-01-01

Research indicates that motivational enhancement therapy (MET) helps catalyze reductions in problem drinking among emerging adults. However, moderators of this intervention remain relatively unknown. Therefore, the objectives of this study were: (1) to test whether a single session of MET increased motivation to reduce drinking and drinking outcomes; and (2) to examine whether genetic dopamine D4 receptor L (DRD4 L) and individual personality risk factors (impulsivity and novelty seeking) moderated the effects of the MET. These hypotheses were evaluated by randomly assigning a sample of emerging adult problem drinkers (n = 67) to receive a single session of MET or alcohol education. Follow-up data indicated that only individuals who were low in impulsivity, novelty seeking and/or who had the short DRD4 variable number of tandem repeats genotype evidenced differentially increased behavior change (taking steps toward reducing drinking) following the MET. PMID:19298319

AB022. Harnessing big data to transform clinical care of cardiovascular diseases

PubMed Central

Cutiongco-de la Paz, Eva Maria

2015-01-01

Diseases of the heart and vascular system are the leading causes of mortality worldwide. A number of risk factors have already been identified such as obesity, diabetes and smoking; in the recent years, research has shifted its focus on genetic risk factors. Discoveries on the role of genes partnered with the technological developments have enabled advances in the understanding of human genetics and its influence on disease and treatment. There are initiatives now to combine medical records and genetic and other molecular data into a single “knowledge network” to achieve these aptly known as precision medicine. With next generation sequencing readily available at a more affordable cost, it is expected that genetic information of patients will be increasingly available and can be used to guide clinical decisions. Big data generated and stored necessitates broad and extensive interpretation to be valuable in clinical care. Accumulating evidence on the use of such genetic information in the cardiovascular clinics will be presented.

Do genetic modifiers of high-density lipoprotein cholesterol and triglyceride levels also modify their response to a lifestyle intervention in the setting of obesity and type-2 diabetes mellitus?: The Action for Health in Diabetes (Look AHEAD) study.

PubMed

Huggins, Gordon S; Papandonatos, George D; Erar, Bahar; Belalcazar, L Maria; Brautbar, Ariel; Ballantyne, Christie; Kitabchi, Abbas E; Wagenknecht, Lynne E; Knowler, William C; Pownall, Henry J; Wing, Rena R; Peter, Inga; McCaffery, Jeanne M

2013-08-01

High-density lipoprotein cholesterol (HDL-C) and triglycerides are cardiovascular risk factors susceptible to lifestyle behavior modification and genetics. We hypothesized that genetic variants identified by genome-wide association studies as associated with HDL-C or triglyceride levels modify 1-year treatment response to an intensive lifestyle intervention, relative to a usual care of diabetes mellitus support and education. We evaluated 82 single-nucleotide polymorphisms, which represent 31 loci demonstrated by genome-wide association studies to be associated with HDL-C and triglycerides, in 3561 participants who consented for genetic studies and met eligibility criteria. Variants associated with higher baseline HDL-C levels, cholesterol ester transfer protein (CETP) rs3764261 and hepatic lipase (LIPC) rs8034802, were found to be associated with HDL-C increases with intensive lifestyle intervention (P=0.0038 and 0.013, respectively) and had nominally significant treatment interactions (P=0.047 and 0.046, respectively). The fatty acid desaturase-2 rs1535 variant, associated with low baseline HDL-C (P=0.017), was associated with HDL-C increases with intensive lifestyle intervention (0.0037) and had a nominal treatment interaction (P=0.035). Apolipoprotein B (rs693) and LIPC (rs8034802) single-nucleotide polymorphisms showed nominally significant associations with HDL-C and triglyceride changes with intensive lifestyle intervention and a treatment interaction (P<0.05). Phosphatidylglycerophosphate synthase-1 single-nucleotide polymorphisms (rs4082919) showed the most significant triglyceride treatment interaction in the full cohort (P=0.0009). This is the first study to identify genetic variants modifying lipid responses to a randomized lifestyle behavior intervention in overweight or obese individuals with diabetes mellitus. The effects of genetic factors on lipid changes may differ from the effects on baseline lipids and are modifiable by behavioral intervention.

Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci

PubMed Central

Thompson, Wesley K.; McEvoy, Linda K.; Schork, Andrew J.; Zuber, Verena; LeBlanc, Marissa; Bettella, Francesco; Mills, Ian G.; Desikan, Rahul S.; Djurovic, Srdjan; Gautvik, Kaare M.; Dale, Anders M.; Andreassen, Ole A.

2015-01-01

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity. PMID:26695485

A mutational approach for the detection of genetic factors affecting seed size in maize.

PubMed

Sangiorgio, Stefano; Carabelli, Laura; Gabotti, Damiano; Manzotti, Priscilla Sofia; Persico, Martina; Consonni, Gabriella; Gavazzi, Giuseppe

2016-12-01

Genes influencing seed size. The designation emp (empty pericarp) refers to a group of defective kernel mutants that exhibit a drastic reduction in endosperm tissue production. They allow the isolation of genes controlling seed development and affecting seed size. Nine independently isolated emp mutants have been analyzed in this study and in all cases longitudinal sections of mature seeds revealed the absence of morphogenesis in the embryo proper, an observation that correlates with their failure to germinate. Complementation tests with the nine emp mutants, crossed inter se in all pairwise combinations, identified complementing and non-complementing pairs in the F 1 progenies. Data were then validated in the F 2 /F 3 generations. Mutant chromosomal location was also established. Overall our study has identified two novel emp genes and a novel allele at the previously identified emp4 gene. The introgression of single emp mutants in a different genetic background revealed the existence of a cryptic genetic variation (CGV) recognizable as a variable increase in the endosperm tissue. The unmasking of CGV by introducing single mutants in different genetic backgrounds is the result of the interaction of the emp mutants with a suppressor that has no obvious phenotype of its own and is present in the genetic background of the inbred lines into which the emp mutants were transferred. On the basis of these results, emp mutants could be used as tools for the detection of genetic factors that enhance the amount of endosperm tissue in the maize kernel and which could thus become valuable targets to exploit in future breeding programs.

Genetic and Environmental Influences on Retinopathy of Prematurity

PubMed Central

Ortega-Molina, J. M.; Anaya-Alaminos, R.; Uberos-Fernández, J.; Solans-Pérez de Larraya, A.; Chaves-Samaniego, M. J.; Salgado-Miranda, A.; Piñar-Molina, R.; Jerez-Calero, A.; García-Serrano, J. L.

2015-01-01

Objective. The goals were to isolate and study the genetic susceptibility to retinopathy of prematurity (ROP), as well as the gene-environment interaction established in this disease. Methods. A retrospective study (2000–2014) was performed about the heritability of retinopathy of prematurity in 257 infants who were born at a gestational age of ≤32 weeks. The ROP was studied and treated by a single pediatric ophthalmologist. A binary logistic regression analysis was completed between the presence or absence of ROP and the predictor variables. Results. Data obtained from 38 monozygotic twins, 66 dizygotic twins, and 153 of simple birth were analyzed. The clinical features of the cohorts of monozygotic and dizygotic twins were not significantly different. Genetic factors represented 72.8% of the variability in the stage of ROP, environmental factors 23.08%, and random factors 4.12%. The environmental variables representing the highest risk of ROP were the number of days of tracheal intubation (p < 0.001), postnatal weight gain (p = 0.001), and development of sepsis (p = 0.0014). Conclusion. The heritability of ROP was found to be 0.73. The environmental factors regulate and modify the expression of the genetic code. PMID:26089603

Risk factors for hospital morbidity and mortality after the Norwood procedure: A report from the Pediatric Heart Network Single Ventricle Reconstruction trial.

PubMed

Tabbutt, Sarah; Ghanayem, Nancy; Ravishankar, Chitra; Sleeper, Lynn A; Cooper, David S; Frank, Deborah U; Lu, Minmin; Pizarro, Christian; Frommelt, Peter; Goldberg, Caren S; Graham, Eric M; Krawczeski, Catherine Dent; Lai, Wyman W; Lewis, Alan; Kirsh, Joel A; Mahony, Lynn; Ohye, Richard G; Simsic, Janet; Lodge, Andrew J; Spurrier, Ellen; Stylianou, Mario; Laussen, Peter

2012-10-01

We sought to identify risk factors for mortality and morbidity during the Norwood hospitalization in newborn infants with hypoplastic left heart syndrome and other single right ventricle anomalies enrolled in the Single Ventricle Reconstruction trial. Potential predictors for outcome included patient- and procedure-related variables and center volume and surgeon volume. Outcome variables occurring during the Norwood procedure and before hospital discharge or stage II procedure included mortality, end-organ complications, length of ventilation, and hospital length of stay. Univariate and multivariable Cox regression analyses were performed with bootstrapping to estimate reliability for mortality. Analysis included 549 subjects prospectively enrolled from 15 centers; 30-day and hospital mortality were 11.5% (63/549) and 16.0% (88/549), respectively. Independent risk factors for both 30-day and hospital mortality included lower birth weight, genetic abnormality, extracorporeal membrane oxygenation (ECMO) and open sternum on the day of the Norwood procedure. In addition, longer duration of deep hypothermic circulatory arrest was a risk factor for 30-day mortality. Shunt type at the end of the Norwood procedure was not a significant risk factor for 30-day or hospital mortality. Independent risk factors for postoperative renal failure (n = 46), sepsis (n = 93), increased length of ventilation, and hospital length of stay among survivors included genetic abnormality, lower center/surgeon volume, open sternum, and post-Norwood operations. Innate patient factors, ECMO, open sternum, and lower center/surgeon volume are important risk factors for postoperative mortality and/or morbidity during the Norwood hospitalization. Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Linking transcriptional and genetic tumor heterogeneity through allele analysis of single-cell RNA-seq data.

PubMed

Fan, Jean; Lee, Hae-Ock; Lee, Soohyun; Ryu, Da-Eun; Lee, Semin; Xue, Catherine; Kim, Seok Jin; Kim, Kihyun; Barkas, Nikolas; Park, Peter J; Park, Woong-Yang; Kharchenko, Peter V

2018-06-13

Characterization of intratumoral heterogeneity is critical to cancer therapy, as presence of phenotypically diverse cell populations commonly fuels relapse and resistance to treatment. Although genetic variation is a well-studied source of intratumoral heterogeneity, the functional impact of most genetic alterations remains unclear. Even less understood is the relative importance of other factors influencing heterogeneity, such as epigenetic state or tumor microenvironment. To investigate the relationship between genetic and transcriptional heterogeneity in a context of cancer progression, we devised a computational approach called HoneyBADGER to identify copy number variation and loss-of-heterozygosity in individual cells from single-cell RNA-sequencing data. By integrating allele and normalized expression information, HoneyBADGER is able to identify and infer the presence of subclone-specific alterations in individual cells and reconstruct underlying subclonal architecture. Examining several tumor types, we show that HoneyBADGER is effective at identifying deletion, amplifications, and copy-neutral loss-of-heterozygosity events, and is capable of robustly identifying subclonal focal alterations as small as 10 megabases. We further apply HoneyBADGER to analyze single cells from a progressive multiple myeloma patient to identify major genetic subclones that exhibit distinct transcriptional signatures relevant to cancer progression. Surprisingly, other prominent transcriptional subpopulations within these tumors did not line up with the genetic subclonal structure, and were likely driven by alternative, non-clonal mechanisms. These results highlight the need for integrative analysis to understand the molecular and phenotypic heterogeneity in cancer. Published by Cold Spring Harbor Laboratory Press.

Pantoea ananatis Genetic Diversity Analysis Reveals Limited Genomic Diversity as Well as Accessory Genes Correlated with Onion Pathogenicity.

PubMed

Stice, Shaun P; Stumpf, Spencer D; Gitaitis, Ron D; Kvitko, Brian H; Dutta, Bhabesh

2018-01-01

Pantoea ananatis is a member of the family Enterobacteriaceae and an enigmatic plant pathogen with a broad host range. Although P. ananatis strains can be aggressive on onion causing foliar necrosis and onion center rot, previous genomic analysis has shown that P. ananatis lacks the primary virulence secretion systems associated with other plant pathogens. We assessed a collection of fifty P. ananatis strains collected from Georgia over three decades to determine genetic factors that correlated with onion pathogenic potential. Previous genetic analysis studies have compared strains isolated from different hosts with varying diseases potential and isolation sources. Strains varied greatly in their pathogenic potential and aggressiveness on different cultivated Allium species like onion, leek, shallot, and chive. Using multi-locus sequence analysis (MLSA) and repetitive extragenic palindrome repeat (rep)-PCR techniques, we did not observe any correlation between onion pathogenic potential and genetic diversity among strains. Whole genome sequencing and pan-genomic analysis of a sub-set of 10 strains aided in the identification of a novel series of genetic regions, likely plasmid borne, and correlating with onion pathogenicity observed on single contigs of the genetic assemblies. We named these loci Onion Virulence Regions (OVR) A-D. The OVR loci contain genes involved in redox regulation as well as pectate lyase and rhamnogalacturonase genes. Previous studies have not identified distinct genetic loci or plasmids correlating with onion foliar pathogenicity or pathogenicity on a single host pathosystem. The lack of focus on a single host system for this phytopathgenic disease necessitates the pan-genomic analysis performed in this study.

American Journal of Ophthalmology Contributions to Ophthalmic Genetics.

PubMed

MacDonald, Ian M; Sieving, Pamela C

2018-06-01

To review the contributions to ophthalmic genetics through the American Journal of Ophthalmology (AJO). Perspective. A literature search to retrieve original articles, letters, editorials, and published lectures from 1966 to 2017, providing a 50-year review. Titles were excluded that gave no reference to genetics or that presented findings related to a nongenetic ocular condition. From a search of the Scopus database, 719 articles were ascertained. Of these, 115 were excluded because the title did not reference a genetic condition or have a focus on genetic factors; 4 were excluded because they described animal phenotypes (1966-1967); and 4 were excluded owing to having received no citations up to and including 2015. The highest number of citations was 283 times for a single article on familial aggregation in age-related macular degeneration. The Web of Science database yielded 771 articles; of these, 118 were excluded owing to not reporting human genetic studies; 55 received no citations. The highest number of citations was 307 for a single article, a 1991 paper on Leber hereditary optic neuropathy. The Journal's contributions to our understanding of the heritability of human ocular traits have been broad and deep, with international reach. The development of new techniques fostered new concepts and new approaches to rapidly expand the number of known single gene disorders with a defined molecular genetic cause. Reports on Mendelian and complex traits in the AJO abound, along with 6 Edward Jackson Memorial Lectures on retinal dystrophies, Leber congenital amaurosis, age-related macular degeneration, and glaucoma. Copyright © 2018 Elsevier Inc. All rights reserved.

Pantoea ananatis Genetic Diversity Analysis Reveals Limited Genomic Diversity as Well as Accessory Genes Correlated with Onion Pathogenicity

PubMed Central

Stice, Shaun P.; Stumpf, Spencer D.; Gitaitis, Ron D.; Kvitko, Brian H.; Dutta, Bhabesh

2018-01-01

Pantoea ananatis is a member of the family Enterobacteriaceae and an enigmatic plant pathogen with a broad host range. Although P. ananatis strains can be aggressive on onion causing foliar necrosis and onion center rot, previous genomic analysis has shown that P. ananatis lacks the primary virulence secretion systems associated with other plant pathogens. We assessed a collection of fifty P. ananatis strains collected from Georgia over three decades to determine genetic factors that correlated with onion pathogenic potential. Previous genetic analysis studies have compared strains isolated from different hosts with varying diseases potential and isolation sources. Strains varied greatly in their pathogenic potential and aggressiveness on different cultivated Allium species like onion, leek, shallot, and chive. Using multi-locus sequence analysis (MLSA) and repetitive extragenic palindrome repeat (rep)-PCR techniques, we did not observe any correlation between onion pathogenic potential and genetic diversity among strains. Whole genome sequencing and pan-genomic analysis of a sub-set of 10 strains aided in the identification of a novel series of genetic regions, likely plasmid borne, and correlating with onion pathogenicity observed on single contigs of the genetic assemblies. We named these loci Onion Virulence Regions (OVR) A-D. The OVR loci contain genes involved in redox regulation as well as pectate lyase and rhamnogalacturonase genes. Previous studies have not identified distinct genetic loci or plasmids correlating with onion foliar pathogenicity or pathogenicity on a single host pathosystem. The lack of focus on a single host system for this phytopathgenic disease necessitates the pan-genomic analysis performed in this study. PMID:29491851

Contribution of Genetic Background, Traditional Risk Factors, and HIV-Related Factors to Coronary Artery Disease Events in HIV-Positive Persons

PubMed Central

Rotger, Margalida; Glass, Tracy R.; Junier, Thomas; Lundgren, Jens; Neaton, James D.; Poloni, Estella S.; van 't Wout, Angélique B.; Lubomirov, Rubin; Colombo, Sara; Martinez, Raquel; Rauch, Andri; Günthard, Huldrych F.; Neuhaus, Jacqueline; Wentworth, Deborah; van Manen, Danielle; Gras, Luuk A.; Schuitemaker, Hanneke; Albini, Laura; Torti, Carlo; Jacobson, Lisa P.; Li, Xiuhong; Kingsley, Lawrence A.; Carli, Federica; Guaraldi, Giovanni; Ford, Emily S.; Sereti, Irini; Hadigan, Colleen; Martinez, Esteban; Arnedo, Mireia; Egaña-Gorroño, Lander; Gatell, Jose M.; Law, Matthew; Bendall, Courtney; Petoumenos, Kathy; Rockstroh, Jürgen; Wasmuth, Jan-Christian; Kabamba, Kabeya; Delforge, Marc; De Wit, Stephane; Berger, Florian; Mauss, Stefan; de Paz Sierra, Mariana; Losso, Marcelo; Belloso, Waldo H.; Leyes, Maria; Campins, Antoni; Mondi, Annalisa; De Luca, Andrea; Bernardino, Ignacio; Barriuso-Iglesias, Mónica; Torrecilla-Rodriguez, Ana; Gonzalez-Garcia, Juan; Arribas, José R.; Fanti, Iuri; Gel, Silvia; Puig, Jordi; Negredo, Eugenia; Gutierrez, Mar; Domingo, Pere; Fischer, Julia; Fätkenheuer, Gerd; Alonso-Villaverde, Carlos; Macken, Alan; Woo, James; McGinty, Tara; Mallon, Patrick; Mangili, Alexandra; Skinner, Sally; Wanke, Christine A.; Reiss, Peter; Weber, Rainer; Bucher, Heiner C.; Fellay, Jacques; Telenti, Amalio; Tarr, Philip E.

2013-01-01

Background Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection. Methods In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort. Results A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9×10−4). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05–2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06–1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16–1.96), diabetes (OR = 1.66; 95% CI, 1.10–2.49), ≥1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06–1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17–2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD. Conclusions In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD. PMID:23532479

Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors.

PubMed

Burgess, Stephen; Scott, Robert A; Timpson, Nicholas J; Davey Smith, George; Thompson, Simon G

2015-07-01

Finding individual-level data for adequately-powered Mendelian randomization analyses may be problematic. As publicly-available summarized data on genetic associations with disease outcomes from large consortia are becoming more abundant, use of published data is an attractive analysis strategy for obtaining precise estimates of the causal effects of risk factors on outcomes. We detail the necessary steps for conducting Mendelian randomization investigations using published data, and present novel statistical methods for combining data on the associations of multiple (correlated or uncorrelated) genetic variants with the risk factor and outcome into a single causal effect estimate. A two-sample analysis strategy may be employed, in which evidence on the gene-risk factor and gene-outcome associations are taken from different data sources. These approaches allow the efficient identification of risk factors that are suitable targets for clinical intervention from published data, although the ability to assess the assumptions necessary for causal inference is diminished. Methods and guidance are illustrated using the example of the causal effect of serum calcium levels on fasting glucose concentrations. The estimated causal effect of a 1 standard deviation (0.13 mmol/L) increase in calcium levels on fasting glucose (mM) using a single lead variant from the CASR gene region is 0.044 (95 % credible interval -0.002, 0.100). In contrast, using our method to account for the correlation between variants, the corresponding estimate using 17 genetic variants is 0.022 (95 % credible interval 0.009, 0.035), a more clearly positive causal effect.

Estimating the contribution of genetic variants to difference in incidence of disease between population groups.

PubMed

Moonesinghe, Ramal; Ioannidis, John P A; Flanders, W Dana; Yang, Quanhe; Truman, Benedict I; Khoury, Muin J

2012-08-01

Genome-wide association studies have identified multiple genetic susceptibility variants to several complex human diseases. However, risk-genotype frequency at loci showing robust associations might differ substantially among different populations. In this paper, we present methods to assess the contribution of genetic variants to the difference in the incidence of disease between different population groups for different scenarios. We derive expressions for the contribution of a single genetic variant, multiple genetic variants, and the contribution of the joint effect of a genetic variant and an environmental factor to the difference in the incidence of disease. The contribution of genetic variants to the difference in incidence increases with increasing difference in risk-genotype frequency, but declines with increasing difference in incidence between the two populations. The contribution of genetic variants also increases with increasing relative risk and the contribution of joint effect of genetic and environmental factors increases with increasing relative risk of the gene-environmental interaction. The contribution of genetic variants to the difference in incidence between two populations can be expressed as a function of the population attributable risks of the genetic variants in the two populations. The contribution of a group of genetic variants to the disparity in incidence of disease could change considerably by adding one more genetic variant to the group. Any estimate of genetic contribution to the disparity in incidence of disease between two populations at this stage seems to be an elusive goal.

Estimating the contribution of genetic variants to difference in incidence of disease between population groups

PubMed Central

Moonesinghe, Ramal; Ioannidis, John PA; Flanders, W Dana; Yang, Quanhe; Truman, Benedict I; Khoury, Muin J

2012-01-01

Genome-wide association studies have identified multiple genetic susceptibility variants to several complex human diseases. However, risk-genotype frequency at loci showing robust associations might differ substantially among different populations. In this paper, we present methods to assess the contribution of genetic variants to the difference in the incidence of disease between different population groups for different scenarios. We derive expressions for the contribution of a single genetic variant, multiple genetic variants, and the contribution of the joint effect of a genetic variant and an environmental factor to the difference in the incidence of disease. The contribution of genetic variants to the difference in incidence increases with increasing difference in risk-genotype frequency, but declines with increasing difference in incidence between the two populations. The contribution of genetic variants also increases with increasing relative risk and the contribution of joint effect of genetic and environmental factors increases with increasing relative risk of the gene–environmental interaction. The contribution of genetic variants to the difference in incidence between two populations can be expressed as a function of the population attributable risks of the genetic variants in the two populations. The contribution of a group of genetic variants to the disparity in incidence of disease could change considerably by adding one more genetic variant to the group. Any estimate of genetic contribution to the disparity in incidence of disease between two populations at this stage seems to be an elusive goal. PMID:22333905

A Mouse Model for Conditional Secretion of Specific Single-Chain Antibodies Provides Genetic Evidence for Regulation of Cortical Plasticity by a Non-cell Autonomous Homeoprotein Transcription Factor.

PubMed

Bernard, Clémence; Vincent, Clémentine; Testa, Damien; Bertini, Eva; Ribot, Jérôme; Di Nardo, Ariel A; Volovitch, Michel; Prochiantz, Alain

2016-05-01

During postnatal life the cerebral cortex passes through critical periods of plasticity allowing its physiological adaptation to the environment. In the visual cortex, critical period onset and closure are influenced by the non-cell autonomous activity of the Otx2 homeoprotein transcription factor, which regulates the maturation of parvalbumin-expressing inhibitory interneurons (PV cells). In adult mice, the maintenance of a non-plastic adult state requires continuous Otx2 import by PV cells. An important source of extra-cortical Otx2 is the choroid plexus, which secretes Otx2 into the cerebrospinal fluid. Otx2 secretion and internalization requires two small peptidic domains that are part of the DNA-binding domain. Thus, mutating these "transfer" sequences also modifies cell autonomous transcription, precluding this approach to obtain a cell autonomous-only mouse. Here, we develop a mouse model with inducible secretion of an anti-Otx2 single-chain antibody to trap Otx2 in the extracellular milieu. Postnatal secretion of this single-chain antibody by PV cells delays PV maturation and reduces plasticity gene expression. Induced adult expression of this single-chain antibody in cerebrospinal fluid decreases Otx2 internalization by PV cells, strongly induces plasticity gene expression and reopens physiological plasticity. We provide the first mammalian genetic evidence for a signaling mechanism involving intercellular transfer of a homeoprotein transcription factor. Our single-chain antibody mouse model is a valid strategy for extracellular neutralization that could be applied to other homeoproteins and signaling molecules within and beyond the nervous system.

A kernel machine method for detecting effects of interaction between multidimensional variable sets: an imaging genetics application.

PubMed

Ge, Tian; Nichols, Thomas E; Ghosh, Debashis; Mormino, Elizabeth C; Smoller, Jordan W; Sabuncu, Mert R

2015-04-01

Measurements derived from neuroimaging data can serve as markers of disease and/or healthy development, are largely heritable, and have been increasingly utilized as (intermediate) phenotypes in genetic association studies. To date, imaging genetic studies have mostly focused on discovering isolated genetic effects, typically ignoring potential interactions with non-genetic variables such as disease risk factors, environmental exposures, and epigenetic markers. However, identifying significant interaction effects is critical for revealing the true relationship between genetic and phenotypic variables, and shedding light on disease mechanisms. In this paper, we present a general kernel machine based method for detecting effects of the interaction between multidimensional variable sets. This method can model the joint and epistatic effect of a collection of single nucleotide polymorphisms (SNPs), accommodate multiple factors that potentially moderate genetic influences, and test for nonlinear interactions between sets of variables in a flexible framework. As a demonstration of application, we applied the method to the data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to detect the effects of the interactions between candidate Alzheimer's disease (AD) risk genes and a collection of cardiovascular disease (CVD) risk factors, on hippocampal volume measurements derived from structural brain magnetic resonance imaging (MRI) scans. Our method identified that two genes, CR1 and EPHA1, demonstrate significant interactions with CVD risk factors on hippocampal volume, suggesting that CR1 and EPHA1 may play a role in influencing AD-related neurodegeneration in the presence of CVD risks. Copyright © 2015 Elsevier Inc. All rights reserved.

Musculoskeletal complaints, anxiety-depression symptoms, and neuroticism: A study of middle-aged twins.

PubMed

Vassend, Olav; Røysamb, Espen; Nielsen, Christopher Sivert; Czajkowski, Nikolai Olavi

2017-08-01

Musculoskeletal (MS) complaints are reported commonly, but the extent to which such complaints reflect the severity of site-specific pathology or a more generalized susceptibility to feel pain/discomfort is uncertain. Both site-specific and more widespread MS conditions have been shown to be linked to anxiety and depression, but the nature of this relationship is poorly understood. In the present study the role of neuroticism as a shared risk factor that may possibly explain the co-occurrence between anxiety-depression and MS complaints was investigated. The sample consisted of 746 monozygotic and 770 dizygotic twins in the age group of 50-65 years (M = 57.11, SD = 4.5). Using Cholesky modeling, genetic and environmental influences on neuroticism, anxiety-depression and MS symptoms, and the associations among these phenotypes were determined. A single factor accounted for about 50% of the overall variance in MS symptom reporting. The best-fitting biometric model included sex-specific additive genetic and individual-specific environmental effects. All 3 phenotypes were strongly influenced by genetic factors, heritability (h2) = 0.41-0.56. Furthermore, while there was a considerable overlap in genetic risk factors among the 3 phenotypes, a substantial proportion of the genetic risk shared between MS complaints and anxiety-depression was independent of neuroticism. Evidence for a common underlying susceptibility to report MS symptoms, genetically linked to both neuroticism and anxiety-depression symptoms, was found. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Genetics of Oxidative Stress in Obesity

PubMed Central

Rupérez, Azahara I.; Gil, Angel; Aguilera, Concepción M.

2014-01-01

Obesity is a multifactorial disease characterized by the excessive accumulation of fat in adipose tissue and peripheral organs. Its derived metabolic complications are mediated by the associated oxidative stress, inflammation and hypoxia. Oxidative stress is due to the excessive production of reactive oxygen species or diminished antioxidant defenses. Genetic variants, such as single nucleotide polymorphisms in antioxidant defense system genes, could alter the efficacy of these enzymes and, ultimately, the risk of obesity; thus, studies investigating the role of genetic variations in genes related to oxidative stress could be useful for better understanding the etiology of obesity and its metabolic complications. The lack of existing literature reviews in this field encouraged us to gather the findings from studies focusing on the impact of single nucleotide polymorphisms in antioxidant enzymes, oxidative stress-producing systems and transcription factor genes concerning their association with obesity risk and its phenotypes. In the future, the characterization of these single nucleotide polymorphisms (SNPs) in obese patients could contribute to the development of controlled antioxidant therapies potentially beneficial for the treatment of obesity-derived metabolic complications. PMID:24562334

Genetics of oxidative stress in obesity.

PubMed

Rupérez, Azahara I; Gil, Angel; Aguilera, Concepción M

2014-02-20

Obesity is a multifactorial disease characterized by the excessive accumulation of fat in adipose tissue and peripheral organs. Its derived metabolic complications are mediated by the associated oxidative stress, inflammation and hypoxia. Oxidative stress is due to the excessive production of reactive oxygen species or diminished antioxidant defenses. Genetic variants, such as single nucleotide polymorphisms in antioxidant defense system genes, could alter the efficacy of these enzymes and, ultimately, the risk of obesity; thus, studies investigating the role of genetic variations in genes related to oxidative stress could be useful for better understanding the etiology of obesity and its metabolic complications. The lack of existing literature reviews in this field encouraged us to gather the findings from studies focusing on the impact of single nucleotide polymorphisms in antioxidant enzymes, oxidative stress-producing systems and transcription factor genes concerning their association with obesity risk and its phenotypes. In the future, the characterization of these single nucleotide polymorphisms (SNPs) in obese patients could contribute to the development of controlled antioxidant therapies potentially beneficial for the treatment of obesity-derived metabolic complications.

Epigenetics in Developmental Disorder: ADHD and Endophenotypes

PubMed Central

Archer, Trevor; Oscar-Berman, Marlene; Blum, Kenneth

2011-01-01

Heterogeneity in attention-deficit/hyperactivity disorder (ADHD), with complex interactive operations of genetic and environmental factors, is expressed in a variety of disorder manifestations: severity, co-morbidities of symptoms, and the effects of genes on phenotypes. Neurodevelopmental influences of genomic imprinting have set the stage for the structural-physiological variations that modulate the cognitive, affective, and pathophysiological domains of ADHD. The relative contributions of genetic and environmental factors provide rapidly proliferating insights into the developmental trajectory of the condition, both structurally and functionally. Parent-of-origin effects seem to support the notion that genetic risks for disease process debut often interact with the social environment, i.e., the parental environment in infants and young children. The notion of endophenotypes, markers of an underlying liability to the disorder, may facilitate detection of genetic risks relative to a complex clinical disorder. Simple genetic association has proven insufficient to explain the spectrum of ADHD. At a primary level of analysis, the consideration of epigenetic regulation of brain signalling mechanisms, dopamine, serotonin, and noradrenaline is examined. Neurotrophic factors that participate in the neurogenesis, survival, and functional maintenance of brain systems, are involved in neuroplasticity alterations underlying brain disorders, and are implicated in the genetic predisposition to ADHD, but not obviously, nor in a simple or straightforward fashion. In the context of intervention, genetic linkage studies of ADHD pharmacological intervention have demonstrated that associations have fitted the “drug response phenotype,” rather than the disorder diagnosis. Despite conflicting evidence for the existence, or not, of genetic associations between disorder diagnosis and genes regulating the structure and function of neurotransmitters and brain-derived neurotrophic factor (BDNF), associations between symptoms-profiles endophenotypes and single nucleotide polymorphisms appear reassuring. PMID:22224195

Genetic Forms of Epilepsies and other Paroxysmal Disorders

PubMed Central

Olson, Heather E.; Poduri, Annapurna; Pearl, Phillip L.

2016-01-01

Genetic mechanisms explain the pathophysiology of many forms of epilepsy and other paroxysmal disorders such as alternating hemiplegia of childhood, familial hemiplegic migraine, and paroxysmal dyskinesias. Epilepsy is a key feature of well-defined genetic syndromes including Tuberous Sclerosis Complex, Rett syndrome, Angelman syndrome, and others. There is an increasing number of singe gene causes or susceptibility factors associated with several epilepsy syndromes, including the early onset epileptic encephalopathies, benign neonatal/infantile seizures, progressive myoclonus epilepsies, genetic generalized and benign focal epilepsies, epileptic aphasias, and familial focal epilepsies. Molecular mechanisms are diverse, and a single gene can be associated with a broad range of phenotypes. Additional features, such as dysmorphisms, head size, movement disorders, and family history may provide clues to a genetic diagnosis. Genetic testing can impact medical care and counseling. We discuss genetic mechanisms of epilepsy and other paroxysmal disorders, tools and indications for genetic testing, known genotype-phenotype associations, the importance of genetic counseling, and a look towards the future of epilepsy genetics. PMID:25192505

Occupational and genetic risk factors associated with intervertebral disc disease.

PubMed

Virtanen, Iita M; Karppinen, Jaro; Taimela, Simo; Ott, Jürg; Barral, Sandra; Kaikkonen, Kaisu; Heikkilä, Olli; Mutanen, Pertti; Noponen, Noora; Männikkö, Minna; Tervonen, Osmo; Natri, Antero; Ala-Kokko, Leena

2007-05-01

Cross-sectional epidemiologic study. To evaluate the interaction between known genetic risk factors and whole-body vibration for symptomatic intervertebral disc disease (IDD) in an occupational sample. Risk factors of IDD include, among others, whole-body vibration and heredity. In this study, the importance of a set of known genetic risk factors and whole-body vibration was evaluated in an occupational sample of train engineers and sedentary controls. Eleven variations in 8 genes (COL9A2, COL9A3, COL11A2, IL1A, IL1B, IL6, MMP-3, and VDR) were genotyped in 150 male train engineers with an average of 21-year exposure to whole-body vibration and 61 male paper mill workers with no exposure to vibration. Subjects were classified into IDD-phenotype and asymptomatic groups, based on the latent class analysis. The number of individuals belonging to the IDD-phenotype was significantly higher among train engineers (42% of train engineers vs. 17.5% of sedentary workers; P = 0.005). IL1A -889T allele represented a significant risk factor for the IDD-phenotype both in the single marker allelic association test (P = 0.043) and in the logistic regression analysis (P = 0.01). None of the other allele markers was significantly associated with symptoms when analyzed independently. However, for all the SNP markers considered, whole-body vibration represents a nominally significant risk factor. The results suggest that whole-body vibration is a risk factor for symptomatic IDD. Moreover, whole-body vibration had an additive effect with genetic risk factors increasing the likelihood of belonging to the IDD-phenotype group. Of the independent genetic markers, IL1A -889T allele had strongest association with IDD-phenotype.

A comprehensive screen for SNP associations on chromosome region 5q31-33 in Swedish/Norwegian celiac disease families.

PubMed

Amundsen, Silja Svanstrøm; Adamovic, Svetlana; Hellqvist, Asa; Nilsson, Staffan; Gudjónsdóttir, Audur H; Ascher, Henry; Ek, Johan; Larsson, Kristina; Wahlström, Jan; Lie, Benedicte A; Sollid, Ludvig M; Naluai, Asa Torinsson

2007-09-01

Celiac disease (CD) is a gluten-induced enteropathy, which results from the interplay between environmental and genetic factors. There is a strong human leukocyte antigen (HLA) association with the disease, and HLA-DQ alleles represent a major genetic risk factor. In addition to HLA-DQ, non-HLA genes appear to be crucial for CD development. Chromosomal region 5q31-33 has demonstrated linkage with CD in several genome-wide studies, including in our Swedish/Norwegian cohort. In a European meta-analysis 5q31-33 was the only region that reached a genome-wide level of significance except for the HLA region. To identify the genetic variant(s) responsible for this linkage signal, we performed a comprehensive single nucleotide polymorphism (SNP) association screen in 97 Swedish/Norwegian multiplex families who demonstrate linkage to the region. We selected tag SNPs from a 16 Mb region representing the 95% confidence interval of the linkage peak. A total of 1,404 SNPs were used for the association analysis. We identified several regions with SNPs demonstrating moderate single- or multipoint associations. However, the isolated association signals appeared insufficient to account for the linkage signal seen in our cohort. Collective effects of multiple risk genes within the region, incomplete genetic coverage or effects related to copy number variation are possible explanations for our findings.

Race, Genetic Ancestry and Response to Antidepressant Treatment for Major Depression

PubMed Central

Murphy, Eleanor; Hou, Liping; Maher, Brion S; Woldehawariat, Girma; Kassem, Layla; Akula, Nirmala; Laje, Gonzalo; McMahon, Francis J

2013-01-01

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study revealed poorer antidepressant treatment response among black compared with white participants. This racial disparity persisted even after socioeconomic and baseline clinical factors were taken into account. Some studies have suggested genetic contributions to this disparity, but none have attempted to disentangle race and genetic ancestry. Here we used genome-wide single-nucleotide polymorphism (SNP) data to examine independent contributions of race and genetic ancestry to citalopram response. Secondary data analyses included 1877 STAR*D participants who completed an average of 10 weeks of citalopram treatment and provided DNA samples. Participants reported their race as White (n=1464), black (n=299) or other/mixed (n=114). Genetic ancestry was estimated by multidimensional scaling (MDS) analyses of about 500 000 SNPs. Ancestry proportions were estimated by STRUCTURE. Structural equation modeling was used to examine the direct and indirect effects of observed and latent predictors of response, defined as change in the Quick Inventory of Depressive Symptomatology (QIDS) score from baseline to exit. Socioeconomic and baseline clinical factors, race, and anxiety significantly predicted response, as previously reported. However, direct effects of race disappeared in all models that included genetic ancestry. Genetic African ancestry predicted lower treatment response in all models. Although socioeconomic and baseline clinical factors drive racial differences in antidepressant response, genetic ancestry, rather than self-reported race, explains a significant fraction of the residual differences. Larger samples would be needed to identify the specific genetic mechanisms that may be involved, but these findings underscore the importance of including more African-American patients in drug trials. PMID:23827886

Interaction between Social/Psychosocial Factors and Genetic Variants on Body Mass Index: A Gene-Environment Interaction Analysis in a Longitudinal Setting.

PubMed

Zhao, Wei; Ware, Erin B; He, Zihuai; Kardia, Sharon L R; Faul, Jessica D; Smith, Jennifer A

2017-09-29

Obesity, which develops over time, is one of the leading causes of chronic diseases such as cardiovascular disease. However, hundreds of BMI (body mass index)-associated genetic loci identified through large-scale genome-wide association studies (GWAS) only explain about 2.7% of BMI variation. Most common human traits are believed to be influenced by both genetic and environmental factors. Past studies suggest a variety of environmental features that are associated with obesity, including socioeconomic status and psychosocial factors. This study combines both gene/regions and environmental factors to explore whether social/psychosocial factors (childhood and adult socioeconomic status, social support, anger, chronic burden, stressful life events, and depressive symptoms) modify the effect of sets of genetic variants on BMI in European American and African American participants in the Health and Retirement Study (HRS). In order to incorporate longitudinal phenotype data collected in the HRS and investigate entire sets of single nucleotide polymorphisms (SNPs) within gene/region simultaneously, we applied a novel set-based test for gene-environment interaction in longitudinal studies (LGEWIS). Childhood socioeconomic status (parental education) was found to modify the genetic effect in the gene/region around SNP rs9540493 on BMI in European Americans in the HRS. The most significant SNP (rs9540488) by childhood socioeconomic status interaction within the rs9540493 gene/region was suggestively replicated in the Multi-Ethnic Study of Atherosclerosis (MESA) ( p = 0.07).

Interaction between Social/Psychosocial Factors and Genetic Variants on Body Mass Index: A Gene-Environment Interaction Analysis in a Longitudinal Setting

PubMed Central

Zhao, Wei; He, Zihuai; Kardia, Sharon L. R.; Faul, Jessica D.

2017-01-01

Obesity, which develops over time, is one of the leading causes of chronic diseases such as cardiovascular disease. However, hundreds of BMI (body mass index)-associated genetic loci identified through large-scale genome-wide association studies (GWAS) only explain about 2.7% of BMI variation. Most common human traits are believed to be influenced by both genetic and environmental factors. Past studies suggest a variety of environmental features that are associated with obesity, including socioeconomic status and psychosocial factors. This study combines both gene/regions and environmental factors to explore whether social/psychosocial factors (childhood and adult socioeconomic status, social support, anger, chronic burden, stressful life events, and depressive symptoms) modify the effect of sets of genetic variants on BMI in European American and African American participants in the Health and Retirement Study (HRS). In order to incorporate longitudinal phenotype data collected in the HRS and investigate entire sets of single nucleotide polymorphisms (SNPs) within gene/region simultaneously, we applied a novel set-based test for gene-environment interaction in longitudinal studies (LGEWIS). Childhood socioeconomic status (parental education) was found to modify the genetic effect in the gene/region around SNP rs9540493 on BMI in European Americans in the HRS. The most significant SNP (rs9540488) by childhood socioeconomic status interaction within the rs9540493 gene/region was suggestively replicated in the Multi-Ethnic Study of Atherosclerosis (MESA) (p = 0.07). PMID:28961216

Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes.

PubMed

Miller, F W; Chen, W; O'Hanlon, T P; Cooper, R G; Vencovsky, J; Rider, L G; Danko, K; Wedderburn, L R; Lundberg, I E; Pachman, L M; Reed, A M; Ytterberg, S R; Padyukov, L; Selva-O'Callaghan, A; Radstake, T R; Isenberg, D A; Chinoy, H; Ollier, W E R; Scheet, P; Peng, B; Lee, A; Byun, J; Lamb, J A; Gregersen, P K; Amos, C I

2015-10-01

Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5×10(-8)) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.

Genome-wide Association Study Identifies HLA 8.1 Ancestral Haplotype Alleles as Major Genetic Risk Factors for Myositis Phenotypes

PubMed Central

Miller, Frederick W.; Chen, Wei; O’Hanlon, Terrance P.; Cooper, Robert G.; Vencovsky, Jiri; Rider, Lisa G.; Danko, Katalin; Wedderburn, Lucy R.; Lundberg, Ingrid E.; Pachman, Lauren M.; Reed, Ann M.; Ytterberg, Steven R.; Padyukov, Leonid; Selva-O’Callaghan, Albert; Radstake, Timothy R.; Isenberg, David A.; Chinoy, Hector; Ollier, William E.R.; Scheet, Paul; Peng, Bo; Lee, Annette; Byun, Jinyoung; Lamb, Janine A.; Gregersen, Peter K.; Amos, Christopher I.

2016-01-01

Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis; 473 juvenile dermatomyositis; 532 polymyositis; and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P < 5 × 10−8) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1haplotype comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations. PMID:26291516

An Autosomal Factor from Drosophila Arizonae Restores Normal Spermatogenesis in Drosophila Mojavensis Males Carrying the D. Arizonae Y Chromosome

PubMed Central

Pantazidis, A. C.; Galanopoulos, V. K.; Zouros, E.

1993-01-01

Males of Drosophila mojavensis whose Y chromosome is replaced by the Y chromosome of the sibling species Drosophila arizonae are sterile. It is shown that genetic material from the fourth chromosome of D. arizonae is necessary and sufficient, in single dose, to restore fertility in these males. In introgression and mapping experiments this material segregates as a single Mendelian factor (sperm motility factor, SMF). Light and electron microscopy studies of spermatogenesis in D. mojavensis males whose Y chromosome is replaced by introgression with the Y chromosome of D. arizonae (these males are symbolized as mojY(a)) revealed postmeiotic abnormalities all of which are restored when the SMF of D. arizonae is co-introgressed (these males are symbolized as mojY(a)SMF(a)). The number of mature sperm per bundle in mojY(a)SMF(a) is slightly less than in pure D. mojavensis and is even smaller in males whose fertility is rescued by introgression of the entire fourth chromosome of D. arizonae. These observations establish an interspecific incompatibility between the Y chromosome and an autosomal factor (or more than one tightly linked factors) that can be useful for the study of the evolution of male hybrid sterility in Drosophila and the genetic control of spermatogenesis. PMID:8514139

Molecular Analysis of Single Tumor Glands Using the Crypt Isolation Method in Endometrial Carcinomas.

PubMed

Nagasawa, Takayuki; Sugai, Tamotsu; Shoji, Tadahiro; Habano, Wataru; Sugiyama, Toru

2016-11-01

Endometrial adenocarcinomas are characterized by the presence of many single tumor glands in which multiple genetic changes have accumulated. To elucidate the differences in molecular abnormalities among single tumor glands, individual tumor glands were analyzed and microsatellite alterations (loss of heterozygosity (LOH) and microsatellite instability [MSI]) were examined using the crypt isolation method in glands from each tumor from patients with endometrial carcinoma. Twenty-five patients with endometrial adenocarcinoma who underwent surgery were included in this study. We obtained cancerous individual isolated tumor glands from each patient using the crypt isolation method. For LOH and MSI analyses, we used 15 microsatellite markers (3p, 5q, 10q, 13q, 17p, 18q, BAT25, and BAT26) and the promoter regions of 6 genes (transforming growth factor beta receptor II, BAX, insulin-like growth factor II receptor, E2F4, MutS homolog 3, and MSH6). Loss of heterozygosity was detected in 8 (32%) of 25 patients, and MSI was detected in 9 (36%) of 25 patients. Some MSI-positive carcinomas had LOH in single tumor gland samples, and the coexistence of LOH and MSI was confirmed. In 16 (64%) of 25 cases, intratumoral genetic heterogeneity among single tumor gland samples was detected. By analyzing multiple single tumor glands within the same tumor, we found that endometrial adenocarcinoma was composed of various tumor glands with different molecular abnormalities, even in a limited region within the same tumor.

Familial aggregation and linkage analysis with covariates for metabolic syndrome risk factors.

PubMed

Naseri, Parisa; Khodakarim, Soheila; Guity, Kamran; Daneshpour, Maryam S

2018-06-15

Mechanisms of metabolic syndrome (MetS) causation are complex, genetic and environmental factors are important factors for the pathogenesis of MetS In this study, we aimed to evaluate familial and genetic influences on metabolic syndrome risk factor and also assess association between FTO (rs1558902 and rs7202116) and CETP(rs1864163) genes' single nucleotide polymorphisms (SNP) with low HDL_C in the Tehran Lipid and Glucose Study (TLGS). The design was a cross-sectional study of 1776 members of 227 randomly-ascertained families. Selected families contained at least one affected metabolic syndrome and at least two members of the family had suffered a loss of HDL_C according to ATP III criteria. In this study, after confirming the familial aggregation with intra-trait correlation coefficients (ICC) of Metabolic syndrome (MetS) and the quantitative lipid traits, the genetic linkage analysis of HDL_C was performed using conditional logistic method with adjusted sex and age. The results of the aggregation analysis revealed a higher correlation between siblings than between parent-offspring pairs representing the role of genetic factors in MetS. In addition, the conditional logistic model with covariates showed that the linkage results between HDL_C and three marker, rs1558902, rs7202116 and rs1864163 were significant. In summary, a high risk of MetS was found in siblings confirming the genetic influences of metabolic syndrome risk factor. Moreover, the power to detect linkage increases in the one parameter conditional logistic model regarding the use of age and sex as covariates. Copyright © 2018. Published by Elsevier B.V.

A physico-genetic module for the polarisation of auxin efflux carriers PIN-FORMED (PIN)

NASA Astrophysics Data System (ADS)

Hernández-Hernández, Valeria; Barrio, Rafael A.; Benítez, Mariana; Nakayama, Naomi; Romero-Arias, José Roberto; Villarreal, Carlos

2018-05-01

Intracellular polarisation of auxin efflux carriers is crucial for understanding how auxin gradients form in plants. The polarisation dynamics of auxin efflux carriers PIN-FORMED (PIN) depends on both biomechanical forces as well as chemical, molecular and genetic factors. Biomechanical forces have shown to affect the localisation of PIN transporters to the plasma membrane. We propose a physico-genetic module of PIN polarisation that integrates biomechanical, molecular, and cellular processes as well as their non-linear interactions. The module was implemented as a discrete Boolean model and then approximated to a continuous dynamic system, in order to explore the relative contribution of the factors mediating PIN polarisation at the scale of single cell. Our models recovered qualitative behaviours that have been experimentally observed and enable us to predict that, in the context of PIN polarisation, the effects of the mechanical forces can predominate over the activity of molecular factors such as the GTPase ROP6 and the ROP-INTERACTIVE CRIB MOTIF-CONTAINING PROTEIN RIC1.

Lack of genetic linkage evidence for a trans-acting factor having a large effect on plasma lipoprotein[a] levels in African Americans.

PubMed

Barkley, Ruth Ann; Brown, Andrew C; Hanis, Craig L; Kardia, Sharon L; Turner, Stephen T; Boerwinkle, Eric

2003-07-01

The distribution of plasma lipoprotein[a] (Lp[a]) concentrations, a risk factor for cardiovascular disease, varies greatly among racial groups, with African Americans having values that are shifted toward higher levels than those of whites. The underlying cause of this heterogeneity is unknown, but a role for "trans-acting" factors has been hypothesized. This study used genetic linkage analysis to localize genetic factors influencing Lp[a] levels in African Americans that were absent in other populations; linkage results were analyzed separately in non-Hispanic whites, Hispanic whites, and African Americans. As expected, all three samples showed highly significant linkage at the approximate location of the lysophosphatidic acid locus. The white populations also independently had regions of significant linkage on chromosome 19 (LOD 3.80) and suggestive linkage on chromosomes 12 (LOD 1.60), 14 (LOD 2.56), and 19 (LOD 2.52). No linkage evidence was found to support the hypothesis of another single gene with large effects specifically segregating in African Americans that may account for their elevated Lp[a] levels.

A systematic review of the factors associated with interest in predictive genetic testing for obesity, type II diabetes and heart disease.

PubMed

Collins, J; Ryan, L; Truby, H

2014-10-01

In the future, it may be possible for individuals to take a genetic test to determine their genetic predisposition towards developing lifestyle-related chronic diseases. A systematic review of the literature was undertaken to identify the factors associated with an interest in having predictive genetic testing for obesity, type II diabetes and heart disease amongst unaffected adults. Ovid Medline, PsycINFO and EMBASE online databases were searched using predefined search terms. Publications meeting the inclusion criteria (English language, free-living adult population not selected as a result of their disease diagnosis, reporting interest as an outcome, not related to a single gene inherited disease) were assessed for quality and content. Narrative synthesis of the results was undertaken. From the 2329 publications retrieved, eight studies met the inclusion criteria and were included in the review. Overall, the evidence base was small but of positive quality. Interest was associated with personal attitudes towards disease risk and the provision of information about genetic testing, shaped by perceived risk of disease and expected outcomes of testing. The role of demographic factors was investigated with largely inconclusive findings. Interest in predictive genetic testing for obesity, type II diabetes or heart disease was greatest amongst those who perceived the risk of disease to be high and/or the outcomes of testing to be beneficial. © 2013 The British Dietetic Association Ltd.

Genetic dissection of milk yield traits and mastitis resistance quantitative trait loci on chromosome 20 in dairy cattle.

PubMed

Kadri, Naveen K; Guldbrandtsen, Bernt; Lund, Mogens S; Sahana, Goutam

2015-12-01

Intense selection to increase milk yield has had negative consequences for mastitis incidence in dairy cattle. Due to low heritability of mastitis resistance and an unfavorable genetic correlation with milk yield, a reduction in mastitis through traditional breeding has been difficult to achieve. Here, we examined quantitative trait loci (QTL) that segregate for clinical mastitis and milk yield on Bos taurus autosome 20 (BTA20) to determine whether both traits are affected by a single polymorphism (pleiotropy) or by multiple closely linked polymorphisms. In the latter but not the former situation, undesirable genetic correlation could potentially be broken by selecting animals that have favorable variants for both traits. First, we performed a within-breed association study using a haplotype-based method in Danish Holstein cattle (HOL). Next, we analyzed Nordic Red dairy cattle (RDC) and Danish Jersey cattle (JER) with the goal of determining whether these QTL identified in Holsteins were segregating across breeds. Genotypes for 12,566 animals (5,966 HOL, 5,458 RDC, and 1,142 JER) were determined by using the Illumina Bovine SNP50 BeadChip (50K; Illumina, San Diego, CA), which identifies 1,568 single nucleotide polymorphisms on BTA20. Data were combined, phased, and clustered into haplotype states, followed by within- and across-breed haplotype-based association analyses using a linear mixed model. Association signals for both clinical mastitis and milk yield peaked in the 26- to 40-Mb region on BTA20 in HOL. Single-variant association analyses were carried out in the QTL region using whole sequence level variants imputed from references of 2,036 HD genotypes (BovineHD BeadChip; Illumina) and 242 whole-genome sequences. The milk QTL were also segregating in RDC and JER on the BTA20-targeted region; however, an indication of differences in the causal factor(s) was observed across breeds. A previously reported F279Y mutation (rs385640152) within the growth hormone receptor gene showed strong association with milk, fat, and protein yields. In HOL, the highest peaks for milk yield and susceptibility to mastitis were separated by over 3.5 Mb (3.8 Mb by haplotype analysis, 3.6 Mb by single nucleotide polymorphism analysis), suggesting separate genetic variants for the traits. Further analysis yielded 2 candidate mutations for the mastitis QTL, at 33,642,072 bp (rs378947583) in an intronic region of the caspase recruitment domain protein 6 gene and 35,969,994 bp (rs133596506) in an intronic region of the leukemia-inhibitory factor receptor gene. These findings suggest that it may be possible to separate these beneficial and detrimental genetic factors through targeted selective breeding. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Peptidic tools applied to redirect alternative splicing events.

PubMed

Nancy, Martínez-Montiel; Nora, Rosas-Murrieta; Rebeca, Martínez-Contreras

2015-05-01

Peptides are versatile and attractive biomolecules that can be applied to modulate genetic mechanisms like alternative splicing. In this process, a single transcript yields different mature RNAs leading to the production of protein isoforms with diverse or even antagonistic functions. During splicing events, errors can be caused either by mutations present in the genome or by defects or imbalances in regulatory protein factors. In any case, defects in alternative splicing have been related to several genetic diseases including muscular dystrophy, Alzheimer's disease and cancer from almost every origin. One of the most effective approaches to redirect alternative splicing events has been to attach cell-penetrating peptides to oligonucleotides that can modulate a single splicing event and restore correct gene expression. Here, we summarize how natural existing and bioengineered peptides have been applied over the last few years to regulate alternative splicing and genetic expression. Under different genetic and cellular backgrounds, peptides have been shown to function as potent vehicles for splice correction, and their therapeutic benefits have reached clinical trials and patenting stages, emphasizing the use of regulatory peptides as an exciting therapeutic tool for the treatment of different genetic diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

Potential Genetic Risk Factors for Chronic TMD: Genetic Associations from the OPPERA Case Control Study

PubMed Central

Smith, Shad B.; Maixner, Dylan; Greenspan, Joel; Dubner, Ron; Fillingim, Roger; Ohrbach, Richard; Knott, Charles; Slade, Gary; Bair, Eric; Gibson, Dustin G.; Zaykin, Dmitri V.; Weir, Bruce; Maixner, William; Diatchenko, Luda

2011-01-01

Genetic factors play a role in the etiology of persistent pain conditions, putatively by modulating underlying processes such as nociceptive sensitivity, psychological well-being, inflammation, and autonomic response. However, to date, only a few genes have been associated with temporomandibular disorders (TMD). This study evaluated 358 genes involved in pain processes, comparing allelic frequencies between 166 cases with chronic TMD and 1442 controls enrolled in the OPPERA (Orofacial Pain: Prospective Evaluation and Risk Assessment) study cooperative agreement. To enhance statistical power, 182 TMD cases and 170 controls from a similar study were included in the analysis. Genotyping was performed using the Pain Research Panel, an Affymetrix gene chip representing 3295 single nucleotide polymorphisms, including ancestry-informative markers that were used to adjust for population stratification. Adjusted associations between genetic markers and TMD case status were evaluated using logistic regression. The OPPERA findings provided evidence supporting previously-reported associations between TMD and two genes: HTR2A and COMT. Other genes were revealed as potential new genetic risk factors for TMD, including NR3C1, CAMK4, CHRM2, IFRD1, and GRK5. While these findings need to be replicated in independent cohorts, the genes potentially represent important markers of risk for TMD and they identify potential targets for therapeutic intervention. PMID:22074755

[Genetic factors in myocardial infarction].

PubMed

Hara, Masahiko; Sakata, Yasuhiko; Sato, Hiroshi

2013-02-01

One of the main mechanisms of acute myocardial infarction (AMI) is plaque rupture or erosion followed by intraluminal thrombus formation and occlusion of the coronary arteries. Thus far, many underlying conditions or environmental factors, such as hypertension, diabetes, dyslipidemia, smoking or obesity, as well as a family history of coronary artery diseases have been identified as risks for the onset of AMI. These risks suggest that AMI occurs due to interactions between underlying conditions and multiple genetic susceptibilities. For this reason, many target gene-disease association studies have been performed with the recent introduction of genome-wide association studies (GWAS) that have further revealed new genetic susceptibilities for AMI. GWAS is a way to examine many common genetic variants in different individuals to see if any variant is associated with a trait in a case-control fashion, and typically focuses on associations between single-nucleotide polymorphisms (SNP) and traits. SNP on chromosome 9p21 is one of the robust susceptibility variants for AMI which has been identified by many GWAS. In this review, we overview the methodology of GWAS, introduce genetic variants identified by GWAS as those with susceptibility for AMI, and describe the foresight of using GWAS to investigate genetic susceptibility to AMI.

Genetic control of disease resistance and immunoresponsiveness.

PubMed

Kelm, S C; Freeman, A E; Kehrli, M E

2001-11-01

A great deal of evidence points to substantial genetic control over at least some of the immune responses, although genetic parameters for clinical disease have been less favorable. The past two decades have illustrated that single genes with a large impact on food animal health do exist and can be used to improve the health of domestic populations. The current focus on molecular genetics within food animal species will likely unveil numerous other examples of single genes with large effects, although the use of animals possessing favorable genotypes for disease resistance may represent a compromise in selection for increased production of raw product. Moreover, it is also clear that genetic control over the immune system is not limited to a few genes but is more likely influenced by many genes, each with small effects. The use of this information in animal improvement programs is not straightforward because of factors complicating the identification of superior individuals within the population. The scarcity of information dealing with phenotypic and genetic relationships between measures of disease resistance and aspects of immune response complicates the situation even further. Despite these potential hurdles, the potential for permanent improvement of disease resistance within food animal species in the future is tantalizing and merits intensified future study.

Estrogen Receptor 1 ( ESR1) Gene Polymorphisms and Obesity Phenotypes in a Population of Young Adults.

PubMed

Correa-Rodríguez, María; Schmidt-RioValle, Jacqueline; González-Jiménez, Emilio; Rueda-Medina, Blanca

2017-06-01

Obesity is considered an increasingly serious health problem determined by multiple genetic and environmental factors. Estrogens have been found to play a major role in body weight and adiposity regulation through estrogen receptor 1 ( ESR1). The aim of this study was to determine whether genotype and haplotype frequencies of ESR1 polymorphisms are associated with body composition measures in a population of 572 young adults. A lack of significant association between genotypes of ESR1 gene polymorphisms and obesity phenotypes was seen after adjustment for confounding factors. Linkage disequilibrium (LD) analysis identified a single LD block for the ESR1 gene including PvuII and XbaI single-nucleotide polymorphisms (SNPs) (pairwise r 2 = .66). None of the haplotypes identified revealed statistically significant associations with any of the obesity phenotypes. Our results suggest that polymorphisms of the ESR1 gene do not contribute significantly to the genetic risk for obesity phenotypes in a population of young Caucasian adults.

Association of the rs7903146 single nucleotide polymorphism at the Transcription Factor 7-like 2 (TCF7L2) locus with type 2 diabetes in Brazilian subjects.

PubMed

Barra, Gustavo Barcelos; Dutra, Ludmila Alves Sanches; Watanabe, Sílvia Conde; Costa, Patrícia Godoy Garcia; Cruz, Patrícia Sales Marques da; Azevedo, Monalisa Ferreira; Amato, Angélica Amorim

2012-11-01

To investigate the association of the T allele of the single nucleotide polymorphism (SNP) rs7903146 of TCF7L2 with the occurrence of T2D in a sample of subjects followed up at the Brasilia University Hospital. The SNP rs7903146 of TCF7L2 was genotyped by allele-specific PCR in 113 patients with known T2D and in 139 non-diabetic controls in Brasilia, Brazil. We found that the T allele of the SNP rs7903146 of TCF7L2 was significantly associated with T2D risk (odds ratio of 3.92 for genotype TT in the recessive genetic model, p = 0.004 and 1.5 for T allele, p = 0.032). These results reinforce previous findings on the consistent association of this genetic factor and the risk of T2D in populations of diverse ethnic backgrounds.

New insights into the genetics of glioblastoma multiforme by familial exome sequencing

PubMed Central

Backes, Christina; Harz, Christian; Fischer, Ulrike; Schmitt, Jana; Ludwig, Nicole; Petersen, Britt-Sabina; Mueller, Sabine C.; Kim, Yoo-Jin; Wolf, Nadine M.; Katus, Hugo A.; Meder, Benjamin; Furtwängler, Rhoikos; Franke, Andre; Bohle, Rainer; Henn, Wolfram; Graf, Norbert; Keller, Andreas; Meese, Eckart

2015-01-01

Glioblastoma multiforme (GBM) is the most aggressive and malignant subtype of human brain tumors. While a family clustering of GBM has long been acknowledged, relevant hereditary factors still remained elusive. Exome sequencing of families offers the option to discover respective genetic factors. We sequenced blood samples of one of the rare affected families: while both parents were healthy, both children were diagnosed with GBM. We report 85 homozygous non-synonymous single nucleotide variations (SNVs) in both siblings that were heterozygous in the parents. Beyond known key players for GBM such as ERBB2, PMS2, or CHI3L1, we identified over 50 genes that have not been associated to GBM so far. We also discovered three accumulative effects potentially adding to the tumorigenesis in the siblings: a clustering of multiple variants in single genes (e.g. PTPRB, CROCC), the aggregation of affected genes on specific molecular pathways (e.g. Focal adhesion or ECM receptor interaction) and genomic proximity (e.g. chr22.q12.2, chr1.p36.33). We found a striking accumulation of SNVs in specific genes for the daughter, who developed not only a GBM at the age of 12 years but was subsequently diagnosed with a pilocytic astrocytoma, a common acute lymphatic leukemia and a diffuse pontine glioma. The reported variants underline the relevance of genetic predisposition and cancer development in this family and demonstrate that GBM has a complex and heterogeneous genetic background. Sequencing of other affected families will help to further narrow down the driving genetic causes for this disease. PMID:25537509

Comparative genetics of longevity and cancer: insights from long-lived rodents

PubMed Central

Gorbunova, Vera; Seluanov, Andrei; Zhang, Zhengdong; Gladyshev, Vadim N.; Vijg, Jan

2015-01-01

Mammals have evolved a dramatic diversity of aging rates. Within the single order of Rodentia maximum lifespans differ from four years in mice to 32 years in naked mole rats. Cancer rates also differ significantly, from cancer-prone mice to virtually cancer-proof naked and blind mole rats. Recent progress in rodent comparative biology, in combination with the emergence of whole genome sequence information, has opened opportunities for the discovery of genetic factors controlling longevity and cancer susceptibility. PMID:24981598

Childhood physical, environmental, and genetic predictors of adult hypertension: the cardiovascular risk in young Finns study.

PubMed

Juhola, Jonna; Oikonen, Mervi; Magnussen, Costan G; Mikkilä, Vera; Siitonen, Niina; Jokinen, Eero; Laitinen, Tomi; Würtz, Peter; Gidding, Samuel S; Taittonen, Leena; Seppälä, Ilkka; Jula, Antti; Kähönen, Mika; Hutri-Kähönen, Nina; Lehtimäki, Terho; Viikari, Jorma S A; Juonala, Markus; Raitakari, Olli T

2012-07-24

Hypertension is a major modifiable cardiovascular risk factor. The present longitudinal study aimed to examine the best combination of childhood physical and environmental factors to predict adult hypertension and furthermore whether newly identified genetic variants for blood pressure increase the prediction of adult hypertension. The study cohort included 2625 individuals from the Cardiovascular Risk in Young Finns Study who were followed up for 21 to 27 years since baseline (1980; age, 3-18 years). In addition to dietary factors and biomarkers related to blood pressure, we examined whether a genetic risk score based on 29 newly identified single-nucleotide polymorphisms enhances the prediction of adult hypertension. Hypertension in adulthood was defined as systolic blood pressure ≥ 130 mm Hg and/or diastolic blood pressure ≥ 85 mm Hg or medication for the condition. Independent childhood risk factors for adult hypertension included the individual's own blood pressure (P<0.0001), parental hypertension (P<0.0001), childhood overweight/obesity (P=0.005), low parental occupational status (P=0.003), and high genetic risk score (P<0.0001). Risk assessment based on childhood overweight/obesity status, parental hypertension, and parental occupational status was superior in predicting hypertension compared with the approach using only data on childhood blood pressure levels (C statistics, 0.718 versus 0.733; P=0.0007). Inclusion of both parental hypertension history and data on novel genetic variants for hypertension further improved the C statistics (0.742; P=0.015). Prediction of adult hypertension was enhanced by taking into account known physical and environmental childhood risk factors, family history of hypertension, and novel genetic variants. A multifactorial approach may be useful in identifying children at high risk for adult hypertension.

Genetic and Non-genetic Factors Associated With Constipation in Cancer Patients Receiving Opioids.

PubMed

Laugsand, Eivor A; Skorpen, Frank; Kaasa, Stein; Sabatowski, Rainer; Strasser, Florian; Fayers, Peter; Klepstad, Pål

2015-06-18

To examine whether the inter-individual variation in constipation among patients receiving opioids for cancer pain is associated with genetic or non-genetic factors. Cancer patients receiving opioids were included from 17 centers in 11 European countries. Intensity of constipation was reported by 1,568 patients on a four-point categorical scale. Non-genetic factors were included as covariates in stratified regression analyses on the association between constipation and 75 single-nucleotide polymorphisms (SNPs) within 15 candidate genes related to opioid- or constipation-signaling pathways (HTR3E, HTR4, HTR2A, TPH1, ADRA2A, CHRM3, TACR1, CCKAR, KIT, ARRB2, GHRL, ABCB1, COMT, OPRM1, and OPRD1). The non-genetic factors significantly associated with constipation were type of laxative, mobility and place of care among patients receiving laxatives (N=806), in addition to Karnofsky performance status and presence of metastases among patients not receiving laxatives (N=762) (P<0.01). Age, gender, body mass index, cancer diagnosis, time on opioids, opioid dose, and type of opioid did not contribute to the inter-individual differences in constipation. Five SNPs, rs1800532 in TPH1, rs1799971 in OPRM1, rs4437575 in ABCB1, rs10802789 in CHRM3, and rs2020917 in COMT were associated with constipation (P<0.01). Only rs2020917 in COMT passed the Benjamini-Hochberg criterion for a 10% false discovery rate. Type of laxative, mobility, hospitalization, Karnofsky performance status, presence of metastases, and five SNPs within TPH1, OPRM1, ABCB1, CHRM3, and COMT may contribute to the variability in constipation among cancer patients treated with opioids. Knowledge of these factors may help to develop new therapies and to identify patients needing a more individualized approach to treatment.

Genetics of Addiction: Future Focus on Gene × Environment Interaction?

PubMed

Vink, Jacqueline M

2016-09-01

The heritability of substance use is moderate to high. Successful efforts to find genetic variants associated with substance use (smoking, alcohol, cannabis) have been undertaken by large consortia. However, the proportion of phenotypic variance explained by the identified genetic variants is small. Interestingly, there is overlap between the genetic variants that influence different substances. Moreover, there are sets of "substance-specific" genes and sets of genes contributing to a "vulnerability for addictive behavior" in general. It is important to recognize that genes alone do not determine addiction phenotypes: Environmental factors such as parental monitoring, peer pressure, or socioeconomic status also play an important role. Despite a rich epidemiologic literature focused on the social determinants of substance use, few studies have examined the moderation of genetic influences like gene-environment (G × E) interactions. Understanding this balance may hold the key to understanding the individual differences in substance use, abuse, and addictive behavior. Recommendations for future research are described in this commentary and include increasing the power of G × E studies by using state-of-the-art methods such as polygenic risk scores instead of single genetic variants and taking genetic overlap between substances into account. Future genetic studies should also investigate environmental risk factors for addictive behavior more extensively to unravel the interaction between nature and nurture. Focusing on G × E interactions not only will give insight into the underlying biological mechanism but will also characterize subgroups (based on environmental factors) at high risk for addictive behaviors. With this information, we could bridge the gap between fundamental research and applications for society.

Genes for normal sleep and sleep disorders.

PubMed

Tafti, Mehdi; Maret, Stéphanie; Dauvilliers, Yves

2005-01-01

Sleep and wakefulness are complex behaviors that are influenced by many genetic and environmental factors, which are beginning to be discovered. The contribution of genetic components to sleep disorders is also increasingly recognized as important. Point mutations in the prion protein, period 2, and the prepro-hypocretin/orexin gene have been found as the cause of a few sleep disorders but the possibility that other gene defects may contribute to the pathophysiology of major sleep disorders is worth in-depth investigations. However, single gene disorders are rare and most common disorders are complex in terms of their genetic susceptibility, environmental effects, gene-gene, and gene-environment interactions. We review here the current progress in the genetics of normal and pathological sleep.

Genetic causes of male infertility.

PubMed

Stouffs, Katrien; Seneca, Sara; Lissens, Willy

2014-05-01

Male infertility, affecting around half of the couples with a problem to get pregnant, is a very heterogeneous condition. Part of patients are having a defect in spermatogenesis of which the underlying causes (including genetic ones) remain largely unknown. The only genetic tests routinely used in the diagnosis of male infertility are the analyses for the presence of Yq microdeletions and/or chromosomal abnormalities. Various other single gene or polygenic defects have been proposed to be involved in male fertility. Yet, their causative effect often remains to be proven. The recent evolution in the development of whole genome-based techniques may help in clarifying the role of genes and other genetic factors involved in spermatogenesis and spermatogenesis defects. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Genetic factors in exercise adoption, adherence and obesity.

PubMed

Herring, M P; Sailors, M H; Bray, M S

2014-01-01

Physical activity and exercise play critical roles in energy balance. While many interventions targeted at increasing physical activity have demonstrated efficacy in promoting weight loss or maintenance in the short term, long term adherence to such programmes is not frequently observed. Numerous factors have been examined for their ability to predict and/or influence physical activity and exercise adherence. Although physical activity has been demonstrated to have a strong genetic component in both animals and humans, few studies have examined the association between genetic variation and exercise adherence. In this review, we provide a detailed overview of the non-genetic and genetic predictors of physical activity and adherence to exercise. In addition, we report the results of analysis of 26 single nucleotide polymorphisms in six candidate genes examined for association to exercise adherence, duration, intensity and total exercise dose in young adults from the Training Interventions and Genetics of Exercise Response (TIGER) Study. Based on both animal and human research, neural signalling and pleasure/reward systems in the brain may drive in large part the propensity to be physically active and to adhere to an exercise programme. Adherence/compliance research in other fields may inform future investigation of the genetics of exercise adherence. © 2013 The Authors. obesity reviews © 2013 International Association for the Study of Obesity.

To what extent is the familial risk of rheumatoid arthritis explained by established rheumatoid arthritis risk factors?

PubMed

Jiang, Xia; Frisell, Thomas; Askling, Johan; Karlson, Elizabeth W; Klareskog, Lars; Alfredsson, Lars; Källberg, Henrik

2015-02-01

Family history of rheumatoid arthritis (RA) is one of the strongest risk factors for developing RA, and information on family history is, therefore, routinely collected in clinical practice. However, as more genetic and environmental risk factors shared by relatives are identified, the importance of family history may diminish. The aim of this study was to determine how much of the familial risk of RA can be explained by established genetic and nongenetic risk factors. History of RA among first-degree relatives of individuals in the Epidemiological Investigation of Rheumatoid Arthritis case-control study was assessed through linkage to the Swedish Multigeneration Register and the Swedish Patient Register. We used logistic regression models to investigate the decrease in familial risk after successive adjustment for combinations of nongenetic risk factors (smoking, alcohol intake, parity, silica exposure, body mass index, fatty fish consumption, and education), and genetic risk factors (shared epitope [SE] and 76 single-nucleotide polymorphisms [SNPs]). Established nongenetic risk factors did not explain familial risk of either seropositive or seronegative RA to any significant degree. Genetic risk factors accounted for a limited proportion of the familial risk of seropositive RA (unadjusted odds ratio [OR] 4.10, SE-adjusted OR 3.72, SNP-adjusted OR 3.46, and SE and SNP-adjusted OR 3.35). Established risk factors only provided an explanation for familial risk of RA in minor part, suggesting that many (familial) risk factors remain to be identified, in particular for seronegative RA. Family history of RA therefore remains an important clinical risk factor for RA, the value of which has not yet been superseded by other information. There is thus a need for further etiologic studies of both seropositive and seronegative RA. Copyright © 2015 by the American College of Rheumatology.

A method to associate all possible combinations of genetic and environmental factors using GxE landscape plot.

PubMed

Nagaie, Satoshi; Ogishima, Soichi; Nakaya, Jun; Tanaka, Hiroshi

2015-01-01

Genome-wide association studies (GWAS) and linkage analysis has identified many single nucleotide polymorphisms (SNPs) related to disease. There are many unknown SNPs whose minor allele frequencies (MAFs) as low as 0.005 having intermediate effects with odds ratio between 1.5~3.0. Low frequency variants having intermediate effects on disease pathogenesis are believed to have complex interactions with environmental factors called gene-environment interactions (GxE). Hence, we describe a model using 3D Manhattan plot called GxE landscape plot to visualize the association of p-values for gene-environment interactions (GxE). We used the Gene-Environment iNteraction Simulator 2 (GENS2) program to simulate interactions between two genetic loci and one environmental factor in this exercise. The dataset used for training contains disease status, gender, 20 environmental exposures and 100 genotypes for 170 subjects, and p-values were calculated by Cochran-Mantel-Haenszel chi-squared test on known data. Subsequently, we created a 3D GxE landscape plot of negative logarithm of the association of p-values for all the possible combinations of genetic and environmental factors with their hierarchical clustering. Thus, the GxE landscape plot is a valuable model to predict association of p-values for GxE and similarity among genotypes and environments in the context of disease pathogenesis. GxE - Gene-environment interactions, GWAS - Genome-wide association study, MAFs - Minor allele frequencies, SNPs - Single nucleotide polymorphisms, EWAS - Environment-wide association study, FDR - False discovery rate, JPT+CHB - HapMap population of Japanese in Tokyo, Japan - Han Chinese in Beijing.

Autism genetics: Methodological issues and experimental design.

PubMed

Sacco, Roberto; Lintas, Carla; Persico, Antonio M

2015-10-01

Autism is a complex neuropsychiatric disorder of developmental origin, where multiple genetic and environmental factors likely interact resulting in a clinical continuum between "affected" and "unaffected" individuals in the general population. During the last two decades, relevant progress has been made in identifying chromosomal regions and genes in linkage or association with autism, but no single gene has emerged as a major cause of disease in a large number of patients. The purpose of this paper is to discuss specific methodological issues and experimental strategies in autism genetic research, based on fourteen years of experience in patient recruitment and association studies of autism spectrum disorder in Italy.

Genetic diversity analysis of fruit characteristics of hawthorn germplasm.

PubMed

Su, K; Guo, Y S; Wang, G; Zhao, Y H; Dong, W X

2015-12-07

One hundred and six accessions of hawthorn intraspecific resources, from the National Germplasm Repository at Shenyang, were subjected to genetic diversity and principal component analysis based on evaluation data of 15 fruit traits. Results showed that the genetic diversity of hawthorn fruit traits varied. Among the 15 traits, the fruit shape variable coefficient had the most obvious evaluation, followed by fruit surface state, dot color, taste, weight of single fruit, sepal posture, peduncle form, and metula traits. These are the primary traits by which hawthorn could be classified in the future. The principal component demonstrated that these traits are the most influential factors of hawthorn fruit characteristics.

A single-gene explanation for the probability of having idiopathic talipes equinovarus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rebbeck, T.R.; Buetow, K.H.; Dietz, F.R.

1993-11-01

It has been hypothesized that the pathogenesis of idiopathic talipes equinovarus (ITEV, or clubfoot) is explained by genetic regulation of development and growth. The objective of the present study was to determine whether a single Mendelian gene explains the probability of having ITEV in a sample of 143 Caucasian pedigrees from Iowa. These pedigrees were ascertained through probands with ITEV. Complex segregation analyses were undertaken using a regressive logistic model. The results of these analyses strongly rejected the hypotheses that the probability of having ITEV in these pedigrees was explained by a non-Mendelian pattern of transmission with residual sibling correlation,more » a nontransmitted (environmental) factor with residual sibling correlation, or residual sibling correlation alone. These results were consistent with the hypothesis that the probability of having ITEV was explained by the Mendelian segregation of a single gene with two alleles plus the effects of some unmeasured factor(s) shared among siblings. The segregation of alleles at this single Mendelian gene indicated that the disease allele A was incompletely dominant to the nondisease allele B. The disease allele A, associated with ITEV affection, was estimated to occur in the population of inference with a frequency of .007. After adjusting for sex-specific population incidences of ITEV, the conditional probability (penetrance) of ITEV affection given the AA, AB, and BB genotypes was computed to be 1.0, 0.039, and .0006, respectively. Individual pedigrees in this sample that most strongly supported the single Mendelian gene hypothesis were identified. These pedigrees are candidates for genetic linkage analyses or DNA association studies. 35 refs., 2 figs., 7 tabs.« less

Pathology supported genetic testing and treatment of cardiovascular disease in middle age for prevention of Alzheimer's disease.

PubMed

Kotze, Maritha J; van Rensburg, Susan J

2012-09-01

Chronic, multi-factorial conditions caused by a complex interaction between genetic and environmental risk factors frequently share common disease mechanisms, as evidenced by an overlap between genetic risk factors for cardiovascular disease (CVD) and Alzheimer's disease (AD). Single nucleotide polymorphisms (SNPs) in several genes including ApoE, MTHFR, HFE and FTO are known to increase the risk of both conditions. The E4 allele of the ApoE polymorphism is the most extensively studied risk factor for AD and increases the risk of coronary heart disease by approximately 40%. It furthermore displays differential therapeutic responses with use of cholesterol-lowering statins and acetylcholinesterase inhibitors, which may also be due to variation in the CYP2D6 gene in some patients. Disease expression may be triggered by gene-environment interaction causing conversion of minor metabolic abnormalities into major brain disease due to cumulative risk. A growing body of evidence supports the assessment and treatment of CVD risk factors in midlife as a preventable cause of cognitive decline, morbidity and mortality in old age. In this review, the concept of pathology supported genetic testing (PSGT) for CVD is described in this context. PSGT combines DNA testing with biochemical measurements to determine gene expression and to monitor response to treatment. The aim is to diagnose treatable disease subtypes of complex disorders, facilitate prevention of cumulative risk and formulate intervention strategies guided from the genetic background. CVD provides a model to address the lifestyle link in most chronic diseases with a genetic component. Similar preventative measures would apply for optimisation of heart and brain health.

Optimization and evaluation of single-cell whole-genome multiple displacement amplification.

PubMed

Spits, C; Le Caignec, C; De Rycke, M; Van Haute, L; Van Steirteghem, A; Liebaers, I; Sermon, K

2006-05-01

The scarcity of genomic DNA can be a limiting factor in some fields of genetic research. One of the methods developed to overcome this difficulty is whole genome amplification (WGA). Recently, multiple displacement amplification (MDA) has proved very efficient in the WGA of small DNA samples and pools of cells, the reaction being catalyzed by the phi29 or the Bst DNA polymerases. The aim of the present study was to develop a reliable, efficient, and fast protocol for MDA at the single-cell level. We first compared the efficiency of phi29 and Bst polymerases on DNA samples and single cells. The phi29 polymerase generated accurately, in a short time and from a single cell, sufficient DNA for a large set of tests, whereas the Bst enzyme showed a low efficiency and a high error rate. A single-cell protocol was optimized using the phi29 polymerase and was evaluated on 60 single cells; the DNA obtained DNA was assessed by 22 locus-specific PCRs. This new protocol can be useful for many applications involving minute quantities of starting material, such as forensic DNA analysis, prenatal and preimplantation genetic diagnosis, or cancer research. (c) 2006 Wiley-Liss, Inc.

Assessment and Treatment in Autism Spectrum Disorders: A Focus on Genetics and Psychiatry

PubMed Central

Butler, Merlin G.; Youngs, Erin L.; Roberts, Jennifer L.; Hellings, Jessica A.

2012-01-01

Autism spectrum disorders (ASDs) are neurobehavioral disorders characterized by abnormalities in three behavioral domains including social interaction, impaired communication, and repetitive stereotypic behaviors. ASD affects approximately 1% of children and is on the rise with significant genetic mechanisms underlying these disorders. We review the current understanding of the role of genetic and metabolic factors contributing to ASD with the use of new genetic technology. Fifty percent is diagnosed with chromosomal abnormalities, small DNA deletions/duplications, single-gene conditions, or metabolic disturbances. Genetic evaluation is discussed along with psychiatric treatment and approaches for selection of medication to treat associated challenging behaviors or comorbidities seen in ASD. We emphasize the importance of prioritizing treatment based on target symptom clusters and in what order for individuals with ASD, as the treatment may vary from patient to patient. PMID:22934170

Biobehavioral Development. From Cells to Selves.

ERIC Educational Resources Information Center

National Inst. of Child Health and Human Development (NIH), Bethesda, MD.

Key to the mission of the National Institute of Child Health and Human Development (NICHD) is answering fundamental questions about how a single fertilized cell eventually develops into a fully functional adult human being and how a multitude of genetic and environmental factors influence that process. This document details part of NICHD's…

Studying plant-pathogen interactions in the genomics era: beyond molecular Koch’s postulates to systems biology

USDA-ARS?s Scientific Manuscript database

Molecular factors enabling microbial pathogens to cause plant diseases have been sought with increasing efficacy over three research eras, which successively introduced the tools of disease physiology, single-gene molecular genetics, and genomics. From this work emerged a unified model of the intera...

Association of Genetic Markers in the BCL-2 Family of Apoptosis-Related Genes with Endometrial Cancer Risk in a Chinese Population

PubMed Central

Dorjgochoo, Tsogzolmaa; Xiang, Yong-Bing; Long, Jirong; Shi, Jiajun; Deming, Sandra; Xu, Wang-Hong; Cai, Hui; Cheng, Jiarong; Cai, Qiuyin; Zheng, Wei; Shu, Xiao-Ou

2013-01-01

Background In vitro studies have demonstrated the role of the BCL-2 family of genes in endometrial carcinogenesis. The role of genetic variants in BCL-2 genes and their interactions with non-genetic factors in the development of endometrial cancer has not been investigated in epidemiological studies. Patients and Methods We examined the relationship between BCL-2 gene family variants and endometrial cancer risk among 1,028 patients and 1,922 age-matched community controls from Shanghai, China. We also investigated possible interactions between genetic variants and established risk factors (demographic, lifestyle and clinical). Individuals were genotyped for 86 tagging single nucleotide polymorphisms (SNPs) in the BCL2, BAX, BAD and BAK1 genes. Results Significant associations with endometrial cancer risk were found for 9 SNPs in the BCL2 gene (P trend<0.05 for all). For SNPs rs17759659 and rs7243091 (minor allele for both: G), the associations were independent. The odds ratio was 1.27 (95% CI: 1.04–1.53) for women with AG genotype for the SNP rs17759659 and 1.82 (95% CI: 1.21–2.73) for women with the GG genotype for the SNP rs7243091. No interaction between these two SNPs and established non-genetic risk factors of endometrial cancer was noticed. Conclusion Genetic polymorphisms in the BCL2 gene may be associated with the risk of endometrial cancer in Chinese women. PMID:23637776

How well do you know your mutation? Complex effects of genetic background on expressivity, complementation, and ordering of allelic effects

PubMed Central

Choi, Lin; DeNieu, Michael; Sonnenschein, Anne; Hummel, Kristen; Marier, Christian; Victory, Andrew; Porter, Cody; Mammel, Anna; Holms, Julie; Sivaratnam, Gayatri

2017-01-01

For a given gene, different mutations influence organismal phenotypes to varying degrees. However, the expressivity of these variants not only depends on the DNA lesion associated with the mutation, but also on factors including the genetic background and rearing environment. The degree to which these factors influence related alleles, genes, or pathways similarly, and whether similar developmental mechanisms underlie variation in the expressivity of a single allele across conditions and among alleles is poorly understood. Besides their fundamental biological significance, these questions have important implications for the interpretation of functional genetic analyses, for example, if these factors alter the ordering of allelic series or patterns of complementation. We examined the impact of genetic background and rearing environment for a series of mutations spanning the range of phenotypic effects for both the scalloped and vestigial genes, which influence wing development in Drosophila melanogaster. Genetic background and rearing environment influenced the phenotypic outcome of mutations, including intra-genic interactions, particularly for mutations of moderate expressivity. We examined whether cellular correlates (such as cell proliferation during development) of these phenotypic effects matched the observed phenotypic outcome. While cell proliferation decreased with mutations of increasingly severe effects, surprisingly it did not co-vary strongly with the degree of background dependence. We discuss these findings and propose a phenomenological model to aid in understanding the biology of genes, and how this influences our interpretation of allelic effects in genetic analysis. PMID:29166655

A full genomic characterization of the development of a stable Small Colony Variant cell-type by a clinical Staphylococcus aureus strain.

PubMed

Bui, Long M G; Kidd, Stephen P

2015-12-01

A key to persistent and recurrent Staphylococcus aureus infections is its ability to adapt to diverse and toxic conditions. This ability includes a switch into a biofilm or to the quasi-dormant Small Colony Variant (SCV). The development and molecular attributes of SCVs have been difficult to study due to their rapid reversion to their parental cell-type. We recently described the unique induction of a matrix-embedded and stable SCV cell-type in a clinical S. aureus strain (WCH-SK2) by growing the cells with limiting conditions for a prolonged timeframe. Here we further study their characteristics. They possessed an increased viability in the presence of antibiotics compared to their non-SCV form. Their stability implied that there had been genetic changes; we therefore determined both the genome sequence of WCH-SK2 and its stable SCV form at a single base resolution, employing Single Molecular Real-Time (SMRT) sequencing that enabled the methylome to also be determined. The genetic features of WCH-SK2 have been identified; the SCCmec type, the pathogenicity and genetic islands and virulence factors. The genetic changes that had occurred in the stable SCV form were identified; most notably being in MgrA, a global regulator, and RsbU, a phosphoserine phosphatase within the regulatory pathway of the sigma factor SigB. There was a shift in the methylomes of the non-SCV and stable SCV forms. We have also shown a similar induction of this cell-type in other S. aureus strains and performed a genetic comparison to these and other S. aureus genomes. We additionally map RNAseq data to the WCH-SK2 genome in a transcriptomic analysis of the parental, SCV and stable SCV cells. The results from this study represent the unique identification of a suite of epigenetic, genetic and transcriptional factors that are implicated in the switch in S. aureus to its persistent SCV form. Copyright © 2015 Elsevier B.V. All rights reserved.

Advances in the genetically complex autoinflammatory diseases.

PubMed

Ombrello, Michael J

2015-07-01

Monogenic diseases usually demonstrate Mendelian inheritance and are caused by highly penetrant genetic variants of a single gene. In contrast, genetically complex diseases arise from a combination of multiple genetic and environmental factors. The concept of autoinflammation originally emerged from the identification of individual, activating lesions of the innate immune system as the molecular basis of the hereditary periodic fever syndromes. In addition to these rare, monogenic forms of autoinflammation, genetically complex autoinflammatory diseases like the periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, chronic recurrent multifocal osteomyelitis (CRMO), Behçet's disease, and systemic arthritis also fulfill the definition of autoinflammatory diseases-namely, the development of apparently unprovoked episodes of inflammation without identifiable exogenous triggers and in the absence of autoimmunity. Interestingly, investigations of these genetically complex autoinflammatory diseases have implicated both innate and adaptive immune abnormalities, blurring the line between autoinflammation and autoimmunity. This reinforces the paradigm of concerted innate and adaptive immune dysfunction leading to genetically complex autoinflammatory phenotypes.

Disentangling the heterogeneity of autism spectrum disorder through genetic findings

PubMed Central

Jeste, Shafali S.; Geschwind, Daniel H.

2014-01-01

Autism spectrum disorder (ASD) represents a heterogeneous group of disorders, which presents a substantial challenge to diagnosis and treatment. Over the past decade, considerable progress has been made in the identification of genetic risk factors for ASD that define specific mechanisms and pathways underlying the associated behavioural deficits. In this Review, we discuss how some of the latest advances in the genetics of ASD have facilitated parsing of the phenotypic heterogeneity of this disorder. We argue that only through such advances will we begin to define endophenotypes that can benefit from targeted, hypothesis-driven treatments. We review the latest technologies used to identify and characterize the genetics underlying ASD and then consider three themes—single-gene disorders, the gender bias in ASD, and the genetics of neurological comorbidities—that highlight ways in which we can use genetics to define the many phenotypes within the autism spectrum. We also present current clinical guidelines for genetic testing in ASD and their implications for prognosis and treatment. PMID:24468882

High genetic-risk individuals benefit less from resistance exercise intervention

PubMed Central

Klimentidis, Yann C.; Bea, Jennifer W.; Lohman, Timothy; Hsieh, Pei-Shan; Going, Scott; Chen, Zhao

2015-01-01

Background/Objectives Genetic factors play an important role in body mass index (BMI) variation, and also likely play a role in the weight-loss and body composition response to physical activity/exercise. With the recent identification of BMI–associated genetic variants, it is possible to investigate the interaction of these genetic factors with exercise on body composition outcomes. Subjects/Methods In a block-randomized clinical trial of resistance exercise among women (n=148), we examined whether the putative effect of exercise on weight and DXA-derived body composition measurements differs according to genetic risk for obesity. Approximately one-half of the sample was randomized to an intervention consisting of a supervised, intensive, resistance exercise program, lasting one year. Genetic risk for obesity was defined as a genetic risk score (GRS) comprised of 21 SNPs known to be associated with normal BMI variation. We examined the interaction of exercise intervention and the GRS on anthropometric and body composition measurements after one year of the exercise intervention. Results We found statistically significant interactions for body weight (p=0.01), body fat (p=0.01), body fat % (p=0.02), and abdominal fat (p=0.02), whereby the putative effect of exercise is greater among those with a lower level of genetic risk for obesity. No single SNP appears to be a major driver of these interactions. Conclusions The weight-loss response to resistance exercise, including changes in body composition, differs according to an individual’s genetic risk for obesity. PMID:25924711

Does population size affect genetic diversity? A test with sympatric lizard species.

PubMed

Hague, M T J; Routman, E J

2016-01-01

Genetic diversity is a fundamental requirement for evolution and adaptation. Nonetheless, the forces that maintain patterns of genetic variation in wild populations are not completely understood. Neutral theory posits that genetic diversity will increase with a larger effective population size and the decreasing effects of drift. However, the lack of compelling evidence for a relationship between genetic diversity and population size in comparative studies has generated some skepticism over the degree that neutral sequence evolution drives overall patterns of diversity. The goal of this study was to measure genetic diversity among sympatric populations of related lizard species that differ in population size and other ecological factors. By sampling related species from a single geographic location, we aimed to reduce nuisance variance in genetic diversity owing to species differences, for example, in mutation rates or historical biogeography. We compared populations of zebra-tailed lizards and western banded geckos, which are abundant and short-lived, to chuckwallas and desert iguanas, which are less common and long-lived. We assessed population genetic diversity at three protein-coding loci for each species. Our results were consistent with the predictions of neutral theory, as the abundant species almost always had higher levels of haplotype diversity than the less common species. Higher population genetic diversity in the abundant species is likely due to a combination of demographic factors, including larger local population sizes (and presumably effective population sizes), faster generation times and high rates of gene flow with other populations.

Predicting stroke through genetic risk functions: the CHARGE Risk Score Project.

PubMed

Ibrahim-Verbaas, Carla A; Fornage, Myriam; Bis, Joshua C; Choi, Seung Hoan; Psaty, Bruce M; Meigs, James B; Rao, Madhu; Nalls, Mike; Fontes, Joao D; O'Donnell, Christopher J; Kathiresan, Sekar; Ehret, Georg B; Fox, Caroline S; Malik, Rainer; Dichgans, Martin; Schmidt, Helena; Lahti, Jari; Heckbert, Susan R; Lumley, Thomas; Rice, Kenneth; Rotter, Jerome I; Taylor, Kent D; Folsom, Aaron R; Boerwinkle, Eric; Rosamond, Wayne D; Shahar, Eyal; Gottesman, Rebecca F; Koudstaal, Peter J; Amin, Najaf; Wieberdink, Renske G; Dehghan, Abbas; Hofman, Albert; Uitterlinden, André G; Destefano, Anita L; Debette, Stephanie; Xue, Luting; Beiser, Alexa; Wolf, Philip A; Decarli, Charles; Ikram, M Arfan; Seshadri, Sudha; Mosley, Thomas H; Longstreth, W T; van Duijn, Cornelia M; Launer, Lenore J

2014-02-01

Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors. The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke. In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3×10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7×10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)). The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.

Gout in Older Adults: The Atherosclerosis Risk in Communities Study

PubMed Central

Burke, Bridget Teevan; Köttgen, Anna; Law, Andrew; Grams, Morgan; Baer, Alan N.; Coresh, Josef

2016-01-01

Background: It is unclear whether traditional and genetic risk factors in middle age predict the onset of gout in older age. Methods: We studied the incidence of gout in older adults using the Atherosclerosis Risk in Communities study, a prospective U.S. population–based cohort of middle-aged adults enrolled between 1987 and 1989 with ongoing follow-up. A genetic urate score was formed from common urate-associated single nucleotide polymorphisms for eight genes. The adjusted hazard ratio and 95% confidence interval of incident gout by traditional and genetic risk factors in middle age were estimated using a Cox proportional hazards model. Results: The cumulative incidence from middle age to age 65 was 8.6% in men and 2.5% in women; by age 75 the cumulative incidence was 11.8% and 5.0%. In middle age, increased adiposity, beer intake, protein intake, smoking status, hypertension, diuretic use, and kidney function (but not sex) were associated with an increased gout risk in older age. In addition, a 100 µmol/L increase in genetic urate score was associated with a 3.29-fold (95% confidence interval: 1.63–6.63) increased gout risk in older age. Conclusions: These findings suggest that traditional and genetic risk factors in middle age may be useful for identifying those at risk of gout in older age. PMID:26714568

Novel genetic risk factors for asthma in African American children: Precision Medicine and the SAGE II Study.

PubMed

White, Marquitta J; Risse-Adams, O; Goddard, P; Contreras, M G; Adams, J; Hu, D; Eng, C; Oh, S S; Davis, A; Meade, K; Brigino-Buenaventura, E; LeNoir, M A; Bibbins-Domingo, K; Pino-Yanes, M; Burchard, E G

2016-07-01

Asthma, an inflammatory disorder of the airways, is the most common chronic disease of children worldwide. There are significant racial/ethnic disparities in asthma prevalence, morbidity, and mortality among US children. This trend is mirrored in obesity, which may share genetic and environmental risk factors with asthma. The majority of asthma biomedical research has been performed in populations of European decent. We sought to identify genetic risk factors for asthma in African American children. We also assessed the generalizability of genetic variants associated with asthma in European and Asian populations to African American children. Our study population consisted of 1227 (812 asthma cases, 415 controls) African American children with genome-wide single nucleotide polymorphism (SNP) data. Logistic regression was used to identify associations between SNP genotype and asthma status. We identified a novel variant in the PTCHD3 gene that is significantly associated with asthma (rs660498, p = 2.2 × 10(-7)) independent of obesity status. Approximately 5 % of previously reported asthma genetic associations identified in European populations replicated in African Americans. Our identification of novel variants associated with asthma in African American children, coupled with our inability to replicate the majority of findings reported in European Americans, underscores the necessity for including diverse populations in biomedical studies of asthma.

Obesity and diabetes genes are associated with being born small for gestational age: Results from the Auckland Birthweight Collaborative study

PubMed Central

2010-01-01

Background Individuals born small for gestational age (SGA) are at increased risk of rapid postnatal weight gain, later obesity and diseases in adulthood such as type 2 diabetes, hypertension and cardiovascular diseases. Environmental risk factors for SGA are well established and include smoking, low pregnancy weight, maternal short stature, maternal diet, ethnic origin of mother and hypertension. However, in a large proportion of SGA, no underlying cause is evident, and these individuals may have a larger genetic contribution. Methods In this study we tested the association between SGA and polymorphisms in genes that have previously been associated with obesity and/or diabetes. We undertook analysis of 54 single nucleotide polymorphisms (SNPs) in 546 samples from the Auckland Birthweight Collaborative (ABC) study. 227 children were born small for gestational age (SGA) and 319 were appropriate for gestational age (AGA). Results and Conclusion The results demonstrated that genetic variation in KCNJ11, BDNF, PFKP, PTER and SEC16B were associated with SGA and support the concept that genetic factors associated with obesity and/or type 2 diabetes are more prevalent in those born SGA compared to those born AGA. We have previously determined that environmental factors are associated with differences in birthweight in the ABC study and now we have demonstrated a significant genetic contribution, suggesting that the interaction between genetics and the environment are important. PMID:20712903

Genetic diversity shaped by historical and recent factors in the live-bearing twoline skiffia Neotoca bilineata.

PubMed

Ornelas-García, C P; Alda, F; Díaz-Pardo, E; Gutiérrez-Hernández, A; Doadrio, I

2012-11-01

The endangered twoline skiffia Neotoca bilineata, a viviparous fish of the subfamily Goodeinae, endemic to central Mexico (inhabiting two basins, Cuitzeo and Lerma-Santiago) was evaluated using genetic and habitat information. The genetic variation of all remaining populations of the species was analysed using both mitochondrial and microsatellite markers and their habitat conditions were assessed using a water quality index (I(WQ)). An 80% local extinction was found across the distribution of N. bilineata. The species was found in three of the 16 historical localities plus one previously unreported site. Most areas inhabited by the remaining populations had I(WQ) scores unsuitable for the conservation of freshwater biodiversity. Populations showed low but significant genetic differentiation with both markers (mtDNA φ(ST) = 0.076, P < 0.001; microsatellite F(ST) = 0.314, P < 0.001). Borbollon, in the Cuitzeo Basin, showed the highest level of differentiation and was identified as a single genetic unit by Bayesian assignment methods. Rio Grande de Morelia and Salamanca populations showed the highest genetic diversity and also a high migration rate facilitated by an artificial channel that connected the two basins. Overall, high genetic diversity values were observed compared with other freshwater fishes (average N(a) = 16 alleles and loci and mean ±S.D. H(o) = 0.63 ± 0.10 and nucleotide diversity π = 0.006). This suggests that the observed genetic diversity has not diminished as rapidly as the species' habitat destruction. No evidence of correlation between habitat conditions and genetic diversity was found. The current pattern of genetic diversity may be the result of both historical factors and recent modifications of the hydrological system. The main threat to the species may be the rapid habitat deterioration and associated demographic stochasticity rather than genetic factors. © 2012 The Authors. Journal of Fish Biology © 2012 The Fisheries Society of the British Isles.

Genome-wide association study of bipolar disorder accounting for effect of body mass index identifies a new risk allele in TCF7L2.

PubMed

Winham, S J; Cuellar-Barboza, A B; Oliveros, A; McElroy, S L; Crow, S; Colby, C; Choi, D-S; Chauhan, M; Frye, M; Biernacka, J M

2014-09-01

Bipolar disorder (BD) is associated with higher body mass index (BMI) and increased metabolic comorbidity. Considering the associated phenotypic traits in genetic studies of complex diseases, either by adjusting for covariates or by investigating interactions between genetic variants and covariates, may help to uncover the missing heritability. However, obesity-related traits have not been incorporated in prior genome-wide analyses of BD as covariates or potential interacting factors. To investigate the genetic factors underlying BD while considering BMI, we conducted genome-wide analyses using data from the Genetic Association Information Network BD study. We analyzed 729,454 genotyped single-nucleotide polymorphism (SNP) markers on 388 European-American BD cases and 1020 healthy controls with available data for maximum BMI. We performed genome-wide association analyses of the genetic effects while accounting for the effect of maximum BMI, and also evaluated SNP-BMI interactions. A joint test of main and interaction effects demonstrated significant evidence of association at the genome-wide level with rs12772424 in an intron of TCF7L2 (P=2.85E-8). This SNP exhibited interaction effects, indicating that the bipolar susceptibility risk of this SNP is dependent on BMI. TCF7L2 codes for the transcription factor TCF/LF, part of the Wnt canonical pathway, and is one of the strongest genetic risk variants for type 2 diabetes (T2D). This is consistent with BD pathophysiology, as the Wnt pathway has crucial implications in neurodevelopment, neurogenesis and neuroplasticity, and is involved in the mechanisms of action of BD and depression treatments. We hypothesize that genetic risk for BD is BMI dependent, possibly related to common genetic risk with T2D.

Population structure and genetic diversity of greater sage-grouse (Centrocercus urophasianus) in fragmented landscapes at the northern edge of their range

USGS Publications Warehouse

Bush, K.L.; Dyte, C.K.; Moynahan, B.J.; Aldridge, Cameron L.; Sauls, H.S.; Battazzo, A.M.; Walker, B.L.; Doherty, K.E.; Tack, J.; Carlson, J.; Eslinger, D.; Nicholson, J.; Boyce, M.S.; Naugle, D.E.; Paszkowski, C.A.; Coltman, D.W.

2011-01-01

Range-edge dynamics and anthropogenic fragmentation are expected to impact patterns of genetic diversity, and understanding the influence of both factors is important for effective conservation of threatened wildlife species. To examine these factors, we sampled greater sage-grouse (Centrocercus urophasianus) from a declining, fragmented region at the northern periphery of the species' range and from a stable, contiguous core region. We genotyped 2,519 individuals at 13 microsatellite loci from 104 leks in Alberta, Saskatchewan, Montana, and Wyoming. Birds from northern Montana, Alberta, and Saskatchewan were identified as a single population that exhibited significant isolation by distance, with the Milk River demarcating two subpopulations. Both subpopulations exhibited high genetic diversity with no evidence that peripheral regions were genetically depauperate or highly structured. However, river valleys and a large agricultural region were significant barriers to dispersal. Leks were also composed primarily of non-kin, rejecting the idea that leks form because of male kin association. Northern Montana sage-grouse are maintaining genetic connectivity in fragmented and northern peripheral habitats via dispersal through and around various forms of fragmentation. ?? 2010 Springer Science+Business Media B.V.

Genetics of Congenital Heart Disease: Past and Present.

PubMed

Muntean, Iolanda; Togănel, Rodica; Benedek, Theodora

2017-04-01

Congenital heart disease is the most common congenital anomaly, representing an important cause of infant morbidity and mortality. Congenital heart disease represents a group of heart anomalies that include septal defects, valve defects, and outflow tract anomalies. The exact genetic, epigenetic, or environmental basis of congenital heart disease remains poorly understood, although the exact mechanism is likely multifactorial. However, the development of new technologies including copy number variants, single-nucleotide polymorphism, next-generation sequencing are accelerating the detection of genetic causes of heart anomalies. Recent studies suggest a role of small non-coding RNAs, micro RNA, in congenital heart disease. The recently described epigenetic factors have also been found to contribute to cardiac morphogenesis. In this review, we present past and recent genetic discoveries in congenital heart disease.

Astrophysical data mining with GPU. A case study: Genetic classification of globular clusters

NASA Astrophysics Data System (ADS)

Cavuoti, S.; Garofalo, M.; Brescia, M.; Paolillo, M.; Pescape', A.; Longo, G.; Ventre, G.

2014-01-01

We present a multi-purpose genetic algorithm, designed and implemented with GPGPU/CUDA parallel computing technology. The model was derived from our CPU serial implementation, named GAME (Genetic Algorithm Model Experiment). It was successfully tested and validated on the detection of candidate Globular Clusters in deep, wide-field, single band HST images. The GPU version of GAME will be made available to the community by integrating it into the web application DAMEWARE (DAta Mining Web Application REsource, http://dame.dsf.unina.it/beta_info.html), a public data mining service specialized on massive astrophysical data. Since genetic algorithms are inherently parallel, the GPGPU computing paradigm leads to a speedup of a factor of 200× in the training phase with respect to the CPU based version.

Genetic variation in metallothionein and metal-regulatory transcription factor 1 in relation to urinary cadmium, copper, and zinc

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adams, Scott V., E-mail: sadams@fhcrc.org; Barrick, Brian; Christopher, Emily P.

Background: Metallothionein (MT) proteins play critical roles in the physiological handling of both essential (Cu and Zn) and toxic (Cd) metals. MT expression is regulated by metal-regulatory transcription factor 1 (MTF1). Hence, genetic variation in the MT gene family and MTF1 might influence excretion of these metals. Methods: 321 women were recruited in Seattle, WA and Las Cruces, NM and provided demographic information, urine samples for measurement of metal concentrations by mass spectrometry and creatinine, and blood or saliva for extraction of DNA. Forty-one single nucleotide polymorphisms (SNPs) within the MTF1 gene region and the region of chromosome 16 encodingmore » the MT gene family were selected for genotyping in addition to an ancestry informative marker panel. Linear regression was used to estimate the association of SNPs with urinary Cd, Cu, and Zn, adjusted for age, urinary creatinine, smoking history, study site, and ancestry. Results: Minor alleles of rs28366003 and rs10636 near the MT2A gene were associated with lower urinary Cd, Cu, and Zn. Minor alleles of rs8044719 and rs1599823, near MT1A and MT1B, were associated with lower urinary Cd and Zn, respectively. Minor alleles of rs4653329 in MTF1 were associated with lower urinary Cd. Conclusions: These results suggest that genetic variation in the MT gene region and MTF1 influences urinary Cd, Cu, and Zn excretion. - Highlights: • Genetic variation in metallothionein (MT) genes was assessed in two diverse populations. • Single nucleotide polymorphisms (SNPs) in MT genes were associated with mean urinary Cd, Cu and Zn. • Genetic variation may influence biomarkers of exposure, and associations of exposure with health.« less

Social risk or genetic liability for psychosis? A study of children born in Sweden and reared by adoptive parents.

PubMed

Wicks, Susanne; Hjern, Anders; Dalman, Christina

2010-10-01

Recent studies suggest a role for social factors during childhood in the later development of schizophrenia. Since social conditions in childhood are closely related to parental psychiatric illness, there is a need to disentangle how genes and social environmental factors interact. A total of 13,163 children born in Sweden between 1955 and 1984 and reared in Swedish adoptive families were linked to the National Patient Register until 2006 regarding admissions for non-affective psychoses, including schizophrenia. Hazard ratios for nonaffective psychoses were estimated in relation to three indicators of socioeconomic position in childhood (household data of the rearing family obtained via linkage to the National Censuses of 1960-1985) and in relation to indicator of genetic liability (biological parental inpatient care for psychosis). In addition, the total Swedish-born population was investigated. Increased risks for nonaffective psychosis were found among adoptees (without biological parental history of psychosis) reared in families with disadvantaged socioeconomic position, which consisted of adoptive parental unemployment (hazard ratio=2.0), single-parent household (hazard ratio=1.2), and living in apartments (hazard ratio=1.3). The risk was also increased among persons with genetic liability for psychosis alone (hazard ratio=4.7). Among those exposed to both genetic liability and a disadvantaged socioeconomic situation in childhood, the risk was considerably higher (hazard ratio=15.0, 10.3, and 5.7 for parental unemployment, single-parent household, and apartment living, respectively). Analyses in the larger population supported these results. The results indicate that children reared in families with a disadvantaged socioeconomic position have an increased risk for psychosis. There was also some support for an interaction effect, suggesting that social disadvantage increases this risk more in children with genetic liability for psychosis.

Evaluation and Integration of Genetic Signature for Prediction Risk of Nasopharyngeal Carcinoma in Southern China

PubMed Central

Winkler, Cheryl A.; Li, Ji; Guan, Li; Tang, Minzhong; Liao, Jian; Deng, Hong; de Thé, Guy; Zeng, Yi; O'Brien, Stephen J.

2014-01-01

Genetic factors, as well as environmental factors, play a role in development of nasopharyngeal carcinoma (NPC). A number of single nucleotide polymorphisms (SNPs) have been reported to be associated with NPC. To confirm these genetic associations with NPC, two independent case-control studies from Southern China comprising 1166 NPC cases and 2340 controls were conducted. Seven SNPs in ITGA9 at 3p21.3 and 9 SNPs within the 6p21.3 HLA region were genotyped. To explore the potential clinical application of these genetic markers in NPC, we further evaluate the predictive/diagnostic role of significant SNPs by calculating the area under the curve (AUC). Results. The reported associations between ITGA9 variants and NPC were not replicated. Multiple loci of GABBR1, HLA-F, HLA-A, and HCG9 were statistically significant in both cohorts (P combined range from 5.96 × 10−17 to 0.02). We show for the first time that these factors influence NPC development independent of environmental risk factors. This study also indicated that the SNP alone cannot serve as a predictive/diagnostic marker for NPC. Integrating the most significant SNP with IgA antibodies status to EBV, which is presently used as screening/diagnostic marker for NPC in Chinese populations, did not improve the AUC estimate for diagnosis of NPC. PMID:25180181

Evaluation and integration of genetic signature for prediction risk of nasopharyngeal carcinoma in Southern China.

PubMed

Guo, Xiuchan; Winkler, Cheryl A; Li, Ji; Guan, Li; Tang, Minzhong; Liao, Jian; Deng, Hong; de Thé, Guy; Zeng, Yi; O'Brien, Stephen J

2014-01-01

Genetic factors, as well as environmental factors, play a role in development of nasopharyngeal carcinoma (NPC). A number of single nucleotide polymorphisms (SNPs) have been reported to be associated with NPC. To confirm these genetic associations with NPC, two independent case-control studies from Southern China comprising 1166 NPC cases and 2340 controls were conducted. Seven SNPs in ITGA9 at 3p21.3 and 9 SNPs within the 6p21.3 HLA region were genotyped. To explore the potential clinical application of these genetic markers in NPC, we further evaluate the predictive/diagnostic role of significant SNPs by calculating the area under the curve (AUC). The reported associations between ITGA9 variants and NPC were not replicated. Multiple loci of GABBR1, HLA-F, HLA-A, and HCG9 were statistically significant in both cohorts (P(combined) range from 5.96 × 10(-17) to 0.02). We show for the first time that these factors influence NPC development independent of environmental risk factors. This study also indicated that the SNP alone cannot serve as a predictive/diagnostic marker for NPC. Integrating the most significant SNP with IgA antibodies status to EBV, which is presently used as screening/diagnostic marker for NPC in Chinese populations, did not improve the AUC estimate for diagnosis of NPC.

A new genetic factor for root gravitropism in rice (Oryza sativa L.).

PubMed

Shi, Jiang-hua; Hao, Xi; Wu, Zhong-chang; Wu, Ping

2009-10-01

Root gravitropism is one of the important factors to determine root architecture. To understand the mechanism underlying root gravitropism, we isolated a rice (Xiushui63) mutant defective in root gravitropism, designated as gls1. Vertical sections of root caps revealed that gls1 mutant displayed normal distribution of amyloplast in the columella cells compared with the wild type. The gls1 mutant was less sensitive to 2,4-dichlorophenoxyacetic acid (2,4-D) and alpha-naphthaleneacetic acid (NAA) than the wild type. Genetic analysis indicated that the phenotype of gls1 mutant was caused by a single recessive mutation, which is mapped in a 255-kb region between RM16253 and CAPS1 on the short arm of chromosome 4.

Genetic polymorphisms and the risk of stroke after cardiac surgery.

PubMed

Grocott, Hilary P; White, William D; Morris, Richard W; Podgoreanu, Mihai V; Mathew, Joseph P; Nielsen, Dahlia M; Schwinn, Debra A; Newman, Mark F

2005-09-01

Stroke represents a significant cause of morbidity and mortality after cardiac surgery. Although the risk of stroke varies according to both patient and procedural factors, the impact of genetic variants on stroke risk is not well understood. Therefore, we tested the hypothesis that specific genetic polymorphisms are associated with an increased risk of stroke after cardiac surgery. Patients undergoing cardiac surgery utilizing cardiopulmonary bypass surgery were studied. DNA was isolated from preoperative blood and analyzed for 26 different single-nucleotide polymorphisms. Multivariable logistic regression modeling was used to determine the association of clinical and genetic characteristics with stroke. Permutation analysis was used to adjust for multiple comparisons inherent in genetic association studies. A total of 1635 patients experiencing 28 strokes (1.7%) were included in the final genetic model. The combination of the 2 minor alleles of C-reactive protein (CRP; 3'UTR 1846C/T) and interleukin-6 (IL-6; -174G/C) polymorphisms, occurring in 583 (35.7%) patients, was significantly associated with stroke (odds ratio, 3.3; 95% CI, 1.4 to 8.1; P=0.0023). In a multivariable logistic model adjusting for age, the CRP and IL-6 single-nucleotide polymorphism combination remained significantly associated with stroke (P=0.0020). We demonstrate that common genetic variants of CRP (3'UTR 1846C/T) and IL-6 (-174G/C) are significantly associated with the risk of stroke after cardiac surgery, suggesting a pivotal role of inflammation in post-cardiac surgery stroke.

Alcohol dependence and criminal behavior: preliminary results of an association study of environmental and genetic factors in an Italian male population.

PubMed

Terranova, Claudio; Tucci, Marianna; Sartore, Daniela; Cavarzeran, Fabiano; Barzon, Luisa; Palù, Giorgio; Ferrara, Santo D

2012-09-01

The aim of this study is to propose an innovative approach evaluating the connection between alcohol use disorders and criminal behavior. The research, structured as a case-control study, was based on the analysis of environmental (social variables) and genetic factors (single nucleotide polymorphisms of glutamic acid decarboxylase) in a population (N = 173) of Italian alcohol-dependent men. Group 1 (N = 47, convicted subjects) was compared with Group 2 (N = 126, no previous criminal conduct). Grade repetition, work problems, and drug problems were statistically associated with criminal behavior. Having daily family meals together and having children were inversely related to convictions. The genotype distribution of the two groups was similar. The association between environmental factors and antisocial behavior confirms previous findings in the literature. The lack of genetic association does not exclude the role of the gamma-aminobutyric acid (GABA) system in determining antisocial behavior; further studies with larger samples are needed, together with investigation of other components of the GABA pathway. © 2012 American Academy of Forensic Sciences.

Genetic and Environmental Factors Associated with Cannabis Involvement

PubMed Central

Bogdan, Ryan; Winstone, Jonathan MA; Agrawal, Arpana

2016-01-01

Approximately 50-70% of the variation in cannabis use and use disorders can be attributed to heritable factors. For cannabis use, the remaining variance can be parsed in to familial and person-specific environmental factors while for use disorders, only the latter contribute. While numerous candidate gene studies have identified the role of common variation influencing liability to cannabis involvement, replication has been elusive. To date, no genomewide association study has been sufficiently powered to identify significant loci. Despite this, studies adopting polygenic techniques and integrating genetic variation with neural phenotypes and measures of environmental risk, such as childhood adversity, are providing promising new leads. It is likely that the small effect sizes associated with variants related to cannabis involvement will only be robustly identified in substantially larger samples. Results of such large-scale efforts will provide valuable single variant targets for translational research in neurogenetic, pharmacogenetic and non-human animal models as well as polygenic risk indices that can be used to explore a host of other genetic hypotheses related to cannabis use and misuse. PMID:27642547

Navigating the current landscape of clinical genetic testing for inherited retinal dystrophies.

PubMed

Lee, Kristy; Garg, Seema

2015-04-01

Inherited eye disorders are a significant cause of vision loss. Genetic testing can be particularly helpful for patients with inherited retinal dystrophies because of genetic heterogeneity and overlapping phenotypes. The need to identify a molecular diagnosis for retinal dystrophies is particularly important in the era of developing novel gene therapy-based treatments, such as the RPE65 gene-based clinical trials and others on the horizon, as well as recent advances in reproductive options. The introduction of massively parallel sequencing technologies has significantly advanced the identification of novel gene candidates and has expanded the landscape of genetic testing. In a relatively short time clinical medicine has progressed from limited testing options to a plethora of choices ranging from single-gene testing to whole-exome sequencing. This article outlines currently available genetic testing and factors to consider when selecting appropriate testing for patients with inherited retinal dystrophies.

Exome-Wide Association Analysis of Coronary Artery Disease in the Kingdom of Saudi Arabia Population

PubMed Central

de Kovel, Carolien G.; Mulder, Flip; van Setten, Jessica; van ‘t Slot, Ruben; Al-Rubaish, Abdullah; Alshehri, Abdullah M.; Al Faraidy, Khalid; Al-Ali, Abdullah; Al-Madan, Mohammed; Al Aqaili, Issa; Larbi, Emmanuel; Al-Ali, Rudaynah; Alzahrani, Alhusain; Asselbergs, Folkert W.; Koeleman, Bobby P. C.; Al-Ali, Amein

2016-01-01

Coronary Artery Disease (CAD) remains the leading cause of mortality worldwide. Mortality rates associated with CAD have shown an exceptional increase particularly in fast developing economies like the Kingdom of Saudi Arabia (KSA). Over the past twenty years, CAD has become the leading cause of death in KSA and has reached epidemic proportions. This rise is undoubtedly caused by fast urbanization that is associated with a life-style that promotes CAD. However, the question remains whether genetics play a significant role and whether genetic susceptibility is increased in KSA compared to the well-studied Western European populations. Therefore, we performed an Exome-wide association study (EWAS) in 832 patients and 1,076 controls of Saudi Arabian origin to test whether population specific, strong genetic risk factors for CAD exist, or whether the polygenic risk score for known genetic risk factors for CAD, lipids, and Type 2 Diabetes show evidence for an enriched genetic burden. Our results do not show significant associations for a single genetic locus. However, the heritability estimate for CAD for this population was high (h2 = 0.53, S.E. = 0.1, p = 4e-12) and we observed a significant association of the polygenic risk score for CAD that demonstrates that the population of KSA, at least in part, shares the genetic risk associated to CAD in Western populations. PMID:26849363

PNPLA3 genetic variation in alcoholic steatosis and liver disease progression

PubMed Central

Hampe, Jochen; Trépo, Eric; Datz, Christian; Romeo, Stefano

2015-01-01

Alcoholic liver disease (ALD) accounts for the majority of chronic liver diseases in Western countries, and alcoholic cirrhosis is among the premier causes of liver failure, hepatocellular carcinoma (HCC) and liver-related mortality causes. Studies in different genders and ethnic groups, as well as in twins provide strong evidence for a significant contribution of host genetic factors to liver disease development in drinkers. The intense quest for genetic modifiers of alcohol-induced fibrosis progression have identified and repeatedly confirmed a genetic polymorphism in the gene coding for patatin-like phospholipase domain-containing 3 (PNPLA3; adiponutrin; rs738409 C/G, M148I) as a risk factor for alcoholic cirrhosis and its related complication, HCC, in different populations. Although carriership of one or both mutated PNPLA3 alleles does not explain the entire liver phenotypic variability in drinkers, it clearly represents one of the strongest single genetic modulators in a complex trait such as ALD. As more genetic data supporting its important role aggregates, novel insight as to PNPLA3’s function and that of its genetic variation in liver injury is unveiled pointing to an important novel pathway in alcohol-mediated hepatic lipid turnover with strong implications on inflammation, extra cellular matrix remodelling, and hepatocarcinogenesis. Future study shall decipher whether the gathered knowledge can be translated into therapeutic benefits of patients. PMID:26151055

The association of environmental, individual factors, and dopamine pathway gene variation with smoking cessation.

PubMed

Li, Suyun; Wang, Qiang; Pan, Lulu; Yang, Xiaorong; Li, Huijie; Jiang, Fan; Zhang, Nan; Han, Mingkui; Jia, Chongqi

2017-09-01

This study aimed to examine whether dopamine (DA) pathway gene variation were associated with smoking cessation, and compare the relative importance of infulence factors on smoking cessation. Participants were recruited from 17 villages of Shandong Province, China. Twenty-five single nucleotide polymorphisms in 8 DA pathway genes were genotyped. Weighted gene score of each gene was used to analyze the whole gene effect. Logistic regression was used to calculate odds ratios (OR) of the total gene score for smoking cessation. Dominance analysis was employed to compare the relative importance of individual, heaviness of smoking, psychological and genetic factors on smoking cessation. 415 successful spontaneous smoking quitters served as the cases, and 404 unsuccessful quitters served as the controls. A significant negative association of total DA pathway gene score and smoking cessation was observed (p < 0.001, OR: 0.25, 95% CI 0.16-0.38). Dominance analysis showed that the most important predictor for smoking cessation was heaviness of smoking score (42%), following by individual (40%), genetic (10%) and psychological score (8%). In conclusion, although the DA pathway gene variation was significantly associated with successful smoking cessation, heaviness of smoking and individual factors had bigger effect than genetic factors on smoking cessation.

Comprehensive genetic assessment of the human embryo: can empiric application of microarray comparative genomic hybridization reduce multiple gestation rate by single fresh blastocyst transfer?

PubMed

Sills, Eric Scott; Yang, Zhihong; Walsh, David J; Salem, Shala A

2012-09-01

The unacceptable multiple gestation rate currently associated with in vitro fertilization (IVF) would be substantially alleviated if the routine practice of transferring more than one embryo were reconsidered. While transferring a single embryo is an effective method to reduce the clinical problem of multiple gestation, rigid adherence to this approach has been criticized for negatively impacting clinical pregnancy success in IVF. In general, single embryo transfer is viewed cautiously by IVF patients although greater acceptance would result from a more effective embryo selection method. Selection of one embryo for fresh transfer on the basis of chromosomal normalcy should achieve the dual objective of maintaining satisfactory clinical pregnancy rates and minimizing the multiple gestation problem, because embryo aneuploidy is a major contributing factor in implantation failure and miscarriage in IVF. The initial techniques for preimplantation genetic screening unfortunately lacked sufficient sensitivity and did not yield the expected results in IVF. However, newer molecular genetic methods could be incorporated with standard IVF to bring the goal of single embryo transfer within reach. Aiming to make multiple embryo transfers obsolete and unnecessary, and recognizing that array comparative genomic hybridization (aCGH) will typically require an additional 12 h of laboratory time to complete, we propose adopting aCGH for mainstream use in clinical IVF practice. As aCGH technology continues to develop and becomes increasingly available at lower cost, it may soon be considered unusual for IVF laboratories to select a single embryo for fresh transfer without regard to its chromosomal competency. In this report, we provide a rationale supporting aCGH as the preferred methodology to provide a comprehensive genetic assessment of the single embryo before fresh transfer in IVF. The logistics and cost of integrating aCGH with IVF to enable fresh embryo transfer are also discussed.

Infectious mononucleosis-linked HLA class I single nucleotide polymorphism is associated with multiple sclerosis.

PubMed

Jafari, Naghmeh; Broer, Linda; Hoppenbrouwers, Ilse A; van Duijn, Cornelia M; Hintzen, Rogier Q

2010-11-01

Multiple sclerosis is a presumed autoimmune disease associated with genetic and environmental risk factors such as infectious mononucleosis. Recent research has shown infectious mononucleosis to be associated with a specific HLA class I polymorphism. Our aim was to test if the infectious mononucleosis-linked HLA class I single nucleotide polymorphism (rs6457110) is also associated with multiple sclerosis. Genotyping of the HLA-A single nucleotide polymorphism rs6457110 using TaqMan was performed in 591 multiple sclerosis cases and 600 controls. The association of multiple sclerosis with the HLA-A single nucleotide polymorphism was tested using logistic regression adjusted for age, sex and HLA-DRB1*1501. HLA-A minor allele (A) is associated with multiple sclerosis (OR = 0.68; p = 4.08 × 10( -5)). After stratification for HLA-DRB1*1501 risk allele (T) carrier we showed a significant OR of 0.70 (p = 0.003) for HLA-A. HLA class I single nucleotide polymorphism rs6457110 is associated with infectious mononucleosis and multiple sclerosis, independent of the major class II allele, supporting the hypothesis that shared genetics may contribute to the association between infectious mononucleosis and multiple sclerosis.

Gene flow connects coastal populations of a habitat specialist, the Clapper Rail Rallus crepitans

USGS Publications Warehouse

Coster, Stephanie S.; Welsh, Amy B.; Costanzo, Gary R.; Harding, Sergio R.; Anderson, James T.; Katzner, Todd

2018-01-01

Examining population genetic structure can reveal patterns of reproductive isolation or population mixing and inform conservation management. Some avian species are predicted to exhibit minimal genetic differentiation among populations as a result of the species high mobility, with habitat specialists tending to show greater fine‐scale genetic structure. To explore the relationship between habitat specialization and gene flow, we investigated the genetic structure of a saltmarsh specialist with high potential mobility across a wide geographic range of fragmented habitat. Little variation among mitochondrial sequences (620 bp from ND2) was observed among 149 individual Clapper Rails Rallus crepitans sampled along the Atlantic coast of North America, with the majority of individuals at all sampling sites sharing a single haplotype. Genotyping of nine microsatellite loci across 136 individuals revealed moderate genetic diversity, no evidence of bottlenecks, and a weak pattern of genetic differentiation that increased with geographic distance. Multivariate analyses, Bayesian clustering and an AMOVA all suggested a lack of genetic structuring across the North American Atlantic coast, with all individuals grouped into a single interbreeding population. Spatial autocorrelation analyses showed evidence of weak female philopatry and a lack of male philopatry. We conclude that high gene flow connecting populations of this habitat specialist may result from the interaction of ecological and behavioral factors that promote dispersal and limit natal philopatry and breeding‐site fidelity. As climate change threatens saltmarshes, the genetic diversity and population connectivity of Clapper Rails may promote resilience of their populations. This finding helps inform about potential fates of other similarly behaving saltmarsh specialists on the Atlantic coast.

Monogenic and chromosomal causes of isolated speech and language impairment.

PubMed

Barnett, C P; van Bon, B W M

2015-11-01

The importance of a precise molecular diagnosis for children with intellectual disability, autism spectrum disorder and epilepsy has become widely accepted and genetic testing is an integral part of the diagnostic evaluation of these children. In contrast, children with an isolated speech or language disorder are not often genetically evaluated, despite recent evidence supporting a role for genetic factors in the aetiology of these disorders. Several chromosomal copy number variants and single gene disorders associated with abnormalities of speech and language have been identified. Individuals without a precise genetic diagnosis will not receive optimal management including interventions such as early testosterone replacement in Klinefelter syndrome, otorhinolaryngological and audiometric evaluation in 22q11.2 deletion syndrome, cardiovascular surveillance in 7q11.23 duplications and early dietary management to prevent obesity in proximal 16p11.2 deletions. This review summarises the clinical features, aetiology and management options of known chromosomal and single gene disorders that are associated with speech and language pathology in the setting of normal or only mildly impaired cognitive function. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Genetic and non-iodine-related factors in the aetiology of nodular goitre.

PubMed

Knudsen, Nils; Brix, Thomas Heiberg

2014-08-01

Genetic and a large number of environmental non-iodine-related factors play a role in the cause of nodular goitre. Most evidence for the influence of genetic and environmental factors in the cause of goitre is from cross-sectional, population-based studies. Only a few studies have included prospective data on risk factors for nodular goitre, although few prospective data are available on the effect of iodine and tobacco smoking on goitre development. Goitre is not one single phenotype. Many epidemiological studies do not distinguish diffuse from nodular goitre, as the investigated parameter is often thyroid volume or frequency with increased thyroid volume. Moreover, information on the presence and effect of gene-environment, gene-gene, and environment-environment effect modifications is limited. Thus, firm conclusions about the relative contributions and causality of the investigated risk factors should be made with caution. Smoking seems to be an established risk factor for nodular goitre, possibly with effect modification from iodine intake, as the risk associated with smoking is smaller or absent in areas with sufficient iodine intake. The use of oral contraceptives might have protective effects against goitre, and childbirth is an increased risk factor for goitre in areas with non-optimal iodine intake. Insulin resistance is a recently investigated risk factor, and the risk of goitre may be reversible with metformin treatment. Iodine remains the major environmental risk factor for nodular goitre. Copyright © 2014 Elsevier Ltd. All rights reserved.

Interaction of insulin-like growth factor-I and insulin resistance-related genetic variants with lifestyle factors on postmenopausal breast cancer risk.

PubMed

Jung, Su Yon; Ho, Gloria; Rohan, Thomas; Strickler, Howard; Bea, Jennifer; Papp, Jeanette; Sobel, Eric; Zhang, Zuo-Feng; Crandall, Carolyn

2017-07-01

Genetic variants and traits in metabolic signaling pathways may interact with obesity, physical activity, and exogenous estrogen (E), influencing postmenopausal breast cancer risk, but these inter-related pathways are incompletely understood. We used 75 single-nucleotide polymorphisms (SNPs) in genes related to insulin-like growth factor-I (IGF-I)/insulin resistance (IR) traits and signaling pathways, and data from 1003 postmenopausal women in Women's Health Initiative Observation ancillary studies. Stratifying via obesity and lifestyle modifiers, we assessed the role of IGF-I/IR traits (fasting IGF-I, IGF-binding protein 3, insulin, glucose, and homeostatic model assessment-insulin resistance) in breast cancer risk as a mediator or influencing factor. Seven SNPs in IGF-I and INS genes were associated with breast cancer risk. These associations differed between non-obese/active and obese/inactive women and between exogenous E non-users and users. The mediation effects of IGF-I/IR traits on the relationship between these SNPs and cancer differed between strata, but only roughly 35% of the cancer risk due to the SNPs was mediated by traits. Similarly, carriers of 20 SNPs in PIK3R1, AKT1/2, and MAPK1 genes (signaling pathways-genetic variants) had different associations with breast cancer between strata, and the proportion of the SNP-cancer relationship explained by traits varied 45-50% between the strata. Our findings suggest that IGF-I/IR genetic variants interact with obesity and lifestyle factors, altering cancer risk partially through pathways other than IGF-I/IR traits. Unraveling gene-phenotype-lifestyle interactions will provide data on potential genetic targets in clinical trials for cancer prevention and intervention strategies to reduce breast cancer risk.

The value of genetic information for diabetes risk prediction - differences according to sex, age, family history and obesity.

PubMed

Mühlenbruch, Kristin; Jeppesen, Charlotte; Joost, Hans-Georg; Boeing, Heiner; Schulze, Matthias B

2013-01-01

Genome-wide association studies have identified numerous single nucleotide polymorphisms associated with type 2 diabetes through the past years. In previous studies, the usefulness of these genetic markers for prediction of diabetes was found to be limited. However, differences may exist between substrata of the population according to the presence of major diabetes risk factors. This study aimed to investigate the added predictive value of genetic information (42 single nucleotide polymorphisms) in subgroups of sex, age, family history of diabetes, and obesity. A case-cohort study (random subcohort N = 1,968; incident cases: N = 578) within the European Prospective Investigation into Cancer and Nutrition Potsdam study was used. Prediction models without and with genetic information were evaluated in terms of the area under the receiver operating characteristic curve and the integrated discrimination improvement. Stratified analyses included subgroups of sex, age (<50 or ≥50 years), family history (positive if either father or mother or a sibling has/had diabetes), and obesity (BMI< or ≥30 kg/m(2)). A genetic risk score did not improve prediction above classic and metabolic markers, but - compared to a non-invasive prediction model - genetic information slightly improved the area under the receiver operating characteristic curve (difference [95%-CI]: 0.007 [0.002-0.011]). Stratified analyses showed stronger improvement in the older age group (0.010 [0.002-0.018]), the group with a positive family history (0.012 [0.000-0.023]) and among obese participants (0.015 [-0.005-0.034]) compared to the younger participants (0.005 [-0.004-0.014]), participants with a negative family history (0.003 [-0.001-0.008]) and non-obese (0.007 [0.000-0.014]), respectively. No difference was found between men and women. There was no incremental value of genetic information compared to standard non-invasive and metabolic markers. Our study suggests that inclusion of genetic variants in diabetes risk prediction might be useful for subgroups with already manifest risk factors such as older age, a positive family history and obesity.

Genetics and Genomics of Single-Gene Cardiovascular Diseases: Common Hereditary Cardiomyopathies as Prototypes of Single-Gene Disorders

PubMed Central

Marian, Ali J.; van Rooij, Eva; Roberts, Robert

2016-01-01

This is the first of 2 review papers on genetics and genomics appearing as part of the series on “omics.” Genomics pertains to all components of an organism’s genes, whereas genetics involves analysis of a specific gene(s) in the context of heredity. The paper provides introductory comments, describes the basis of human genetic diversity, and addresses the phenotypic consequences of genetic variants. Rare variants with large effect sizes are responsible for single-gene disorders, whereas complex polygenic diseases are typically due to multiple genetic variants, each exerting a modest effect size. To illustrate the clinical implications of genetic variants with large effect sizes, 3 common forms of hereditary cardiomyopathies are discussed as prototypic examples of single-gene disorders, including their genetics, clinical manifestations, pathogenesis, and treatment. The genetic basis of complex traits is discussed in a separate paper. PMID:28007145

The effects of socioeconomic status, clinical factors, and genetic ancestry on pulmonary tuberculosis disease in northeastern Mexico.

PubMed

Young, Bonnie N; Rendón, Adrian; Rosas-Taraco, Adrian; Baker, Jack; Healy, Meghan; Gross, Jessica M; Long, Jeffrey; Burgos, Marcos; Hunley, Keith L

2014-01-01

Diverse socioeconomic and clinical factors influence susceptibility to tuberculosis (TB) disease in Mexico. The role of genetic factors, particularly those that differ between the parental groups that admixed in Mexico, is unclear. The objectives of this study are to identify the socioeconomic and clinical predictors of the transition from latent TB infection (LTBI) to pulmonary TB disease in an urban population in northeastern Mexico, and to examine whether genetic ancestry plays an independent role in this transition. We recruited 97 pulmonary TB disease patients and 97 LTBI individuals from a public hospital in Monterrey, Nuevo León. Socioeconomic and clinical variables were collected from interviews and medical records, and genetic ancestry was estimated for a subset of 142 study participants from 291,917 single nucleotide polymorphisms (SNPs). We examined crude associations between the variables and TB disease status. Significant predictors from crude association tests were analyzed using multivariable logistic regression. We also compared genetic ancestry between LTBI individuals and TB disease patients at 1,314 SNPs in 273 genes from the TB biosystem in the NCBI BioSystems database. In crude association tests, 12 socioeconomic and clinical variables were associated with TB disease. Multivariable logistic regression analyses indicated that marital status, diabetes, and smoking were independently associated with TB status. Genetic ancestry was not associated with TB disease in either crude or multivariable analyses. Separate analyses showed that LTBI individuals recruited from hospital staff had significantly higher European genetic ancestry than LTBI individuals recruited from the clinics and waiting rooms. Genetic ancestry differed between individuals with LTBI and TB disease at SNPs located in two genes in the TB biosystem. These results indicate that Monterrey may be structured with respect to genetic ancestry, and that genetic differences in TB susceptibility in parental populations may contribute to variation in disease susceptibility in the region.

The Effects of Socioeconomic Status, Clinical Factors, and Genetic Ancestry on Pulmonary Tuberculosis Disease in Northeastern Mexico

PubMed Central

Young, Bonnie N.; Rendón, Adrian; Rosas-Taraco, Adrian; Baker, Jack; Healy, Meghan; Gross, Jessica M.; Long, Jeffrey; Burgos, Marcos; Hunley, Keith L.

2014-01-01

Diverse socioeconomic and clinical factors influence susceptibility to tuberculosis (TB) disease in Mexico. The role of genetic factors, particularly those that differ between the parental groups that admixed in Mexico, is unclear. The objectives of this study are to identify the socioeconomic and clinical predictors of the transition from latent TB infection (LTBI) to pulmonary TB disease in an urban population in northeastern Mexico, and to examine whether genetic ancestry plays an independent role in this transition. We recruited 97 pulmonary TB disease patients and 97 LTBI individuals from a public hospital in Monterrey, Nuevo León. Socioeconomic and clinical variables were collected from interviews and medical records, and genetic ancestry was estimated for a subset of 142 study participants from 291,917 single nucleotide polymorphisms (SNPs). We examined crude associations between the variables and TB disease status. Significant predictors from crude association tests were analyzed using multivariable logistic regression. We also compared genetic ancestry between LTBI individuals and TB disease patients at 1,314 SNPs in 273 genes from the TB biosystem in the NCBI BioSystems database. In crude association tests, 12 socioeconomic and clinical variables were associated with TB disease. Multivariable logistic regression analyses indicated that marital status, diabetes, and smoking were independently associated with TB status. Genetic ancestry was not associated with TB disease in either crude or multivariable analyses. Separate analyses showed that LTBI individuals recruited from hospital staff had significantly higher European genetic ancestry than LTBI individuals recruited from the clinics and waiting rooms. Genetic ancestry differed between individuals with LTBI and TB disease at SNPs located in two genes in the TB biosystem. These results indicate that Monterrey may be structured with respect to genetic ancestry, and that genetic differences in TB susceptibility in parental populations may contribute to variation in disease susceptibility in the region. PMID:24728409

Developmental Dyslexia: Early Precursors, Neurobehavioral Markers, and Biological Substrates

ERIC Educational Resources Information Center

Benasich, April A., Ed.; Fitch, R. Holly, Ed.

2012-01-01

Understanding the precursors and early indicators of dyslexia is key to early identification and effective intervention. Now there's a single research volume that brings together the very latest knowledge on the earliest stages of dyslexia and the diverse genetic, neurobiological, and cognitive factors that may contribute to it. Based on findings…

Different Neurodevelopmental Symptoms Have a Common Genetic Etiology

ERIC Educational Resources Information Center

Pettersson, Erik; Anckarsäter, Henrik; Gillberg, Christopher; Lichtenstein, Paul

2013-01-01

Background: Although neurodevelopmental disorders are demarcated as discrete entities in the Diagnostic Statistical Manual of mental disorders, empirical evidence indicates that there is a high degree of overlap among them. The first aim of this investigation was to explore if a single general factor could account for the large degree of observed…

Young People's Aggressive Behavior in the Context of the Social Situation

ERIC Educational Resources Information Center

Drozdov, A. Iu.

2005-01-01

Aggressive behavior by young people is one of the most urgent social problems. Rising violent crime among adolescents is being observed over the entire post-Soviet space. Scientists have singled out a number of groups of factors causing an individual to engage in aggressive behavior--biological, genetic, and individual psychological…

How single nucleotide polymorphism chips will advance our knowledge of factors controlling puberty and aid in selecting replacement beef females

USDA-ARS?s Scientific Manuscript database

The promise of genomic selection is accurate prediction of animals' genetic potential from their genotypes. Simple DNA tests might replace low accuracy predictions for expensive or lowly heritable measures of puberty and fertility based on performance and pedigree. Knowing which DNA variants affec...

N-acetyltransferase single nucleotide polymorphisms: Emerging concepts serve as a paradigm for understanding complexities of personalized medicine

PubMed Central

Hein, David W.

2009-01-01

Arylamine N-acetyltransferase 1 (NAT1) and 2 (NAT2) exhibit single nucleotide polymorphisms (SNPs) in human populations that modify drug and carcinogen metabolism. This paper updates the identity, location, and functional effects of these SNPs and then follows with emerging concepts for understanding why pharmacogenetic findings may not be replicated consistently. Using this paradigm as an example, laboratory-based mechanistic analyses can reveal complexities such that genetic polymorphisms become biologically and medically relevant when confounding factors are more fully understood and considered. As medical care moves to a more personalized approach, the implications of these confounding factors will be important in understanding the complexities of personalized medicine. PMID:19379125

Beyond main effects of gene-sets: harsh parenting moderates the association between a dopamine gene-set and child externalizing behavior.

PubMed

Windhorst, Dafna A; Mileva-Seitz, Viara R; Rippe, Ralph C A; Tiemeier, Henning; Jaddoe, Vincent W V; Verhulst, Frank C; van IJzendoorn, Marinus H; Bakermans-Kranenburg, Marian J

2016-08-01

In a longitudinal cohort study, we investigated the interplay of harsh parenting and genetic variation across a set of functionally related dopamine genes, in association with children's externalizing behavior. This is one of the first studies to employ gene-based and gene-set approaches in tests of Gene by Environment (G × E) effects on complex behavior. This approach can offer an important alternative or complement to candidate gene and genome-wide environmental interaction (GWEI) studies in the search for genetic variation underlying individual differences in behavior. Genetic variants in 12 autosomal dopaminergic genes were available in an ethnically homogenous part of a population-based cohort. Harsh parenting was assessed with maternal (n = 1881) and paternal (n = 1710) reports at age 3. Externalizing behavior was assessed with the Child Behavior Checklist (CBCL) at age 5 (71 ± 3.7 months). We conducted gene-set analyses of the association between variation in dopaminergic genes and externalizing behavior, stratified for harsh parenting. The association was statistically significant or approached significance for children without harsh parenting experiences, but was absent in the group with harsh parenting. Similarly, significant associations between single genes and externalizing behavior were only found in the group without harsh parenting. Effect sizes in the groups with and without harsh parenting did not differ significantly. Gene-environment interaction tests were conducted for individual genetic variants, resulting in two significant interaction effects (rs1497023 and rs4922132) after correction for multiple testing. Our findings are suggestive of G × E interplay, with associations between dopamine genes and externalizing behavior present in children without harsh parenting, but not in children with harsh parenting experiences. Harsh parenting may overrule the role of genetic factors in externalizing behavior. Gene-based and gene-set analyses offer promising new alternatives to analyses focusing on single candidate polymorphisms when examining the interplay between genetic and environmental factors.

Molecular Genetic of Atopic dermatitis: An Update

PubMed Central

Al-Shobaili, Hani A.; Ahmed, Ahmed A.; Alnomair, Naief; Alobead, Zeiad Abdulaziz; Rasheed, Zafar

2016-01-01

Atopic dermatitis (AD) is a chronic multifactorial inflammatory skin disease. The pathogenesis of AD remains unclear, but the disease results from dysfunctions of skin barrier and immune response, where both genetic and environmental factors play a key role. Recent studies demonstrate the substantial evidences that show a strong genetic association with AD. As for example, AD patients have a positive family history and have a concordance rate in twins. Moreover, several candidate genes have now been suspected that play a central role in the genetic background of AD. In last decade advanced procedures similar to genome-wide association (GWA) and single nucleotide polymorphism (SNP) have been applied on different population and now it has been clarified that AD is significantly associated with genes of innate/adaptive immune systems, human leukocyte antigens (HLA), cytokines, chemokines, drug-metabolizing genes or various other genes. In this review, we will highlight the recent advancements in the molecular genetics of AD, especially on possible functional relevance of genetic variants discovered to date. PMID:27004062

Genetic variability in sublethal tolerance to mixtures of cadmium and zinc in clones of Daphnia magna Straus.

PubMed

Barata, Carlos; Markich, Scott J; Baird, Donald J; Taylor, Graeme; Soares, Amadeu M V M

2002-10-02

To date, studies on genetic variability in the tolerance of aquatic biota to chemicals have focused on exposure to single chemicals. In the field, metals occur as elemental mixtures, and thus it is essential to study whether the genetic consequences of exposure to such mixtures differs from response to single chemicals. This study determined the feeding responses of three Daphnia magna Straus clones exposed to Cd and Zn, both individually and as mixtures. Tolerance to mixtures of Cd and Zn was expressed as the proportional feeding depression of D. magna to Cd at increasing zinc concentrations. A quantitative genetic analysis revealed that genotype and genotype x environmental factors governed population responses to mixtures of both metals. More specifically, genetic variation in tolerance to sublethal levels of Cd decreased at those Zn concentrations where there were no effects on feeding, and increased again at Zn concentrations that affected feeding. The existence of genotype x environmental interactions indicated that the genetic consequences of exposing D. magna to mixtures of Cd and Zn cannot be predicted from the animals' response to single metals alone. Therefore, current ecological risk assessment methodologies for predicting the effects of chemical mixtures may wish to incorporate the concept of genetic variability. Furthermore, exposure to low and moderate concentrations of Zn increased the sublethal tolerance to Cd. This induction of tolerance to Cd by Zn was also observed for D. magna fed algae pre-loaded with both metals. Furthermore, in only one clone, physiological acclimatization to zinc also induced tolerance to cadmium. These results suggest that the feeding responses of D. magna may be related to gut poisoning induced by the release of metals from algae under low pH conditions. In particular, both induction of metallothionein synthesis by Zn and competition between Zn and Cd ions for uptake at target sites on the gut wall may be involved in determining sublethal responses to mixtures of both metals.

Financial and Psychological Risk Attitudes Associated with Two Single Nucleotide Polymorphisms in the Nicotine Receptor (CHRNA4) Gene

PubMed Central

Roe, Brian E.; Tilley, Michael R.; Gu, Howard H.; Beversdorf, David Q.; Sadee, Wolfgang; Haab, Timothy C.; Papp, Audrey C.

2009-01-01

With recent advances in understanding of the neuroscience of risk taking, attention is now turning to genetic factors that may contribute to individual heterogeneity in risk attitudes. In this paper we test for genetic associations with risk attitude measures derived from both the psychology and economics literature. To develop a long-term prospective study, we first evaluate both types of risk attitudes and find that the economic and psychological measures are poorly correlated, suggesting that different genetic factors may underlie human response to risk faced in different behavioral domains. We then examine polymorphisms in a spectrum of candidate genes that affect neurotransmitter systems influencing dopamine regulation or are thought to be associated with risk attitudes or impulsive disorders. Analysis of the genotyping data identified two single nucleotide polymorphisms (SNPs) in the gene encoding the alpha 4 nicotine receptor (CHRNA4, rs4603829 and rs4522666) that are significantly associated with harm avoidance, a risk attitude measurement drawn from the psychology literature. Novelty seeking, another risk attitude measure from the psychology literature, is associated with several COMT (catechol-O-methyl transferase) SNPs while economic risk attitude measures are associated with several VMAT2 (vesicular monoamine transporter) SNPs, but the significance of these associations did not withstand statistical adjustment for multiple testing and requires larger cohorts. These exploratory results provide a starting point for understanding the genetic basis of risk attitudes by considering the range of methods available for measuring risk attitudes and by searching beyond the traditional direct focus on dopamine and serotonin receptor and transporter genes. PMID:19693267

[Virulence factors and pathophysiology of extraintestinal pathogenic Escherichia coli].

PubMed

Bidet, P; Bonarcorsi, S; Bingen, E

2012-11-01

Extraintestinal pathogenic Escherichia coli (ExPEC) causing urinary tract infections, bacteraemia or meningitis are characterized by a particular genetic background (phylogenetic group B2 and D) and the presence, within genetic pathogenicity islands (PAI) or plasmids, of genes encoding virulence factors involved in adhesion to epithelia, crossing of the body barriers (digestive, kidney, bloodbrain), iron uptake and resistance to the immune system. Among the many virulence factors described, two are particularly linked with a pathophysiological process: type P pili PapGII adhesin is linked with acute pyelonephritis, in the absence of abnormal flow of urine, and the K1 capsule is linked with neonatal meningitis. However, if the adhesin PapGII appears as the key factor of pyelonephritis, such that its absence in strain causing the infection is predictive of malformation or a vesico-ureteral reflux, the meningeal virulence of E. coli can not be reduced to a single virulence factor, but results from a combination of factors unique to each clone, and an imbalance between the immune defenses of the host and bacterial virulence. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Genetic and Non-genetic Factors Associated With Constipation in Cancer Patients Receiving Opioids

PubMed Central

Laugsand, Eivor A; Skorpen, Frank; Kaasa, Stein; Sabatowski, Rainer; Strasser, Florian; Fayers, Peter; Klepstad, Pål

2015-01-01

Objectives: To examine whether the inter-individual variation in constipation among patients receiving opioids for cancer pain is associated with genetic or non-genetic factors. Methods: Cancer patients receiving opioids were included from 17 centers in 11 European countries. Intensity of constipation was reported by 1,568 patients on a four-point categorical scale. Non-genetic factors were included as covariates in stratified regression analyses on the association between constipation and 75 single-nucleotide polymorphisms (SNPs) within 15 candidate genes related to opioid- or constipation-signaling pathways (HTR3E, HTR4, HTR2A, TPH1, ADRA2A, CHRM3, TACR1, CCKAR, KIT, ARRB2, GHRL, ABCB1, COMT, OPRM1, and OPRD1). Results: The non-genetic factors significantly associated with constipation were type of laxative, mobility and place of care among patients receiving laxatives (N=806), in addition to Karnofsky performance status and presence of metastases among patients not receiving laxatives (N=762) (P<0.01). Age, gender, body mass index, cancer diagnosis, time on opioids, opioid dose, and type of opioid did not contribute to the inter-individual differences in constipation. Five SNPs, rs1800532 in TPH1, rs1799971 in OPRM1, rs4437575 in ABCB1, rs10802789 in CHRM3, and rs2020917 in COMT were associated with constipation (P<0.01). Only rs2020917 in COMT passed the Benjamini–Hochberg criterion for a 10% false discovery rate. Conclusions: Type of laxative, mobility, hospitalization, Karnofsky performance status, presence of metastases, and five SNPs within TPH1, OPRM1, ABCB1, CHRM3, and COMT may contribute to the variability in constipation among cancer patients treated with opioids. Knowledge of these factors may help to develop new therapies and to identify patients needing a more individualized approach to treatment. PMID:26087058

[Advances in genetic research of cerebral palsy].

PubMed

Wang, Fang-Fang; Luo, Rong; Qu, Yi; Mu, De-Zhi

2017-09-01

Cerebral palsy is a group of syndromes caused by non-progressive brain injury in the fetus or infant and can cause disabilities in childhood. Etiology of cerebral palsy has always been a hot topic for clinical scientists. More and more studies have shown that genetic factors are closely associated with the development of cerebral palsy. With the development and application of various molecular and biological techniques such as chromosome microarray analysis, genome-wide association study, and whole exome sequencing, new achievements have been made in the genetic research of cerebral palsy. Chromosome abnormalities, copy number variations, susceptibility genes, and single gene mutation associated with the development of cerebral palsy have been identified, which provides new opportunities for the research on the pathogenesis of cerebral palsy. This article reviews the advances in the genetic research on cerebral palsy in recent years.

The Glass is Half Full and Half Empty: A population-representative twin study testing if Optimism and Pessimism are distinct systems

PubMed Central

Bates, Timothy C.

2015-01-01

Optimism and pessimism are associated with important outcomes including health and depression. Yet it is unclear if these apparent polar opposites form a single dimension or reflect two distinct systems. The extent to which personality accounts for differences in optimism/pessimism is also controversial. Here, we addressed these questions in a genetically informative sample of 852 pairs of twins. Distinct genetic influences on optimism and pessimism were found. Significant family-level environment effects also emerged, accounting for much of the negative relationship between optimism and pessimism, as well as a link to neuroticism. A general positive genetics factor exerted significant links among both personality and life-orientation traits. Both optimism bias and pessimism also showed genetic variance distinct from all effects of personality, and from each other. PMID:26561494

Use of allele scores as instrumental variables for Mendelian randomization

PubMed Central

Burgess, Stephen; Thompson, Simon G

2013-01-01

Background An allele score is a single variable summarizing multiple genetic variants associated with a risk factor. It is calculated as the total number of risk factor-increasing alleles for an individual (unweighted score), or the sum of weights for each allele corresponding to estimated genetic effect sizes (weighted score). An allele score can be used in a Mendelian randomization analysis to estimate the causal effect of the risk factor on an outcome. Methods Data were simulated to investigate the use of allele scores in Mendelian randomization where conventional instrumental variable techniques using multiple genetic variants demonstrate ‘weak instrument’ bias. The robustness of estimates using the allele score to misspecification (for example non-linearity, effect modification) and to violations of the instrumental variable assumptions was assessed. Results Causal estimates using a correctly specified allele score were unbiased with appropriate coverage levels. The estimates were generally robust to misspecification of the allele score, but not to instrumental variable violations, even if the majority of variants in the allele score were valid instruments. Using a weighted rather than an unweighted allele score increased power, but the increase was small when genetic variants had similar effect sizes. Naive use of the data under analysis to choose which variants to include in an allele score, or for deriving weights, resulted in substantial biases. Conclusions Allele scores enable valid causal estimates with large numbers of genetic variants. The stringency of criteria for genetic variants in Mendelian randomization should be maintained for all variants in an allele score. PMID:24062299

Genetic polymorphisms and their association with the prevalence and severity of chronic postsurgical pain: a systematic review.

PubMed

Hoofwijk, D M N; van Reij, R R I; Rutten, B P; Kenis, G; Buhre, W F; Joosten, E A

2016-12-01

Although several patient characteristic, clinical, and psychological risk factors for chronic postsurgical pain (CPSP) have been identified, genetic variants including single nucleotide polymorphisms have also become of interest as potential risk factors for the development of CPSP. The aim of this review is to summarize the current evidence on genetic polymorphisms associated with the prevalence and severity of CPSP in adult patients. A systematic review of the literature was performed, and additional literature was obtained by reference tracking. The primary outcome was CPSP, defined as pain at least 2 months after the surgery. Studies performed exclusively in animals were excluded. Out of the 1001 identified studies, 14 studies were selected for inclusion. These studies described 5269 participants in 17 cohorts. A meta-analysis was not possible because of heterogeneity of data and data analysis. Associations with the prevalence or severity of CPSP were reported for genetic variants in the COMT gene, OPRM1, potassium channel genes, GCH1, CACNG, CHRNA6, P2X7R, cytokine-associated genes, human leucocyte antigens, DRD2, and ATXN1 CONCLUSIONS: Research on the topic of genetic variants associated with CPSP is still in its initial phase. Hypothesis-free, genome-wide association studies on large cohorts are needed in this field. In addition, future studies may also integrate genetic risk factors and patient characteristic, clinical, and psychological predictors for CPSP. © The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Genetic data and the listing of species under the U.S. Endangered Species Act.

PubMed

Fallon, Sylvia M

2007-10-01

Genetic information is becoming an influential factor in determining whether species, subspecies, and distinct population segments qualify for protection under the U.S. Endangered Species Act. Nevertheless, there are currently no standards or guidelines that define how genetic information should be used by the federal agencies that administer the act. I examined listing decisions made over a 10-year period (February 1996-February 2006) that relied on genetic information. There was wide variation in the genetic data used to inform listing decisions in terms of which genomes (mitochondrial vs. nuclear) were sampled and the number of markers (or genetic techniques) and loci evaluated. In general, whether the federal agencies identified genetic distinctions between putative taxonomic units or populations depended on the type and amount of genetic data. Studies that relied on multiple genetic markers were more likely to detect distinctions, and those organisms were more likely to receive protection than studies that relied on a single genetic marker. Although the results may, in part, reflect the corresponding availability of genetic techniques over the given time frame, the variable use of genetic information for listing decisions has the potential to misguide conservation actions. Future management policy would benefit from guidelines for the critical evaluation of genetic information to list or delist organisms under the Endangered Species Act.

Formation and specification of a Drosophila dopaminergic precursor cell.

PubMed

Watson, Joseph D; Crews, Stephen T

2012-09-01

Dopaminergic neurons play important roles in animal behavior, including motivation, reward and locomotion. The Drosophila dopaminergic H-cell interneuron is an attractive system for studying the genetics of neural development because analysis is focused on a single neuronal cell type. Here we provide a mechanistic understanding of how MP3, the precursor to the H-cell, forms and acquires its identity. We show that the gooseberry/gooseberry-neuro (gsb/gsb-n) transcription factor genes act to specify MP3 cell fate. It is proposed that single-minded commits neuroectodermal cells to a midline fate, followed by a series of signaling events that result in the formation of a single gsb(+)/gsb-n(+) MP3 cell per segment. The wingless signaling pathway establishes a midline anterior domain by activating expression of the forkhead transcription factors sloppy paired 1 and sloppy paired 2. This is followed by hedgehog signaling that activates gsb/gsb-n expression in a subgroup of anterior cells. Finally, Notch signaling results in the selection of a single MP3, with the remaining cells becoming midline glia. In MP3, gsb/gsb-n direct H-cell development, in large part by activating expression of the lethal of scute and tailup H-cell regulatory genes. Thus, a series of signaling and transcriptional events result in the specification of a unique dopaminergic precursor cell. Additional genetic experiments indicate that the molecular mechanisms that govern MP3/H-cell development might also direct the development of non-midline dopaminergic neurons.

Formation and specification of a Drosophila dopaminergic precursor cell

PubMed Central

Watson, Joseph D.; Crews, Stephen T.

2012-01-01

Dopaminergic neurons play important roles in animal behavior, including motivation, reward and locomotion. The Drosophila dopaminergic H-cell interneuron is an attractive system for studying the genetics of neural development because analysis is focused on a single neuronal cell type. Here we provide a mechanistic understanding of how MP3, the precursor to the H-cell, forms and acquires its identity. We show that the gooseberry/gooseberry-neuro (gsb/gsb-n) transcription factor genes act to specify MP3 cell fate. It is proposed that single-minded commits neuroectodermal cells to a midline fate, followed by a series of signaling events that result in the formation of a single gsb+/gsb-n+ MP3 cell per segment. The wingless signaling pathway establishes a midline anterior domain by activating expression of the forkhead transcription factors sloppy paired 1 and sloppy paired 2. This is followed by hedgehog signaling that activates gsb/gsb-n expression in a subgroup of anterior cells. Finally, Notch signaling results in the selection of a single MP3, with the remaining cells becoming midline glia. In MP3, gsb/gsb-n direct H-cell development, in large part by activating expression of the lethal of scute and tailup H-cell regulatory genes. Thus, a series of signaling and transcriptional events result in the specification of a unique dopaminergic precursor cell. Additional genetic experiments indicate that the molecular mechanisms that govern MP3/H-cell development might also direct the development of non-midline dopaminergic neurons. PMID:22874915

Analysis of the trap gene provides evidence for the role of elevation and vector abundance in the genetic diversity of Plasmodium relictum in Hawaii

USGS Publications Warehouse

Farias, Margaret E.M.; Atkinson, Carter T.; LaPointe, Dennis A.; Jarvi, Susan I.

2012-01-01

Background: The avian disease system in Hawaii offers an ideal opportunity to investigate host-pathogen interactions in a natural setting. Previous studies have recognized only a single mitochondrial lineage of avian malaria (Plasmodium relictum) in the Hawaiian Islands, but cloning and sequencing of nuclear genes suggest a higher degree of genetic diversity. Methods: In order to evaluate genetic diversity of P. relictum at the population level and further understand host-parasite interactions, a modified single-base extension (SBE) method was used to explore spatial and temporal distribution patterns of single nucleotide polymorphisms (SNPs) in the thrombospondin-related anonymous protein (trap) gene of P. relictum infections from 121 hatch-year amakihi (Hemignathus virens) on the east side of Hawaii Island. Results: Rare alleles and mixed infections were documented at three of eight SNP loci; this is the first documentation of genetically diverse infections of P. relictum at the population level in Hawaii. Logistic regression revealed that the likelihood of infection with a rare allele increased at low-elevation, but decreased as mosquito capture rates increased. The inverse relationship between vector capture rates and probability of infection with a rare allele is unexpected given current theories of epidemiology developed in human malarias. Conclusions: The results of this study suggest that pathogen diversity in Hawaii may be driven by a complex interaction of factors including transmission rates, host immune pressures, and parasite-parasite competition.

Analysis of the trap gene provides evidence for the role of elevation and vector abundance in the genetic diversity of Plasmodium relictum in Hawaii

PubMed Central

2012-01-01

Background The avian disease system in Hawaii offers an ideal opportunity to investigate host-pathogen interactions in a natural setting. Previous studies have recognized only a single mitochondrial lineage of avian malaria (Plasmodium relictum) in the Hawaiian Islands, but cloning and sequencing of nuclear genes suggest a higher degree of genetic diversity. Methods In order to evaluate genetic diversity of P. relictum at the population level and further understand host-parasite interactions, a modified single-base extension (SBE) method was used to explore spatial and temporal distribution patterns of single nucleotide polymorphisms (SNPs) in the thrombospondin-related anonymous protein (trap) gene of P. relictum infections from 121 hatch-year amakihi (Hemignathus virens) on the east side of Hawaii Island. Results Rare alleles and mixed infections were documented at three of eight SNP loci; this is the first documentation of genetically diverse infections of P. relictum at the population level in Hawaii. Logistic regression revealed that the likelihood of infection with a rare allele increased at low-elevation, but decreased as mosquito capture rates increased. The inverse relationship between vector capture rates and probability of infection with a rare allele is unexpected given current theories of epidemiology developed in human malarias. Conclusions The results of this study suggest that pathogen diversity in Hawaii may be driven by a complex interaction of factors including transmission rates, host immune pressures, and parasite-parasite competition. PMID:22943788

Analysis of the trap gene provides evidence for the role of elevation and vector abundance in the genetic diversity of Plasmodium relictum in Hawaii.

PubMed

Farias, Margaret E M; Atkinson, Carter T; LaPointe, Dennis A; Jarvi, Susan I

2012-09-03

The avian disease system in Hawaii offers an ideal opportunity to investigate host-pathogen interactions in a natural setting. Previous studies have recognized only a single mitochondrial lineage of avian malaria (Plasmodium relictum) in the Hawaiian Islands, but cloning and sequencing of nuclear genes suggest a higher degree of genetic diversity. In order to evaluate genetic diversity of P. relictum at the population level and further understand host-parasite interactions, a modified single-base extension (SBE) method was used to explore spatial and temporal distribution patterns of single nucleotide polymorphisms (SNPs) in the thrombospondin-related anonymous protein (trap) gene of P. relictum infections from 121 hatch-year amakihi (Hemignathus virens) on the east side of Hawaii Island. Rare alleles and mixed infections were documented at three of eight SNP loci; this is the first documentation of genetically diverse infections of P. relictum at the population level in Hawaii. Logistic regression revealed that the likelihood of infection with a rare allele increased at low-elevation, but decreased as mosquito capture rates increased. The inverse relationship between vector capture rates and probability of infection with a rare allele is unexpected given current theories of epidemiology developed in human malarias. The results of this study suggest that pathogen diversity in Hawaii may be driven by a complex interaction of factors including transmission rates, host immune pressures, and parasite-parasite competition.

GABA receptors, alcohol dependence and criminal behavior.

PubMed

Terranova, Claudio; Tucci, Marianna; Sartore, Daniela; Cavarzeran, Fabiano; Di Pietra, Laura; Barzon, Luisa; Palù, Giorgio; Ferrara, Santo D

2013-09-01

The aim of this study was to analyze the connection between alcohol dependence and criminal behavior by an integrated genetic-environmental approach. The research, structured as a case-control study, examined 186 alcohol-dependent males; group 1 (N = 47 convicted subjects) was compared with group 2 (N = 139 no previous criminal records). Genetic results were innovative, highlighting differences in genotype distribution (p = 0.0067) in group 1 for single-nucleotide polymorphism rs 3780428, located in the intronic region of subunit 2 of the GABA B receptor gene (GABBR2). Some environmental factors (e.g., grade repetition) were associated with criminal behavior; others (e.g., attendance at Alcoholics Anonymous) were inversely related to convictions. The concomitant presence of the genetic and environmental factors found to be associated with the condition of alcohol-dependent inmate showed a 4-fold increase in the risk of antisocial behavior. The results need to be replicated on a larger population to develop new preventive and therapeutic proposals. © 2013 American Academy of Forensic Sciences.

The association between romantic relationship status and 5-HT1A gene in young adults.

PubMed

Liu, Jinting; Gong, Pingyuan; Zhou, Xiaolin

2014-11-20

What factors determine whether or not a young adult will fall in love? Sociological surveys and psychological studies have shown that non-genetic factors, such as socioeconomic status, external appearance, and personality attributes, are crucial components in romantic relationship formation. Here we demonstrate that genetic variants also contribute to romantic relationship formation. As love-related behaviors are associated with serotonin levels in the brain, this study investigated to what extent a polymorphism (C-1019G, rs6295) of 5-HT1A gene is related to relationship status in 579 Chinese Han people. We found that 50.4% of individuals with the CC genotype and 39.0% with CG/GG genotype were in romantic relationship. Logistic regression analysis indicated that the C-1019G polymorphism was significantly associated with the odds of being single both before and after controlling for socioeconomic status, external appearance, religious beliefs, parenting style, and depressive symptoms. These findings provide, for the first time, direct evidence for the genetic contribution to romantic relationship formation.

Heritability and molecular-genetic basis of the P3 event-related brain potential: A genome-wide association study

PubMed Central

MALONE, STEPHEN M.; VAIDYANATHAN, UMA; BASU, SAONLI; MILLER, MICHAEL B.; MCGUE, MATT; IACONO, WILLIAM G.

2014-01-01

P3 amplitude is a candidate endophenotype for disinhibitory psychopathology, psychosis, and other disorders. The present study is a comprehensive analysis of the behavioral- and molecular-genetic basis of P3 amplitude and a P3 genetic factor score in a large community sample (N = 4,211) of adolescent twins and their parents, genotyped for 527,829 single nucleotide polymorphisms (SNPs). Biometric models indicated that as much as 65% of the variance in each measure was due to additive genes. All SNPs in aggregate accounted for approximately 40% to 50% of the heritable variance. However, analyses of individual SNPs did not yield any significant associations. Analyses of individual genes did not confirm previous associations between P3 amplitude and candidate genes but did yield a novel association with myelin expression factor 2 (MYEF2). Main effects of individual variants may be too small to be detected by GWAS without larger samples. PMID:25387705

Single-Locus versus Multilocus Patterns of Local Adaptation to Climate in Eastern White Pine (Pinus strobus, Pinaceae)

PubMed Central

Zinck, John W. R.

2016-01-01

Natural plant populations are often adapted to their local climate and environmental conditions, and populations of forest trees offer some of the best examples of this pattern. However, little empirical work has focused on the relative contribution of single-locus versus multilocus effects to the genetic architecture of local adaptation in plants/forest trees. Here, we employ eastern white pine (Pinus strobus) to test the hypothesis that it is the inter-genic effects that primarily drive climate-induced local adaptation. The genetic structure of 29 range-wide natural populations of eastern white pine was determined in relation to local climatic factors using both a reference set of SSR markers, and SNPs located in candidate genes putatively involved in adaptive response to climate. Comparisons were made between marker sets using standard single-locus outlier analysis, single-locus and multilocus environment association analyses and a novel implementation of Population Graphs. Magnitudes of population structure were similar between the two marker sets. Outlier loci consistent with diversifying selection were rare for both SNPs and SSRs. However, genetic distances based on the multilocus among population covariances (cGD) were significantly more correlated to climate, even after correcting for spatial effects, for SNPs as compared to SSRs. Coalescent simulations confirmed that the differences in mutation rates between SSRs and SNPs did not affect the topologies of the Population Graphs, and hence values of cGD and their correlations with associated climate variables. We conclude that the multilocus covariances among populations primarily reflect adaptation to local climate and environment in eastern white pine. This result highlights the complexity of the genetic architecture of adaptive traits, as well as the need to consider multilocus effects in studies of local adaptation. PMID:27387485

Utility of genetic and non-genetic risk factors in predicting coronary heart disease in Singaporean Chinese.

PubMed

Chang, Xuling; Salim, Agus; Dorajoo, Rajkumar; Han, Yi; Khor, Chiea-Chuen; van Dam, Rob M; Yuan, Jian-Min; Koh, Woon-Puay; Liu, Jianjun; Goh, Daniel Yt; Wang, Xu; Teo, Yik-Ying; Friedlander, Yechiel; Heng, Chew-Kiat

2017-01-01

Background Although numerous phenotype based equations for predicting risk of 'hard' coronary heart disease are available, data on the utility of genetic information for such risk prediction is lacking in Chinese populations. Design Case-control study nested within the Singapore Chinese Health Study. Methods A total of 1306 subjects comprising 836 men (267 incident cases and 569 controls) and 470 women (128 incident cases and 342 controls) were included. A Genetic Risk Score comprising 156 single nucleotide polymorphisms that have been robustly associated with coronary heart disease or its risk factors ( p < 5 × 10 -8 ) in at least two independent cohorts of genome-wide association studies was built. For each gender, three base models were used: recalibrated Adult Treatment Panel III (ATPIII) Model (M 1 ); ATP III model fitted using Singapore Chinese Health Study data (M 2 ) and M 3 : M 2 + C-reactive protein + creatinine. Results The Genetic Risk Score was significantly associated with incident 'hard' coronary heart disease ( p for men: 1.70 × 10 -10 -1.73 × 10 -9 ; p for women: 0.001). The inclusion of the Genetic Risk Score in the prediction models improved discrimination in both genders (c-statistics: 0.706-0.722 vs. 0.663-0.695 from base models for men; 0.788-0.790 vs. 0.765-0.773 for women). In addition, the inclusion of the Genetic Risk Score also improved risk classification with a net gain of cases being reclassified to higher risk categories (men: 12.4%-16.5%; women: 10.2% (M 3 )), while not significantly reducing the classification accuracy in controls. Conclusions The Genetic Risk Score is an independent predictor for incident 'hard' coronary heart disease in our ethnic Chinese population. Inclusion of genetic factors into coronary heart disease prediction models could significantly improve risk prediction performance.

Validation of candidate genes associated with cardiovascular risk factors in psychiatric patients

PubMed Central

Windemuth, Andreas; de Leon, Jose; Goethe, John W.; Schwartz, Harold I.; Woolley, Stephen; Susce, Margaret; Kocherla, Mohan; Bogaard, Kali; Holford, Theodore R.; Seip, Richard L.; Ruaño, Gualberto

2016-01-01

The purpose of this study was to identify genetic variants predictive of cardiovascular risk factors in a psychiatric population treated with second generation antipsychotics (SGA). 924 patients undergoing treatment for severe mental illness at four US hospitals were genotyped at 1.2 million single nucleotide polymorphisms. Patients were assessed for fasting serum lipid (low density lipoprotein cholesterol [LDLc], high density lipoprotein cholesterol [HDLc], and triglycerides) and obesity phenotypes (body mass index, BMI). Thirteen candidate genes from previous studies of the same phenotypes in non-psychiatric populations were tested for association. We confirmed 8 of the 13 candidate genes at the 95% confidence level. An increased genetic effect size was observed for triglycerides in the psychiatric population compared to that in the cardiovascular population. PMID:21851846

Gout in Older Adults: The Atherosclerosis Risk in Communities Study.

PubMed

Burke, Bridget Teevan; Köttgen, Anna; Law, Andrew; Grams, Morgan; Baer, Alan N; Coresh, Josef; McAdams-DeMarco, Mara A

2016-04-01

It is unclear whether traditional and genetic risk factors in middle age predict the onset of gout in older age. We studied the incidence of gout in older adults using the Atherosclerosis Risk in Communities study, a prospective U.S. population-based cohort of middle-aged adults enrolled between 1987 and 1989 with ongoing follow-up. A genetic urate score was formed from common urate-associated single nucleotide polymorphisms for eight genes. The adjusted hazard ratio and 95% confidence interval of incident gout by traditional and genetic risk factors in middle age were estimated using a Cox proportional hazards model. The cumulative incidence from middle age to age 65 was 8.6% in men and 2.5% in women; by age 75 the cumulative incidence was 11.8% and 5.0%. In middle age, increased adiposity, beer intake, protein intake, smoking status, hypertension, diuretic use, and kidney function (but not sex) were associated with an increased gout risk in older age. In addition, a 100 µmol/L increase in genetic urate score was associated with a 3.29-fold (95% confidence interval: 1.63-6.63) increased gout risk in older age. These findings suggest that traditional and genetic risk factors in middle age may be useful for identifying those at risk of gout in older age. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Genetics of Paget's disease of bone

PubMed Central

Albagha, Omar ME

2015-01-01

Paget's disease of bone (PDB) is a common metabolic bone disease characterised by focal areas of increased bone turnover, which primarily affects people over the age of 55 years. Genetic factors have a fundamental role in the pathogenesis of PDB and are probably the main predisposing factor for the disease. The genetic contribution to PDB susceptibility ranges from rare pathogenic mutations in the single gene SQSTM1 to more common, small effect variants in at least seven genetic loci that predispose to the disease. These loci have additive effects on disease susceptibility and interact with SQSTM1 mutations to affect disease severity, making them a potentially useful tool in predicting disease risk and complication and in managing treatments. Many of these loci harbour genes that have important function in osteoclast differentiation such as CSF1, DCSTAMP and TNFRSF11A. Other susceptibility loci have highlighted new molecular pathways that have not been previously implicated in regulation of bone metabolism such as OPTN, which was recently found to negatively regulate osteoclast differentiation. PDB-susceptibility variants exert their effect either by affecting the protein coding sequence such as variants found in SQSTM1 and RIN3 or by influencing gene expression such as those found in OPTN and DCSTAMP. Epidemiological studies indicate that environmental triggers also have a key role in PDB and interact with genetic factors to influence manifestation and severity of the disease; however, further studies are needed to identify these triggers. PMID:26587225

Impact of Body Mass Index, Age, Prostate Volume, and Genetic Polymorphisms on Prostate-specific Antigen Levels in a Control Population.

PubMed

Cornu, Jean-Nicolas; Cancel-Tassin, Geraldine; Cox, David G; Roupret, Morgan; Koutlidis, Nicolas; Bigot, Pierre; Valeri, Antoine; Ondet, Valerie; Gaffory, Cécile; Fournier, Georges; Azzouzi, Abdel-Rahmene; Cormier, Luc; Cussenot, Olivier

2016-07-01

Prostate-specific antigen (PSA) is still the cornerstone of prostate cancer (PCa) screening and diagnosis in both research and current clinical practice. Inaccuracy of PSA is partly due to the influence of a number of genetic, clinical, and biological factors modifying PSA blood levels. In the present study, we detailed the respective influence of each factor among age, body mass index (BMI), prostate volume, and five single-nucleotide polymorphisms-rs10788160 (10q26), rs10993994 (10q11), rs11067228 (12q24), rs17632542 (19q13.33), and rs2928679 (8p21)-on PSA values in a cohort of 1374 men without PCa. Our results show that genetic factors, when risk variants are combined, influence PSA levels with an effect size similar to that of BMI. Taken together, the respective correlations of clinical parameters and genetic parameters would make it possible to correct and adjust PSA values more effectively in each individual. These results establish the basis to understand and implement a more personalised approach for the interpretation of PSA blood levels in the context of PCa screening and diagnosis. Prostate-specific antigen (PSA) values in an individual may vary according to genetic predisposition. The effect size of this variation can be significant, comparable with those resulting from clinical characteristics. Personalised PSA testing should take this into account. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Integrating environmental and genetic effects to predict responses of tree populations to climate.

PubMed

Wang, Tongli; O'Neill, Gregory A; Aitken, Sally N

2010-01-01

Climate is a major environmental factor affecting the phenotype of trees and is also a critical agent of natural selection that has molded among-population genetic variation. Population response functions describe the environmental effect of planting site climates on the performance of a single population, whereas transfer functions describe among-population genetic variation molded by natural selection for climate. Although these approaches are widely used to predict the responses of trees to climate change, both have limitations. We present a novel approach that integrates both genetic and environmental effects into a single "universal response function" (URF) to better predict the influence of climate on phenotypes. Using a large lodgepole pine (Pinus contorta Dougl. ex Loud.) field transplant experiment composed of 140 populations planted on 62 sites to demonstrate the methodology, we show that the URF makes full use of data from provenance trials to: (1) improve predictions of climate change impacts on phenotypes; (2) reduce the size and cost of future provenance trials without compromising predictive power; (3) more fully exploit existing, less comprehensive provenance tests; (4) quantify and compare environmental and genetic effects of climate on population performance; and (5) predict the performance of any population growing in any climate. Finally, we discuss how the last attribute allows the URF to be used as a mechanistic model to predict population and species ranges for the future and to guide assisted migration of seed for reforestation, restoration, or afforestation and genetic conservation in a changing climate.

Functional and genetic diversity of mycorrhizal fungi from single plants of Caladenia formosa (Orchidaceae)

PubMed Central

Huynh, Tien T.; Thomson, Richard; Mclean, Cassandra B.; Lawrie, Ann C.

2009-01-01

Background and Aims Mycorrhizal associations are essential to the plant kingdom. The largest flowering plant family, the Orchidaceae, relies on mycorrhizal fungi for germination, growth and survival. Evidence suggests varying degrees of fungal-host specificity based on a single fungal isolate from a single plant. This paper shows for the first time the diversity of endophytes colonizing in a single plant over consecutive years and the functional significance of this diversity. Methods Stem-collars of Caladenia formosa were collected in different seasons and years. Mycorrhizal fungi isolated were tested for their efficacy to induce leafing and genetically determined using ITS-RFLP and sequencing. Results Multiple mycorrhizal fungi were repeatedly isolated from a single collar that displayed varying effectiveness in germination percentages and adult leaf length. Additional factors contributed to the isolation of effective mycorrhizal fungi; fungal collection season, year of collection and individual isolates. Surface sterilization only improved the number of isolated mycorrhizal fungi. Dual inoculation did not increase germination. All 59 mycorrhizal fungi effective in germinating seed belonged to one clearly defined ITS (internal transcribed spacer) clade and clustered close to Sebacina vermifera (79–89 % homology). Isolates resulting in the greatest germination were not necessarily those resulting in the greatest survival and growth 1 year after germination. Conclusion Single orchid plants contained multiple mycorrhizal fungal strains of one species that had diverse functional differences. These results suggest that our current knowledge of fungal–host specificity may be incomplete due to experimental and analytical limitations. It also suggests that the long-term effectiveness of a mycorrhizal fungus or fungi could only be found by germination and longer-term growth tests rather than genetically. PMID:19561011

Practitioner Review: What have we learnt about the causes of ADHD?

PubMed Central

Thapar, Anita; Cooper, Miriam; Eyre, Olga; Langley, Kate

2013-01-01

Background Attention deficit hyperactivity disorder (ADHD) and its possible causes still attract controversy. Genes, pre and perinatal risks, psychosocial factors and environmental toxins have all been considered as potential risk factors. Method This review (focussing on literature published since 1997, selected from a search of PubMed) critically considers putative risk factors with a focus on genetics and selected environmental risks, examines their relationships with ADHD and discusses the likelihood that these risks are causal as well as some of the main implications. Results No single risk factor explains ADHD. Both inherited and noninherited factors contribute and their effects are interdependent. ADHD is familial and heritable. Research into the inherited and molecular genetic contributions to ADHD suggest an important overlap with other neurodevelopmental problems, notably, autism spectrum disorders. Having a biological relative with ADHD, large, rare copy number variants, some small effect size candidate gene variants, extreme early adversity, pre and postnatal exposure to lead and low birth weight/prematurity have been most consistently found as risk factors, but none are yet known to be definitely causal. There is a large literature documenting associations between ADHD and a wide variety of putative environmental risks that can, at present, only be regarded as correlates. Findings from research designs that go beyond simply testing for association are beginning to contest the robustness of some environmental exposures previously thought to be ADHD risk factors. Conclusions The genetic risks implicated in ADHD generally tend to have small effect sizes or be rare and often increase risk of many other types of psychopathology. Thus, they cannot be used for prediction, genetic testing or diagnostic purposes beyond what is predicted by a family history. There is a need to consider the possibility of parents and siblings being similarly affected and how this might impact on engagement with families, influence interventions and require integration with adult services. Genetic contributions to disorder do not necessarily mean that medications are the treatment of choice. We also consider how findings might influence the conceptualisation of ADHD, public health policy implications and why it is unhelpful and incorrect to dichotomise genetic/biological and environmental explanations. It is essential that practitioners can interpret genetic and aetiological research findings and impart informed explanations to families. PMID:22963644

Genetic analysis of glucosinolate variability in broccoli florets using genome-anchored single nucleotide polymorphisms.

PubMed

Brown, Allan F; Yousef, Gad G; Reid, Robert W; Chebrolu, Kranthi K; Thomas, Aswathy; Krueger, Christopher; Jeffery, Elizabeth; Jackson, Eric; Juvik, John A

2015-07-01

The identification of genetic factors influencing the accumulation of individual glucosinolates in broccoli florets provides novel insight into the regulation of glucosinolate levels in Brassica vegetables and will accelerate the development of vegetables with glucosinolate profiles tailored to promote human health. Quantitative trait loci analysis of glucosinolate (GSL) variability was conducted with a B. oleracea (broccoli) mapping population, saturated with single nucleotide polymorphism markers from a high-density array designed for rapeseed (Brassica napus). In 4 years of analysis, 14 QTLs were associated with the accumulation of aliphatic, indolic, or aromatic GSLs in floret tissue. The accumulation of 3-carbon aliphatic GSLs (2-propenyl and 3-methylsulfinylpropyl) was primarily associated with a single QTL on C05, but common regulation of 4-carbon aliphatic GSLs was not observed. A single locus on C09, associated with up to 40 % of the phenotypic variability of 2-hydroxy-3-butenyl GSL over multiple years, was not associated with the variability of precursor compounds. Similarly, QTLs on C02, C04, and C09 were associated with 4-methylsulfinylbutyl GSL concentration over multiple years but were not significantly associated with downstream compounds. Genome-specific SNP markers were used to identify candidate genes that co-localized to marker intervals and previously sequenced Brassica oleracea BAC clones containing known GSL genes (GSL-ALK, GSL-PRO, and GSL-ELONG) were aligned to the genomic sequence, providing support that at least three of our 14 QTLs likely correspond to previously identified GSL loci. The results demonstrate that previously identified loci do not fully explain GSL variation in broccoli. The identification of additional genetic factors influencing the accumulation of GSL in broccoli florets provides novel insight into the regulation of GSL levels in Brassicaceae and will accelerate development of vegetables with modified or enhanced GSL profiles.

Environmental versus geographical determinants of genetic structure in two subalpine conifers.

PubMed

Mosca, Elena; González-Martínez, Santiago C; Neale, David B

2014-01-01

Alpine ecosystems are facing rapid human-induced environmental changes, and so more knowledge about tree adaptive potential is needed. This study investigated the relative role of isolation by distance (IBD) versus isolation by adaptation (IBA) in explaining population genetic structure in Abies alba and Larix decidua, based on 231 and 233 single nucleotide polymorphisms (SNPs) sampled across 36 and 22 natural populations, respectively, in the Alps and Apennines. Genetic structure was investigated for both geographical and environmental groups, using analysis of molecular variance (AMOVA). For each species, nine environmental groups were defined using climate variables selected from a multiple factor analysis. Complementary methods were applied to identify outliers based on these groups, and to test for IBD versus IBA. AMOVA showed weak but significant genetic structure for both species, with higher values in L. decidua. Among the potential outliers detected, up to two loci were found for geographical groups and up to seven for environmental groups. A stronger effect of IBD than IBA was found in both species; nevertheless, once spatial effects had been removed, temperature and soil in A. alba, and precipitation in both species, were relevant factors explaining genetic structure. Based on our findings, in the Alpine region, genetic structure seems to be affected by both geographical isolation and environmental gradients, creating opportunities for local adaptation. © 2013 The Authors. New Phytologist © 2013 New Phytologist Trust.

Etiological heterogeneity in the development of antisocial behavior: the Virginia Twin Study of Adolescent Behavioral Development and the Young Adult Follow-Up.

PubMed

Silberg, Judy L; Rutter, Michael; Tracy, Kelly; Maes, Hermine H; Eaves, Lindon

2007-08-01

Longitudinal, genetically informed, prospective data collected on a large population of male twins (n=1037) were used to examine developmental differences in the etiology of antisocial behavior. Analyses were carried out on both mother- and child-reported symptoms of conduct disorder (CD) in 10- to 17-year-old twins from the Virginia Twin Study of Adolescent Behavioral Development (VTSABD) and self-reported antisocial behavior by the twins as young adults from the Young Adult Follow-Up (YAFU) study. The following trends were identified: (1) a single genetic factor influencing antisocial behavior beginning at age 10 through young adulthood ('life-course persistent'); (2) a shared-environmental effect beginning in adolescence ('adolescent-onset'); (3) a transient genetic effect at puberty; and (4) a genetic influence specific to adult antisocial behavior. Overall, these etiological findings are consistent with predictions from Moffitt's developmental theory of antisocial behavior. The genetic effect at puberty at ages 12-15 is also consistent with a genetically mediated influence on the timing of puberty affecting the expression of genetic differences in antisocial outcomes.

Mapping the Schizophrenia Genes by Neuroimaging: The Opportunities and the Challenges

PubMed Central

2018-01-01

Schizophrenia (SZ) is a heritable brain disease originating from a complex interaction of genetic and environmental factors. The genes underpinning the neurobiology of SZ are largely unknown but recent data suggest strong evidence for genetic variations, such as single nucleotide polymorphisms, making the brain vulnerable to the risk of SZ. Structural and functional brain mapping of these genetic variations are essential for the development of agents and tools for better diagnosis, treatment and prevention of SZ. Addressing this, neuroimaging methods in combination with genetic analysis have been increasingly used for almost 20 years. So-called imaging genetics, the opportunities of this approach along with its limitations for SZ research will be outlined in this invited paper. While the problems such as reproducibility, genetic effect size, specificity and sensitivity exist, opportunities such as multivariate analysis, development of multisite consortia for large-scale data collection, emergence of non-candidate gene (hypothesis-free) approach of neuroimaging genetics are likely to contribute to a rapid progress for gene discovery besides to gene validation studies that are related to SZ. PMID:29324666

A Simple Genetic Incompatibility Causes Hybrid Male Sterility in Mimulus

PubMed Central

Sweigart, Andrea L.; Fishman, Lila; Willis, John H.

2006-01-01

Much evidence has shown that postzygotic reproductive isolation (hybrid inviability or sterility) evolves by the accumulation of interlocus incompatibilities between diverging populations. Although in theory only a single pair of incompatible loci is needed to isolate species, empirical work in Drosophila has revealed that hybrid fertility problems often are highly polygenic and complex. In this article we investigate the genetic basis of hybrid sterility between two closely related species of monkeyflower, Mimulus guttatus and M. nasutus. In striking contrast to Drosophila systems, we demonstrate that nearly complete hybrid male sterility in Mimulus results from a simple genetic incompatibility between a single pair of heterospecific loci. We have genetically mapped this sterility effect: the M. guttatus allele at the hybrid male sterility 1 (hms1) locus acts dominantly in combination with recessive M. nasutus alleles at the hybrid male sterility 2 (hms2) locus to cause nearly complete hybrid male sterility. In a preliminary screen to find additional small-effect male sterility factors, we identified one additional locus that also contributes to some of the variation in hybrid male fertility. Interestingly, hms1 and hms2 also cause a significant reduction in hybrid female fertility, suggesting that sex-specific hybrid defects might share a common genetic basis. This possibility is supported by our discovery that recombination is reduced dramatically in a cross involving a parent with the hms1–hms2 incompatibility. PMID:16415357

A simple genetic incompatibility causes hybrid male sterility in mimulus.

PubMed

Sweigart, Andrea L; Fishman, Lila; Willis, John H

2006-04-01

Much evidence has shown that postzygotic reproductive isolation (hybrid inviability or sterility) evolves by the accumulation of interlocus incompatibilities between diverging populations. Although in theory only a single pair of incompatible loci is needed to isolate species, empirical work in Drosophila has revealed that hybrid fertility problems often are highly polygenic and complex. In this article we investigate the genetic basis of hybrid sterility between two closely related species of monkeyflower, Mimulus guttatus and M. nasutus. In striking contrast to Drosophila systems, we demonstrate that nearly complete hybrid male sterility in Mimulus results from a simple genetic incompatibility between a single pair of heterospecific loci. We have genetically mapped this sterility effect: the M. guttatus allele at the hybrid male sterility 1 (hms1) locus acts dominantly in combination with recessive M. nasutus alleles at the hybrid male sterility 2 (hms2) locus to cause nearly complete hybrid male sterility. In a preliminary screen to find additional small-effect male sterility factors, we identified one additional locus that also contributes to some of the variation in hybrid male fertility. Interestingly, hms1 and hms2 also cause a significant reduction in hybrid female fertility, suggesting that sex-specific hybrid defects might share a common genetic basis. This possibility is supported by our discovery that recombination is reduced dramatically in a cross involving a parent with the hms1-hms2 incompatibility.

A single nucleotide polymorphism at the right terminal region of Mexican papita viroid is a virulent determinant factor on tomato

USDA-ARS?s Scientific Manuscript database

Mexican papita viroid (MPVd), a pospiviroid, causes serious disease outbreaks on greenhouse tomato in North America. Two dominant genotypes (MPV-S and MPV-M), sharing 93.8% sequence identity, incited striking different symptom expression (severe and mild) on tomato ‘Rutgers’. To determine genetic ...

Designing Laboratory Exercises for the Undergraduate Molecular Biology/Biochemistry Student: Techniques and Ethical Implications Involved in Personalized Medicine

ERIC Educational Resources Information Center

Weinlander, Kenneth M.; Hall, David J.

2010-01-01

Personalized medicine refers to medical care that involves genetically screening patients for their likelihood to develop various disorders. Commercial genome screening only involves identifying a consumer's genotype for a few single nucleotide polymorphisms. A phenotype (such as an illness) is greatly influenced by three factors: genes, gene…

The effects of ABCG5/G8 polymorphisms on plasma HDL cholesterol concentrations depend on smoking habit in the Boston Puerto Rican Health Study

USDA-ARS?s Scientific Manuscript database

Background-Low high-density lipoprotein cholesterol (HDL-C) is associated with an increased risk for atherosclerosis and concentrations are modulated by genetic and environmental factors such as smoking. Objective- To assess whether the association of common single nucleotide polymorphisms (SNPs...

Gene-Lifestyle Interactions in Complex Diseases: Design and Description of the GLACIER and VIKING Studies

PubMed Central

Kurbasic, Azra; Poveda, Alaitz; Chen, Yan; Ågren, Åsa; Engberg, Elisabeth; Hu, Frank B.; Johansson, Ingegerd; Barroso, Ines; Brändström, Anders; Hallmans, Göran; Renström, Frida; Franks, Paul W.

2014-01-01

Most complex diseases have well-established genetic and non-genetic risk factors. In some instances, these risk factors are likely to interact, whereby their joint effects convey a level of risk that is either significantly more or less than the sum of these risks. Characterizing these gene-environment interactions may help elucidate the biology of complex diseases, as well as to guide strategies for their targeted prevention. In most cases, the detection of gene-environment interactions will require sample sizes in excess of those needed to detect the marginal effects of the genetic and environmental risk factors. Although many consortia have been formed, comprising multiple diverse cohorts to detect gene-environment interactions, few robust examples of such interactions have been discovered. This may be because combining data across studies, usually through meta-analysis of summary data from the contributing cohorts, is often a statistically inefficient approach for the detection of gene-environment interactions. Ideally, single, very large and well-genotyped prospective cohorts, with validated measures of environmental risk factor and disease outcomes should be used to study interactions. The presence of strong founder effects within those cohorts might further strengthen the capacity to detect novel genetic effects and gene-environment interactions. Access to accurate genealogical data would also aid in studying the diploid nature of the human genome, such as genomic imprinting (parent-of-origin effects). Here we describe two studies from northern Sweden (the GLACIER and VIKING studies) that fulfill these characteristics. PMID:25396097

Gene-Lifestyle Interactions in Complex Diseases: Design and Description of the GLACIER and VIKING Studies.

PubMed

Kurbasic, Azra; Poveda, Alaitz; Chen, Yan; Agren, Asa; Engberg, Elisabeth; Hu, Frank B; Johansson, Ingegerd; Barroso, Ines; Brändström, Anders; Hallmans, Göran; Renström, Frida; Franks, Paul W

2014-12-01

Most complex diseases have well-established genetic and non-genetic risk factors. In some instances, these risk factors are likely to interact, whereby their joint effects convey a level of risk that is either significantly more or less than the sum of these risks. Characterizing these gene-environment interactions may help elucidate the biology of complex diseases, as well as to guide strategies for their targeted prevention. In most cases, the detection of gene-environment interactions will require sample sizes in excess of those needed to detect the marginal effects of the genetic and environmental risk factors. Although many consortia have been formed, comprising multiple diverse cohorts to detect gene-environment interactions, few robust examples of such interactions have been discovered. This may be because combining data across studies, usually through meta-analysis of summary data from the contributing cohorts, is often a statistically inefficient approach for the detection of gene-environment interactions. Ideally, single, very large and well-genotyped prospective cohorts, with validated measures of environmental risk factor and disease outcomes should be used to study interactions. The presence of strong founder effects within those cohorts might further strengthen the capacity to detect novel genetic effects and gene-environment interactions. Access to accurate genealogical data would also aid in studying the diploid nature of the human genome, such as genomic imprinting (parent-of-origin effects). Here we describe two studies from northern Sweden (the GLACIER and VIKING studies) that fulfill these characteristics.

Genetics in Diabetic Retinopathy: Current Concepts and New Insights

PubMed Central

Simó-Servat, Olga; Hernández, Cristina; Simó, Rafael

2013-01-01

There is emerging evidence which indicates the essential role of genetic factors in the development of diabetic retinopathy (DR). In this regard it should be highlighted that genetic factors account for 25-50% of the risk of developing DR. Therefore, the use of genetic analysis to identify those diabetic patients most prone to developing DR might be useful in designing a more individualized treatment. In this regard, there are three main research strategies: candidate gene studies, linkage studies and Genome-Wide Association Studies (GWAS). In the candidate gene approach, several genes encoding proteins closely related to DR development have been analyzed. The linkage studies analyze shared alleles among family members with DR under the assumption that these predispose to a more aggressive development of DR. Finally, Genome-Wide Association Studies (GWAS) are a new tool involving a massive evaluation of single nucleotide polymorphisms (SNP) in large samples. In this review the available information using these three methodologies is critically analyzed. A genetic approach in order to identify new candidates in the pathogenesis of DR would permit us to design more targeted therapeutic strategies in order to decrease this devastating complication of diabetes. Basic researchers, ophthalmologists, diabetologists and geneticists should work together in order to gain new insights into this issue. PMID:24403848

Improving Disease Prediction by Incorporating Family Disease History in Risk Prediction Models with Large-Scale Genetic Data.

PubMed

Gim, Jungsoo; Kim, Wonji; Kwak, Soo Heon; Choi, Hosik; Park, Changyi; Park, Kyong Soo; Kwon, Sunghoon; Park, Taesung; Won, Sungho

2017-11-01

Despite the many successes of genome-wide association studies (GWAS), the known susceptibility variants identified by GWAS have modest effect sizes, leading to notable skepticism about the effectiveness of building a risk prediction model from large-scale genetic data. However, in contrast to genetic variants, the family history of diseases has been largely accepted as an important risk factor in clinical diagnosis and risk prediction. Nevertheless, the complicated structures of the family history of diseases have limited their application in clinical practice. Here, we developed a new method that enables incorporation of the general family history of diseases with a liability threshold model, and propose a new analysis strategy for risk prediction with penalized regression analysis that incorporates both large numbers of genetic variants and clinical risk factors. Application of our model to type 2 diabetes in the Korean population (1846 cases and 1846 controls) demonstrated that single-nucleotide polymorphisms accounted for 32.5% of the variation explained by the predicted risk scores in the test data set, and incorporation of family history led to an additional 6.3% improvement in prediction. Our results illustrate that family medical history provides valuable information on the variation of complex diseases and improves prediction performance. Copyright © 2017 by the Genetics Society of America.

Positional cloning in mice and its use for molecular dissection of inflammatory arthritis.

PubMed

Abe, Koichiro; Yu, Philipp

2009-02-01

One of the upcoming next quests in the field of genetics might be molecular dissection of the genetic and environmental components of human complex diseases. In humans, however, there are certain experimental limitations for identification of a single component of the complex interactions by genetic analyses. Experimental animals offer simplified models for genetic and environmental interactions in human complex diseases. In particular, mice are the best mammalian models because of a long history and ample experience for genetic analyses. Forward genetics, which includes genetic screen and subsequent positional cloning of the causative genes, is a powerful strategy to dissect a complex phenomenon without preliminarily molecular knowledge of the process. In this review, first, we describe a general scheme of positional cloning in mice. Next, recent accomplishments on the patho-mechanisms of inflammatory arthritis by forward genetics approaches are introduced; Positional cloning effort for skg, Ali5, Ali18, cmo, and lupo mutants are provided as examples for the application to human complex diseases. As seen in the examples, the identification of genetic factors by positional cloning in the mouse have potential in solving molecular complexity of gene-environment interactions in human complex diseases.

Genetic Variation in the Human SORBS1 Gene is Associated With Blood Pressure Regulation and Age at Onset of Hypertension: A SAPPHIRe Cohort Study.

PubMed

Chang, Tien-Jyun; Wang, Wen-Chang; Hsiung, Chao A; He, Chih-Tsueng; Lin, Ming-Wei; Sheu, Wayne Huey-Herng; Chang, Yi-Cheng; Quertermous, Tom; Chen, Ida; Rotter, Jerome; Chuang, Lee-Ming

2016-03-01

Essential hypertension is a complex disease involving multiple genetic and environmental factors. A human gene containing a sorbin homology domain and 3 SH3 domains in the C-terminal region, termed SORBS1, plays a significant role in insulin signaling. We previously found a significant association between the T228A polymorphism and insulin resistance, obesity, and type 2 diabetes. It has been hypothesized that a set of genes responsible for insulin resistance may be closely linked with genes susceptible to the development of hypertension. Identification of insulin resistance-related genetic factors may, therefore, enhance our understanding of essential hypertension. This study aimed to examine whether common SORBS1 genetic variations are associated with blood pressure and age at onset of hypertension in an ethnic Chinese cohort.We genotyped 9 common tagged single nucleotide polymorphisms of the SORBS1 gene in 1136 subjects of Chinese origin from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance family study. Blood pressure was measured upon enrolment. The associations of the SORBS1 single nucleotide polymorphisms with blood pressure and the presence of hypertension were analyzed with a generalized estimating equation model. We used the false-discovery rate measure Q value with a cutoff <0.1 to adjust for multiple comparisons. In the Cox regression analysis for hypertension-free survival, a robust sandwich variance estimator was used to deal with the within-family correlations with age at onset of hypertension. Gender, body mass index, and antihypertension medication were adjustment covariates in the Cox regression analysis.In this study, genetic variants of rs2281939 and rs2274490 were significantly associated with both systolic and diastolic blood pressure. A genetic variant of rs2274490 was also significantly associated with the presence of hypertension. Furthermore, genetic variants of rs2281939 and rs2274490 were associated with age at onset of hypertension after adjustment for gender, body mass index, and antihypertension medication.In conclusion, we provide evidence for an association between common SORBS1 genetic variations and blood pressure, presence of hypertension, and age at onset of hypertension. The biological mechanism of genetic variation associated with blood pressure regulation needs further investigation.

Utilization of Genetic Testing Prior to Subspecialist Referral for Cerebellar Ataxia

PubMed Central

Fogel, Brent L.; Vickrey, Barbara G.; Walton-Wetzel, Jenny; Lieber, Eli

2013-01-01

Objective: To evaluate the utilization of laboratory testing in the diagnosis of cerebellar ataxia, including the completeness of initial standard testing for acquired causes, the early use of genetic testing, and associated clinical and nonclinical factors, among a cohort referred for subspecialty consultation. Methods: Data were abstracted from records of 95 consecutive ataxia patients referred to one neurogenetics subspecialist from 2006–2010 and linked to publicly available data on characteristics of referral clinicians. Multivariable logistic and linear regression models were used to analyze unique associations of clinical and nonclinical factors with laboratory investigation of acquired causes and with early genetic testing prior to referral. Results: At referral, 27 of 95 patients lacked evidence of any of 14 laboratory studies suggested for initial work-up of an acquired cause for ataxia (average number of tests=4.5). In contrast, 92% of patients had undergone brain magnetic resonance imaging prior to referral. Overall, 41.1% (n=39) had genetic testing prior to referral; there was no association between family history of ataxia and obtaining genetic testing prior to referral (p=0.39). The level of early genetic testing was 31.6%, primarily due to genetic testing despite an incomplete laboratory evaluation for acquired causes and no family history. A positive family history was consistently associated with less extensive laboratory testing (p=0.004), and referral by a neurologist was associated with higher levels of early genetic testing. Conclusions: Among consecutive referrals to a single center, a substantial proportion of sporadic cases had genetic testing without evidence of a work-up for acquired causes. Better strategies to guide decision making and subspecialty referrals in rare neurologic disorders are needed, given the cost and consequences of genetic testing. PMID:23725007

Holarctic phylogeography of the testate amoeba Hyalosphenia papilio (Amoebozoa: Arcellinida) reveals extensive genetic diversity explained more by environment than dispersal limitation.

PubMed

Heger, Thierry J; Mitchell, Edward A D; Leander, Brian S

2013-10-01

Although free-living protists play essential roles in aquatic and soil ecology, little is known about their diversity and phylogeography, especially in terrestrial ecosystems. We used mitochondrial cytochrome c oxidase subunit 1 (COI) gene sequences to investigate the genetic diversity and phylogeography of the testate amoeba morphospecies Hyalosphenia papilio in 42 Sphagnum (moss)-dominated peatlands in North America, Europe and Asia. Based on ≥1% sequence divergence threshold, our results from single-cell PCRs of 301 individuals revealed 12 different genetic lineages and both the general mixed Yule-coalescent (GMYC) model and the automatic barcode gap discovery (ABGD) methods largely support the hypothesis that these 12 H. papilio lineages correspond to evolutionary independent units (i.e. cryptic species). Our data also showed a high degree of genetic heterogeneity within different geographical regions. Furthermore, we used variation partitioning based on partial redundancy analyses (pRDA) to evaluate the contributions of climate and dispersal limitations on the distribution patterns of the different genetic lineages. The largest fraction of the variation in genetic lineage distribution was attributed to purely climatic factors (21%), followed by the joint effect of spatial and bioclimatic factors (13%), and a purely spatial effect (3%). Therefore, these data suggest that the distribution patterns of H. papilio genetic lineages in the Northern Hemisphere are more influenced by climatic conditions than by dispersal limitations. © 2013 John Wiley & Sons Ltd.

Candidate pathway-based genetic association study of platinum and platinum-taxane related toxicity in a cohort of primary lung cancer patients.

PubMed

Johnson, Cassandra; Pankratz, Vernon S; Velazquez, Ana I; Aakre, Jeremiah A; Loprinzi, Charles L; Staff, Nathan P; Windebank, Anthony J; Yang, Ping

2015-02-15

Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity secondary to chemotherapy. Genetic factors may be important in predisposing patients to this adverse effect. We studied 950 primary lung cancer patients, who received platinum or platinum-combination drug chemotherapy and who had DNA available for study. We analyzed epidemiological risk factors in 279 CIPN patients and 456 non-CIPN patients and genetic risk factors in 141 CIPN patients and 259 non-CIPN patients. The risk factors studied included demographic, diagnostic, and treatment data, as well as 174 tag SNPs (single nucleotide polymorphisms) across 43 candidate genes in the glutathione, cell cycle, DNA repair, cell signaling, and apoptosis pathways. Patients who had diabetes mellitus were more likely to have CIPN (p=0.0002). Other epidemiologic risk factors associated with CIPN included number of cycles (p=0.0004) and type of concurrent chemotherapy (p<0.001). SNPs most associated with CIPN were in glutathione peroxidase 7 (GPX7) gene (p values 0.0015 and 0.0028, unadjusted and adjusted) and in ATP-binding cassette sub-family C member 4 (ABCC4) gene (p values 0.037 and 0.006, unadjusted and adjusted). We also found other suggestive associations in methyl-o-guanine-methyl-transferase (MGMT) and glutathione-S-transferase (GST) isoforms. Epidemiological and genetic risk factors associated with CIPN in this cohort, included the type of chemotherapy drug, intensity of chemotherapy treatment, and genes known to be associated with chemotherapy resistance. These findings suggest that differentiating between cytotoxic and neurotoxic mechanisms of chemotherapy drugs is challenging but represents an important step toward individualized therapy and improving quality of life for patients. Copyright © 2015 Elsevier B.V. All rights reserved.

Central causes of hypogonadism--functional and organic.

PubMed

Warren, Michelle P; Vu, Caroline

2003-09-01

Whether caused by environmental factors, lesions, genetic mutations, drug interactions, or unknown origins, the path of the central causes of hypogonadism frequently leads back to the GnRH pulse generator. In some cases, the cause can be unequivocally traced to a single factor, such as some of the congenital syndromes previously described. In most instances, however, hypogonadism is occult or functional. Because of the wide spectrum and complexity of underlying causes, a definitive diagnosis, especially in functional causes of the disorder, is not always attainable.

Single-Cell Quantitative PCR: Advances and Potential in Cancer Diagnostics.

PubMed

Ok, Chi Young; Singh, Rajesh R; Salim, Alaa A

2016-01-01

Tissues are heterogeneous in their components. If cells of interest are a minor population of collected tissue, it would be difficult to obtain genetic or genomic information of the interested cell population with conventional genomic DNA extraction from the collected tissue. Single-cell DNA analysis is important in the analysis of genetics of cell clonality, genetic anticipation, and single-cell DNA polymorphisms. Single-cell PCR using Single Cell Ampligrid/GeXP platform is described in this chapter.

On the difficulties of discriminating between major and minor hybrid male sterility factors in Drosophila by examining the segregation ratio of sterile and fertile sons in backcrossing experiments.

PubMed

Maside, X R; Naveira, H F

1996-10-01

The observation of segregation ratios of sterile and fertile males in offspring samples from backcrossed hybrid females is, in principle, a valid method to unveil the genetic basis of hybrid male sterility in Drosophila. When the female parent is heterozygous (hybrid) for a sterility factor with major effects, equal proportions of fertile and sterile sons are expected in her offspring. However, intact (not recombined) chromosome segments of considerable length are expected to give segregation ratios that can not be easily differentiated from the 1:1 ratio expected from a single factor. When the phenotypic character under analysis can be determined by combinations of minor factors from the donor species spanning a certain chromosome length, very large offspring samples may be needed to test this alternative hypothesis against the null hypothesis of a single major factor. This is particularly the case of hybrid male sterility determinants in Drosophila.

Considering dominance in reduced single-step genomic evaluations.

PubMed

Ertl, J; Edel, C; Pimentel, E C G; Emmerling, R; Götz, K-U

2018-06-01

Single-step models including dominance can be an enormous computational task and can even be prohibitive for practical application. In this study, we try to answer the question whether a reduced single-step model is able to estimate breeding values of bulls and breeding values, dominance deviations and total genetic values of cows with acceptable quality. Genetic values and phenotypes were simulated (500 repetitions) for a small Fleckvieh pedigree consisting of 371 bulls (180 thereof genotyped) and 553 cows (40 thereof genotyped). This pedigree was virtually extended for 2,407 non-genotyped daughters. Genetic values were estimated with the single-step model and with different reduced single-step models. Including more relatives of genotyped cows in the reduced single-step model resulted in a better agreement of results with the single-step model. Accuracies of genetic values were largest with single-step and smallest with reduced single-step when only the cows genotyped were modelled. The results indicate that a reduced single-step model is suitable to estimate breeding values of bulls and breeding values, dominance deviations and total genetic values of cows with acceptable quality. © 2018 Blackwell Verlag GmbH.

Single-cell genome sequencing at ultra-high-throughput with microfluidic droplet barcoding.

PubMed

Lan, Freeman; Demaree, Benjamin; Ahmed, Noorsher; Abate, Adam R

2017-07-01

The application of single-cell genome sequencing to large cell populations has been hindered by technical challenges in isolating single cells during genome preparation. Here we present single-cell genomic sequencing (SiC-seq), which uses droplet microfluidics to isolate, fragment, and barcode the genomes of single cells, followed by Illumina sequencing of pooled DNA. We demonstrate ultra-high-throughput sequencing of >50,000 cells per run in a synthetic community of Gram-negative and Gram-positive bacteria and fungi. The sequenced genomes can be sorted in silico based on characteristic sequences. We use this approach to analyze the distributions of antibiotic-resistance genes, virulence factors, and phage sequences in microbial communities from an environmental sample. The ability to routinely sequence large populations of single cells will enable the de-convolution of genetic heterogeneity in diverse cell populations.

Genetic Structure and Potential Environmental Determinants of Local Genetic Diversity in Japanese Honeybees (Apis cerana japonica)

PubMed Central

Nagamitsu, Teruyoshi; Yasuda, Mika; Saito-Morooka, Fuki; Inoue, Maki N.; Nishiyama, Mio; Goka, Koichi; Sugiura, Shinji; Maeto, Kaoru; Okabe, Kimiko; Taki, Hisatomo

2016-01-01

Declines in honeybee populations have been a recent concern. Although causes of the declines remain unclear, environmental factors may be responsible. We focused on the potential environmental determinants of local populations of wild honeybees, Apis cerana japonica, in Japan. This subspecies has little genetic variation in terms of its mitochondrial DNA sequences, and genetic variations at nuclear loci are as yet unknown. We estimated the genetic structure and environmental determinants of local genetic diversity in nuclear microsatellite genotypes of fathers and mothers, inferred from workers collected at 139 sites. The genotypes of fathers and mothers showed weak isolation by distance and negligible genetic structure. The local genetic diversity was high in central Japan, decreasing toward the peripheries, and depended on the climate and land use characteristics of the sites. The local genetic diversity decreased as the annual precipitation increased, and increased as the proportion of urban and paddy field areas increased. Positive effects of natural forest area, which have also been observed in terms of forager abundance in farms, were not detected with respect to the local genetic diversity. The findings suggest that A. cerana japonica forms a single population connected by gene flow in its main distributional range, and that climate and landscape properties potentially affect its local genetic diversity. PMID:27898704

Altered Immune Regulation in Type 1 Diabetes

PubMed Central

Zóka, András; Műzes, Györgyi; Somogyi, Anikó; Varga, Tímea; Szémán, Barbara; Al-Aissa, Zahra; Hadarits, Orsolya; Firneisz, Gábor

2013-01-01

Research in genetics and immunology was going on separate strands for a long time. Type 1 diabetes mellitus might not be characterized with a single pathogenetic factor. It develops when a susceptible individual is exposed to potential triggers in a given sequence and timeframe that eventually disarranges the fine-tuned immune mechanisms that keep autoimmunity under control in health. Genomewide association studies have helped to understand the congenital susceptibility, and hand-in-hand with the immunological research novel paths of immune dysregulation were described in central tolerance, apoptotic pathways, or peripheral tolerance mediated by regulatory T-cells. Epigenetic factors are contributing to the immune dysregulation. The interplay between genetic susceptibility and potential triggers is likely to play a role at a very early age and gradually results in the loss of balanced autotolerance and subsequently in the development of the clinical disease. Genetic susceptibility, the impaired elimination of apoptotic β-cell remnants, altered immune regulatory functions, and environmental factors such as viral infections determine the outcome. Autoreactivity might exist under physiologic conditions and when the integrity of the complex regulatory process is damaged the disease might develop. We summarized the immune regulatory mechanisms that might have a crucial role in disease pathology and development. PMID:24285974

Hip ontogenesis: how evolution, genes, and load history shape hip morphotype and cartilotype.

PubMed

Hogervorst, Tom; Eilander, Wouter; Fikkers, Joost T; Meulenbelt, Ingrid

2012-12-01

Developmental hip disorders (DHDs), eg, developmental dysplasia of the hip, slipped capitis femoris epiphysis, and femoroacetabular impingement, can be considered morphology variants of the normal hip. The femoroacetabular morphology of DHD is believed to induce osteoarthritis (OA) through local cumulative mechanical overload acting on genetically controlled patterning systems and subsequent damage of joint structures. However, it is unclear why hip morphology differs between individuals with seemingly comparable load histories and why certain hips with DHD progress to symptomatic OA whereas others do not. We asked (1) which mechanical factors influence growth and development of the proximal femur; and (2) which genes or genetic mechanisms are associated with hip ontogenesis. We performed a systematic literature review of mechanical and genetic factors of hip ontogeny. We focused on three fields that in recent years have advanced our knowledge of adult hip morphology: imaging, evolution, and genetics. WHERE ARE WE NOW?: Mechanical factors can be understood in view of human evolutionary peculiarities and may summate to load histories conducive to DHD. Genetic factors most likely act through multiple genes, each with modest effect sizes. Single genes that explain a DHD are therefore unlikely to be found. Apparently, the interplay between genes and load history not only determines hip morphotype, but also joint cartilage robustness ("cartilotype") and resistance to symptomatic OA. WHERE DO WE NEED TO GO?: We need therapies that can improve both morphotype and cartilotype. HOW DO WE GET THERE?: Better phenotyping, improving classification systems of hip morphology, and comparative population studies can be done with existing methods. Quantifying load histories likely requires new tools, but proof of principle of modifying morphotype in treatment of DDH and of cartilotype with exercise is available.

Genetic variants and traits related to insulin-like growth factor-I and insulin resistance and their interaction with lifestyles on postmenopausal colorectal cancer risk

PubMed Central

Rohan, Thomas; Strickler, Howard; Bea, Jennifer; Zhang, Zuo-Feng; Ho, Gloria; Crandall, Carolyn

2017-01-01

Genetic variants and traits in metabolic signaling pathways may interact with lifestyle factors such as obesity, physical activity, and exogenous estrogen (E), influencing postmenopausal colorectal cancer (CRC) risk, but these interrelated pathways are not fully understood. In this case-cohort study, we examined 33 single-nucleotide polymorphisms (SNPs) in genes related to insulin-like growth factor-I (IGF-I)/ insulin resistance (IR) traits and signaling pathways, using data from 704 postmenopausal women in Women’s Health Initiative Observation ancillary studies. Stratifying by the lifestyle modifiers, we assessed the effects of IGF-I/IR traits (fasting total and free IGF-I, IGF binding protein-3, insulin, glucose, and homeostatic model assessment–insulin resistance) on CRC risk as a mediator or influencing factor. Six SNPs in the INS, IGF-I, and IGFBP3 genes were associated with CRC risk, and those associations differed between non-obese/active and obese/inactive women and between E nonusers and users. Roughly 30% of the cancer risk due to the SNP was mediated by IGF-I/IR traits. Likewise, carriers of 11 SNPs in the IRS1 and AKT1/2 genes (signaling pathway–related genetic variants) had different associations with CRC risk between strata, and the proportion of the SNP–cancer association explained by traits varied from 30% to 50%. Our findings suggest that IGF-I/IR genetic variants interact with obesity, physical activity, and exogenous E, altering postmenopausal CRC risk, through IGF-I/IR traits, but also through different pathways. Unraveling gene–phenotype–lifestyle interactions will provide data on potential genetic targets in clinical trials for cancer prevention and intervention strategies to reduce CRC risk. PMID:29023587

Interaction of a genetic risk score with physical activity, physical inactivity, and body mass index in relation to venous thromboembolism risk.

PubMed

Kim, Jihye; Kraft, Peter; Hagan, Kaitlin A; Harrington, Laura B; Lindstroem, Sara; Kabrhel, Christopher

2018-06-01

Venous thromboembolism (VTE) is highly heritable. Physical activity, physical inactivity and body mass index (BMI) are also risk factors, but evidence of interaction between genetic and environmental risk factors is limited. Data on 2,134 VTE cases and 3,890 matched controls were obtained from the Nurses' Health Study (NHS), Nurses' Health Study II (NHS II), and Health Professionals Follow-up Study (HPFS). We calculated a weighted genetic risk score (wGRS) using 16 single nucleotide polymorphisms associated with VTE risk in published genome-wide association studies (GWAS). Data on three risk factors, physical activity (metabolic equivalent [MET] hours per week), physical inactivity (sitting hours per week) and BMI, were obtained from biennial questionnaires. VTE cases were incident since cohort inception; controls were matched to cases on age, cohort, and genotype array. Using conditional logistic regression, we assessed joint effects and interaction effects on both additive and multiplicative scales. We also ran models using continuous wGRS stratified by risk-factor categories. We observed a supra-additive interaction between wGRS and BMI. Having both high wGRS and high BMI was associated with a 3.4-fold greater risk of VTE (relative excess risk due to interaction = 0.69, p = 0.046). However, we did not find evidence for a multiplicative interaction with BMI. No interactions were observed for physical activity or inactivity. We found a synergetic effect between a genetic risk score and high BMI on the risk of VTE. Intervention efforts lowering BMI to decrease VTE risk may have particularly large beneficial effects among individuals with high genetic risk. © 2018 WILEY PERIODICALS, INC.

The Impact of the Emerging Genomics Data on the Management of Agerelated Phenotypes in the Context of Cellular Senescence.

PubMed

Montesanto, Alberto; Geracitano, Silvana; Garasto, Sabrina; Fusco, Sergio; Lattanzio, Fabrizia; Passarino, Giuseppe; Corsonello, Andrea

2016-01-01

Before the last decade, attempts to identify the genetic factors involved in the susceptibility to age-related complex diseases such as cardiovascular disease, diabetes and cancer had very limited success. Recently, two important advancements have provided new opportunities to improve our knowledge in this field. Firstly, it has emerged the concept of studying the molecular mechanisms underlying the age related decline of the organism (such as cellular senescence), rather than the genetics of single disorders. In addition, advances in DNA technology have uncovered an incredible number of common susceptibility variants for several complex traits. Despite these progresses, the translation of these discoveries into clinical practice has been very difficult. To date, several attempts in translating genomics to medicine are being carried out to look for the best way by which genomic discoveries may improve our understanding of fundamental issues in the prediction and prevention of some complex diseases. The successful strategy seems to be testing simultaneously multiple susceptibility variants in combination with traditional risk factors. In fact, such approach showed that genetic factors substantially improve the prediction of complex diseases especially for coronary heart disease and prostate cancer, making possible appropriate behavioural and medical interventions. In the future, the identification of new genetic variants and their inclusion into current risk profile models will probably improve the discrimination power of these models for other complex diseases such as type 2 diabetes mellitus and breast cancer. On the other hand, for traits with low heritability, this improvement will probably be negligible, and this will urge further researches on the role played by traditional and newly discovered non-genetic risk factors.

Clinical, biochemical and genetic risk factors for 30-day and 5-year mortality in 518 adult patients subjected to cardiopulmonary bypass during cardiac surgery - the INFLACOR study.

PubMed

Kowalik, Maciej Michał; Lango, Romuald; Siondalski, Piotr; Chmara, Magdalena; Brzeziński, Maciej; Lewandowski, Krzysztof; Jagielak, Dariusz; Klapkowski, Andrzej; Rogowski, Jan

2018-04-25

There is increasing evidence that genetic variability influences patients' early morbidity after cardiac surgery performed using cardiopulmonary bypass (CPB). The use of mortality as an outcome measure in cardiac surgical genetic association studies is rare. We publish the 30-day and 5-year survival analyses with focus on pre-, intra-, postoperative variables, biochemical parameters, and genetic variants in the INFLACOR (INFLAmmation in Cardiac OpeRations) cohort. In a prospectively recruited cohort of 518 adult Polish Caucasians, who underwent cardiac surgery in which CPB was used, the clinical data, biochemical parameters, IL-6, soluble ICAM-1, TNFα, soluble E-selectin, and 10 single nucleotide polymorphisms were evaluated for their association with 30-day and 5-year mortality. The 30-day mortality was associated with: pre-operative prothrombin international normalized ratio, intra-operative blood lactate, postoperative serum creatine phosphokinase, and acute kidney injury requiring renal replacement therapy (AKI-RRT) in logistic regression. Factors that determined the 5-year survival included: pre-operative NYHA class, history of peripheral artery disease and severe chronic obstructive pulmonary disease, intra-operative blood transfusion; and postoperative peripheral hypothermia, myocardial infarction, infection, and AKI-RRT in Cox regression. Serum levels of IL-6 and ICAM-1 measured three hours after the operation were associated with 30-day and 5-year mortality, respectively. The ICAM1 rs5498 was associated with 30-day and 5-year survival with borderline significance. Different risk factors determined the early (30-day) and late (5-year) survival after adult cardiac surgery in which cardiopulmonary bypass was used. Future genetic association studies in cardiac surgical patients should account for the identified chronic and perioperative risk factors.

What can genes tell us about the relationship between education and health?

PubMed

Boardman, Jason D; Domingue, Benjamin W; Daw, Jonathan

2015-02-01

We use genome wide data from respondents of the Health and Retirement Study (HRS) to evaluate the possibility that common genetic influences are associated with education and three health outcomes: depression, self-rated health, and body mass index. We use a total of 1.7 million single nucleotide polymorphisms obtained from the Illumina HumanOmni2.5-4v1 chip from 4233 non-Hispanic white respondents to characterize genetic similarities among unrelated persons in the HRS. We then used the Genome Wide Complex Trait Analysis (GCTA) toolkit, to estimate univariate and bivariate heritability. We provide evidence that education (h(2) = 0.33), BMI (h(2) = 0.43), depression (h(2) = 0.19), and self-rated health (h(2) = 0.18) are all moderately heritable phenotypes. We also provide evidence that some of the correlation between depression and education as well as self-rated health and education is due to common genetic factors associated with one or both traits. We find no evidence that the correlation between education and BMI is influenced by common genetic factors. Copyright © 2014 Elsevier Ltd. All rights reserved.

The Nature and Nurture of Melody: A Twin Study of Musical Pitch and Rhythm Perception.

PubMed

Seesjärvi, Erik; Särkämö, Teppo; Vuoksimaa, Eero; Tervaniemi, Mari; Peretz, Isabelle; Kaprio, Jaakko

2016-07-01

Both genetic and environmental factors are known to play a role in our ability to perceive music, but the degree to which they influence different aspects of music cognition is still unclear. We investigated the relative contribution of genetic and environmental effects on melody perception in 384 young adult twins [69 full monozygotic (MZ) twin pairs, 44 full dizygotic (DZ) twin pairs, 70 MZ twins without a co-twin, and 88 DZ twins without a co-twin]. The participants performed three online music tests requiring the detection of pitch changes in a two-melody comparison task (Scale) and key and rhythm incongruities in single-melody perception tasks (Out-of-key, Off-beat). The results showed predominantly additive genetic effects in the Scale task (58 %, 95 % CI 42-70 %), shared environmental effects in the Out-of-key task (61 %, 49-70 %), and non-shared environmental effects in the Off-beat task (82 %, 61-100 %). This highly different pattern of effects suggests that the contribution of genetic and environmental factors on music perception depends on the degree to which it calls for acquired knowledge of musical tonal and metric structures.

Worldwide variation in hip fracture incidence weakly aligns with genetic divergence between populations.

PubMed

Wallace, I J; Botigué, L R; Lin, M; Smaers, J B; Henn, B M; Grine, F E

2016-09-01

This study investigates the influence of genetic differentiation in determining worldwide heterogeneity in osteoporosis-related hip fracture rates. The results indicate that global variation in fracture incidence exceeds that expected on the basis of random genetic variance. Worldwide, the incidence of osteoporotic hip fractures varies considerably. This variability is believed to relate mainly to non-genetic factors. It is conceivable, however, that genetic susceptibility indeed differs across populations. Here, we present the first quantitative assessment of the effects of genetic differentiation on global variability in hip fracture rates. We investigate the observed variance in publically reported age-standardized rates of hip fracture among 28 populations from around the world relative to the expected variance given the phylogenetic relatedness of these populations. The extent to which these variances are similar constitutes a "phylogenetic signal," which was measured using the K statistic. Population genetic divergence was calculated using a robust array of genome-wide single nucleotide polymorphisms. While phylogenetic signal is maximized when K > 1, a K value of only 0.103 was detected in the combined-sex fracture rate pattern across the 28 populations, indicating that fracture rates vary more than expected based on phylogenetic relationships. When fracture rates for the sexes were analyzed separately, the degree of phylogenetic signal was also found to be small (females: K = 0.102; males: K = 0.081). The lack of a strong phylogenetic signal underscores the importance of factors other than stochastic genetic diversity in shaping worldwide heterogeneity in hip fracture incidence.

Genetics and genomics of susceptibility and immune response to necrotic enteritis in chicken: a review.

PubMed

Zahoor, Imran; Ghayas, Abdul; Basheer, Atia

2018-02-01

Global poultry production is facing many challenges and is currently under pressure due to the presence of several diseases like Necrotic Enteritis (NE). It is estimated that NE-caused global economic losses has increased from 2 billion to 6 billion US$ in 2015 because it is not easy to diagnose and control disease at the earlier stage of occurrence. Additionally, ban on the in-feed antibiotics and some other genetic and non-genetic predisposing factors affect the occurrence of the disease. Though the incidence of the disease can be reduced by minimizing the predisposing factors and through immunization of birds but there is no single remedy to control the disease. Therefore, we suggest that there is need to find out the genetic variants that could help to select the birds resistant to NE. The current review details the pertinent features about the genetic and genomics of susceptibility and immune response of birds to Necrotic Enteritis. We report here the list of candidate gene reported for their involvement with the susceptibility and/or resistance to the disease. However, most of these genes are involved in immune-related functions. For better understanding of the role of Clostridium perfringens and its toxins in the pathogenesis of disease there is need to unveil the association between any specific genetic variation and clinical status of NE. However, the presence of substantial genetic variations among different breeds/strains of chicken shows that it is possible to develop broiler strain with genetic resistant against NE. It would help in the cost-effective and sustainable production of safe broiler meat.

Genetic epidemiology of single gene defects in Chile.

PubMed Central

Cruz-Coke, R; Moreno, R S

1994-01-01

We have studied the correlation between the ethnic structure and the prevalence of single gene defects in Chile. At present the Chilean population is approximately 64% white and 35% Amerindian with traces of other admixture. Fewer than 4% of the Chilean population are foreign born. Investigations indicate that all severe diseases and many others without impaired reproduction have mutation rates within the range of the white population. Classical ethnic diseases are very rare. Autosomal recessive disorders have a wide range of variability: cystic fibrosis has a low incidence and PKU has a similar incidence to English rates. Only 30% of the inborn errors of metabolism have been described in Chilean medical publications. In addition, no Chilean haemoglobin or haptoglobin variants have been described. Some rare inherited diseases in Chilean human isolates have been described, including achromatopsia, chondrocalcinosis, and Creutzfeldt-Jakob disease. The prevalence of intrahepatic cholestasis of pregnancy and supernumerary nipples is the highest in the world and they are associated with aboriginal origin. Single gene defects in Chile are probably shaped by factors related to its ethnic population structure. These local rare single gene defects may be good markers of population admixture for genetic epidemiological studies. PMID:7815439

Implicit Association to Infant Faces: How Genetics, Early Care Experiences, and Cultural Factors Influence Caregiving Propensities

PubMed Central

Senese, Vincenzo Paolo; Shinohara, Kazuyuki; Esposito, Gianluca; Doi, Hirokazu; Venuti, Paola; Bornstein, Marc H.

2018-01-01

Genetics, early experience, and culture shape caregiving, but it is still not clear how genetics, early experiences, and cultural factors might interact to influence specific caregiving propensities, such as adult responsiveness to infant cues. To address this gap, 80 Italian adults (50% M; 18-25 years) were (1) genotyped for two oxytocin receptor gene polymorphisms (rs53576 and rs2254298) and the serotonin transporter gene polymorphism (5-HTTLPR), which are implicated in parenting behaviour, (2) completed the Adult Parental Acceptance/Rejection Questionnaire to evaluate their recollections of parental behaviours toward them in childhood, and (3) were administered a Single Category Implicit Association Test to evaluate their implicit responses to faces of Italian infants, Japanese infants, and Italian adults. Analysis of implicit associations revealed that Italian infant faces were evaluated as most positive; participants in the rs53576 GG group had the most positive implicit associations to Italian infant faces; the serotonin polymorphism moderated the effect of early care experiences on adults’ implicit association to both Italian infant and adult female faces. Finally, 5-HTTLPR S carriers showed less positive implicit responses to Japanese infant faces. We conclude that adult in-group preference extends to in-group infant faces and that implicit responses to social cues are influenced by interactions of genetics, early care experiences, and cultural factors. These findings have implications for understanding processes that regulate adult caregiving. PMID:27650102

African Ancestry and Its Correlation to Type 2 Diabetes in African Americans: A Genetic Admixture Analysis in Three U.S. Population Cohorts

PubMed Central

Cheng, Ching-Yu; Reich, David; Haiman, Christopher A.; Tandon, Arti; Patterson, Nick; Elizabeth, Selvin; Akylbekova, Ermeg L.; Brancati, Frederick L.; Coresh, Josef; Boerwinkle, Eric; Altshuler, David; Taylor, Herman A.; Henderson, Brian E.; Wilson, James G.; Kao, W. H. Linda

2012-01-01

The risk of type 2 diabetes is approximately 2-fold higher in African Americans than in European Americans even after adjusting for known environmental risk factors, including socioeconomic status (SES), suggesting that genetic factors may explain some of this population difference in disease risk. However, relatively few genetic studies have examined this hypothesis in a large sample of African Americans with and without diabetes. Therefore, we performed an admixture analysis using 2,189 ancestry-informative markers in 7,021 African Americans (2,373 with type 2 diabetes and 4,648 without) from the Atherosclerosis Risk in Communities Study, the Jackson Heart Study, and the Multiethnic Cohort to 1) determine the association of type 2 diabetes and its related quantitative traits with African ancestry controlling for measures of SES and 2) identify genetic loci for type 2 diabetes through a genome-wide admixture mapping scan. The median percentage of African ancestry of diabetic participants was slightly greater than that of non-diabetic participants (study-adjusted difference = 1.6%, P<0.001). The odds ratio for diabetes comparing participants in the highest vs. lowest tertile of African ancestry was 1.33 (95% confidence interval 1.13–1.55), after adjustment for age, sex, study, body mass index (BMI), and SES. Admixture scans identified two potential loci for diabetes at 12p13.31 (LOD = 4.0) and 13q14.3 (Z score = 4.5, P = 6.6×10−6). In conclusion, genetic ancestry has a significant association with type 2 diabetes above and beyond its association with non-genetic risk factors for type 2 diabetes in African Americans, but no single gene with a major effect is sufficient to explain a large portion of the observed population difference in risk of diabetes. There undoubtedly is a complex interplay among specific genetic loci and non-genetic factors, which may both be associated with overall admixture, leading to the observed ethnic differences in diabetes risk. PMID:22438884

A challenge to the striking genotypic heterogeneity of retinitis pigmentosa: a better understanding of the pathophysiology using the newest genetic strategies

PubMed Central

Sorrentino, F S; Gallenga, C E; Bonifazzi, C; Perri, P

2016-01-01

Retinitis pigmentosa (RP) is a group of inherited retinal disorders characterized by a complex association between tremendous genotypic multiplicity and great phenotypic heterogeneity. The severity of the clinical manifestation depends on penetrance and expressivity of the disease-gene. Also, various interactions between gene expression and environmental factors have been hypothesized. More than 250 genes with ~4500 causative mutations have been reported to be involved in different RP-related mechanisms. Nowadays, not more than the 50% of RPs are attributable to identified genes, whereas the rest of molecular defects are still undetectable, especially in populations where few genetic screenings have been performed. Therefore, new genetic strategies can be a remarkably useful tool to aid clinical diagnosis, potentially modifying treatment options, and family counseling. Genome-wide analytical techniques (array comparative genomic hybridization and single-nucleotide polymorphism genotyping) and DNA sequencing strategies (arrayed primer extension, Sanger sequencing, and ultra high-throughput sequencing) are successfully used to early make molecular diagnosis detecting single or multiple mutations in the huge heterogeneity of RPs. To date, further research needs to be carried out to better investigate the genotype/phenotype correlation, putting together genetic and clinical findings to provide detailed information concerning the risk of RP development and novel effective treatments. PMID:27564722

Health-related disparities: influence of environmental factors.

PubMed

Olden, Kenneth; White, Sandra L

2005-07-01

Racial disparities in health cannot be explained solely on the basis of poverty, access to health care, behavior, or environmental factors. Their complex etiology is dependent on interactions between all these factors plus genetics. Scientists have been slow to consider genetics as a risk factor because genetic polymorphisms tend to be more variable within a race than between races. Now that studies are demonstrating the existence of racial differences in allelic frequencies for multiple genes affecting a single biologic mechanism, the present argument for a significant genetic role in contributing to health disparities is gaining support. Individuals vary, often significantly, in their response to environmental agents. This variability provides a high "background noise" when scientists examine human populations to identify environmental links to disease. This variability often masks important environmental contributors to disease risk and is a major impediment to efforts to investigate the causes of diseases.Fortunately, investments in the various genome projects have led to the development of tools and databases that can be used to help identify the genetic variations in environmental response genes that can lead to such wide differences in disease susceptibility. NIEHS developed the environ-mental genome project to catalog these genetic variants (polymorphisms)and to identify the ones that play a major role in human susceptibility to environmental agents. This information is being used in epidemiologic studies to pinpoint environmental contributors to disease better. The research summarized in this article is critically important for tying genetics and the environment to health disparities, and for the development of a rational approach to gauge environmental threats. Common variants in genes play pivotal roles in determining if or when illness or death result from exposure to drugs or environmental xenobiotics. Most common variants exist in all human populations, but their frequency can vary substantially,rendering individuals or groups more or less susceptible to particular environmental exposures. Such findings are consistent with the highly publicized analogy, "genetics loads the gun, but the environment pulls the trigger." That is, one can inherit the genetic predisposition to develop a disease but will do so only if or when exposed to the environmental trigger. Poor people have approximately the same genetic makeup as everyone else,but they have the unfortunate experience of living and working in environments containing multiple and high levels of carcinogens or other toxicants capable of interacting with susceptibility genes to cause disease.Furthermore, certain disadvantaged ethnic groups may have a higher incidence of certain susceptible genes that render them more vulnerable to adverse effects of the environments they inhabit. For both of these reasons,much of the nation's disease burden could likely be reduced through better environmental protection practices, especially in low-income and minority communities. Of the many implications of polymorphisms and frequency variations for public health and the practice of medicine, however, none is more urgent than the choice of drugs in therapy. Using such knowledge,randomized trials have identified race-specific drug response differences between blacks and whites [42].To date, most knowledge of the health effects of environmental factors is derived from studies of single agents. The reality, though, is that environmental contributions to health disparities are mostly from multiple agents. These simultaneous exposures to multiple risk factors, which may accumulate or interact synergistically, remain to be fully explained and defined.Finally, health disparity is a significant public health problem that cannot be solved using "business as usual" approaches for funding and priority setting. The current emphasis on basic and clinical research at the exclusion of public health and the social sciences does not provide the interdisciplinary research teams necessary to address such a complex problem as health disparities. Although the poor will always be with us, their health could be greatly improved if social, environmental, and genetic scientists could find ways to collaborate and develop more insightful and relevant ways to address the health of disadvantaged communities.

The genetic basis for interindividual immune response variation to measles vaccine: new understanding and new vaccine approaches

PubMed Central

Haralambieva, Iana H; Ovsyannikova, Inna G; Pankratz, V Shane; Kennedy, Richard B; Jacobson, Robert M; Poland, Gregory A

2013-01-01

The live-attenuated measles vaccine is effective, but measles outbreaks still occur in vaccinated populations. This warrants elucidation of the determinants of measles vaccine-induced protective immunity. Interindividual variability in markers of measles vaccine-induced immunity, including neutralizing antibody levels, is regulated in part by host genetic factor variations. This review summarizes recent advances in our understanding of measles vaccine immunogenetics relative to the perspective of developing better measles vaccines. Important genetic regulators of measles vaccine-induced immunity, such as HLA class I and HLA class II genotypes, single nucleotide polymorphisms in cytokine/cytokine receptor genes (IL12B, IL12RB1, IL2, IL10) and the cell surface measles virus receptor CD46 gene, have been identified and independently replicated. New technologies present many opportunities for identification of novel genetic signatures and genetic architectures. These findings help explain a variety of immune response-related phenotypes and promote a new paradigm of ‘vaccinomics’ for novel vaccine development. PMID:23256739

Monogenic Autoinflammatory Diseases with Mendelian Inheritance: Genes, Mutations, and Genotype/Phenotype Correlations

PubMed Central

Martorana, Davide; Bonatti, Francesco; Mozzoni, Paola; Vaglio, Augusto; Percesepe, Antonio

2017-01-01

Autoinflammatory diseases (AIDs) are a genetically heterogeneous group of diseases caused by mutations of genes encoding proteins, which play a pivotal role in the regulation of the inflammatory response. In the pathogenesis of AIDs, the role of the genetic background is triggered by environmental factors through the modulation of the innate immune system. Monogenic AIDs are characterized by Mendelian inheritance and are caused by highly penetrant genetic variants in single genes. During the last years, remarkable progress has been made in the identification of disease-associated genes by using new technologies, such as next-generation sequencing, which has allowed the genetic characterization in undiagnosed patients and in sporadic cases by means of targeted resequencing of a gene panel and whole exome sequencing. In this review, we delineate the genetics of the monogenic AIDs, report the role of the most common gene mutations, and describe the evidences of the most sound genotype/phenotype correlations in AID. PMID:28421071

A methodological overview on molecular preimplantation genetic diagnosis and screening: a genomic future?

PubMed

Vendrell, Xavier; Bautista-Llácer, Rosa

2012-12-01

The genetic diagnosis and screening of preimplantation embryos generated by assisted reproduction technology has been consolidated in the prenatal care framework. The rapid evolution of DNA technologies is tending to molecular approaches. Our intention is to present a detailed methodological view, showing different diagnostic strategies based on molecular techniques that are currently applied in preimplantation genetic diagnosis. The amount of DNA from one single, or a few cells, obtained by embryo biopsy is a limiting factor for the molecular analysis. In this sense, genetic laboratories have developed molecular protocols considering this restrictive condition. Nevertheless, the development of whole-genome amplification methods has allowed preimplantation genetic diagnosis for two or more indications simultaneously, like the selection of histocompatible embryos plus detection of monogenic diseases or aneuploidies. Moreover, molecular techniques have permitted preimplantation genetic screening to progress, by implementing microarray-based comparative genome hybridization. Finally, a future view of the embryo-genetics field based on molecular advances is proposed. The normalization, cost-effectiveness analysis, and new technological tools are the next topics for preimplantation genetic diagnosis and screening. Concomitantly, these additions to assisted reproduction technologies could have a positive effect on the schedules of preimplantation studies.

Growth factors and chronic wound healing: past, present, and future.

PubMed

Goldman, Robert

2004-01-01

Growth substances (cytokines and growth factors) are soluble signaling proteins affecting the process of normal wound healing. Cytokines govern the inflammatory phase that clears cellular and extracellular matrix debris. Wound repair is controlled by growth factors (platelet-derived growth factor [PDGF], keratinocyte growth factor, and transforming growth factor beta). Endogenous growth factors communicate across the dermal-epidermal interface. PDGF is important for most phases of wound healing. Becaplermin (PDGF-BB), the only growth factor approved by the Food and Drug Administration, requires daily application for neuropathic wound healing. Gene therapy is under development for more efficient growth factor delivery; a single application will induce constitutive growth factor expression for weeks. Based on dramatic preclinical animal studies, a phase 1 clinical trial planned on a PDGF genetic construct appears promising.

Defining a Contemporary Ischemic Heart Disease Genetic Risk Profile Using Historical Data.

PubMed

Mosley, Jonathan D; van Driest, Sara L; Wells, Quinn S; Shaffer, Christian M; Edwards, Todd L; Bastarache, Lisa; McCarty, Catherine A; Thompson, Will; Chute, Christopher G; Jarvik, Gail P; Crosslin, David R; Larson, Eric B; Kullo, Iftikhar J; Pacheco, Jennifer A; Peissig, Peggy L; Brilliant, Murray H; Linneman, James G; Denny, Josh C; Roden, Dan M

2016-12-01

Continued reductions in morbidity and mortality attributable to ischemic heart disease (IHD) require an understanding of the changing epidemiology of this disease. We hypothesized that we could use genetic correlations, which quantify the shared genetic architectures of phenotype pairs and extant risk factors from a historical prospective study to define the risk profile of a contemporary IHD phenotype. We used 37 phenotypes measured in the ARIC study (Atherosclerosis Risk in Communities; n=7716, European ancestry subjects) and clinical diagnoses from an electronic health record (EHR) data set (n=19 093). All subjects had genome-wide single-nucleotide polymorphism genotyping. We measured pairwise genetic correlations (rG) between the ARIC and EHR phenotypes using linear mixed models. The genetic correlation estimates between the ARIC risk factors and the EHR IHD were modestly linearly correlated with hazards ratio estimates for incident IHD in ARIC (Pearson correlation [r]=0.62), indicating that the 2 IHD phenotypes had differing risk profiles. For comparison, this correlation was 0.80 when comparing EHR and ARIC type 2 diabetes mellitus phenotypes. The EHR IHD phenotype was most strongly correlated with ARIC metabolic phenotypes, including total:high-density lipoprotein cholesterol ratio (rG=-0.44, P=0.005), high-density lipoprotein (rG=-0.48, P=0.005), systolic blood pressure (rG=0.44, P=0.02), and triglycerides (rG=0.38, P=0.02). EHR phenotypes related to type 2 diabetes mellitus, atherosclerotic, and hypertensive diseases were also genetically correlated with these ARIC risk factors. The EHR IHD risk profile differed from ARIC and indicates that treatment and prevention efforts in this population should target hypertensive and metabolic disease. © 2016 American Heart Association, Inc.

Genetic associations with micronutrient levels identified in immune and gastrointestinal networks.

PubMed

Morine, Melissa J; Monteiro, Jacqueline Pontes; Wise, Carolyn; Teitel, Candee; Pence, Lisa; Williams, Anna; Ning, Baitang; McCabe-Sellers, Beverly; Champagne, Catherine; Turner, Jerome; Shelby, Beatrice; Bogle, Margaret; Beger, Richard D; Priami, Corrado; Kaput, Jim

2014-07-01

The discovery of vitamins and clarification of their role in preventing frank essential nutrient deficiencies occurred in the early 1900s. Much vitamin research has understandably focused on public health and the effects of single nutrients to alleviate acute conditions. The physiological processes for maintaining health, however, are complex systems that depend upon interactions between multiple nutrients, environmental factors, and genetic makeup. To analyze the relationship between these factors and nutritional health, data were obtained from an observational, community-based participatory research program of children and teens (age 6-14) enrolled in a summer day camp in the Delta region of Arkansas. Assessments of erythrocyte S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), plasma homocysteine (Hcy) and 6 organic micronutrients (retinol, 25-hydroxy vitamin D3, pyridoxal, thiamin, riboflavin, and vitamin E), and 1,129 plasma proteins were performed at 3 time points in each of 2 years. Genetic makeup was analyzed with 1 M SNP genotyping arrays, and nutrient status was assessed with 24-h dietary intake questionnaires. A pattern of metabolites (met_PC1) that included the ratio of erythrocyte SAM/SAH, Hcy, and 5 vitamins were identified by principal component analysis. Met_PC1 levels were significantly associated with (1) single-nucleotide polymorphisms, (2) levels of plasma proteins, and (3) multilocus genotypes coding for gastrointestinal and immune functions, as identified in a global network of metabolic/protein-protein interactions. Subsequent mining of data from curated pathway, network, and genome-wide association studies identified genetic and functional relationships that may be explained by gene-nutrient interactions. The systems nutrition strategy described here has thus associated a multivariate metabolite pattern in blood with genes involved in immune and gastrointestinal functions.

Predicting attention-deficit/hyperactivity disorder severity from psychosocial stress and stress-response genes: a random forest regression approach

PubMed Central

van der Meer, D; Hoekstra, P J; van Donkelaar, M; Bralten, J; Oosterlaan, J; Heslenfeld, D; Faraone, S V; Franke, B; Buitelaar, J K; Hartman, C A

2017-01-01

Identifying genetic variants contributing to attention-deficit/hyperactivity disorder (ADHD) is complicated by the involvement of numerous common genetic variants with small effects, interacting with each other as well as with environmental factors, such as stress exposure. Random forest regression is well suited to explore this complexity, as it allows for the analysis of many predictors simultaneously, taking into account any higher-order interactions among them. Using random forest regression, we predicted ADHD severity, measured by Conners’ Parent Rating Scales, from 686 adolescents and young adults (of which 281 were diagnosed with ADHD). The analysis included 17 374 single-nucleotide polymorphisms (SNPs) across 29 genes previously linked to hypothalamic–pituitary–adrenal (HPA) axis activity, together with information on exposure to 24 individual long-term difficulties or stressful life events. The model explained 12.5% of variance in ADHD severity. The most important SNP, which also showed the strongest interaction with stress exposure, was located in a region regulating the expression of telomerase reverse transcriptase (TERT). Other high-ranking SNPs were found in or near NPSR1, ESR1, GABRA6, PER3, NR3C2 and DRD4. Chronic stressors were more influential than single, severe, life events. Top hits were partly shared with conduct problems. We conclude that random forest regression may be used to investigate how multiple genetic and environmental factors jointly contribute to ADHD. It is able to implicate novel SNPs of interest, interacting with stress exposure, and may explain inconsistent findings in ADHD genetics. This exploratory approach may be best combined with more hypothesis-driven research; top predictors and their interactions with one another should be replicated in independent samples. PMID:28585928

Joint association of nicotinic acetylcholine receptor variants with abdominal obesity in American Indians: the Strong Heart Family Study.

PubMed

Zhu, Yun; Yang, Jingyun; Yeh, Fawn; Cole, Shelley A; Haack, Karin; Lee, Elisa T; Howard, Barbara V; Zhao, Jinying

2014-01-01

Cigarette smoke is a strong risk factor for obesity and cardiovascular disease. The effect of genetic variants involved in nicotine metabolism on obesity or body composition has not been well studied. Though many genetic variants have previously been associated with adiposity or body fat distribution, a single variant usually confers a minimal individual risk. The goal of this study is to evaluate the joint association of multiple variants involved in cigarette smoke or nicotine dependence with obesity-related phenotypes in American Indians. To achieve this goal, we genotyped 61 tagSNPs in seven genes encoding nicotine acetylcholine receptors (nAChRs) in 3,665 American Indians participating in the Strong Heart Family Study. Single SNP association with obesity-related traits was tested using family-based association, adjusting for traditional risk factors including smoking. Joint association of all SNPs in the seven nAChRs genes were examined by gene-family analysis based on weighted truncated product method (TPM). Multiple testing was controlled by false discovery rate (FDR). Results demonstrate that multiple SNPs showed weak individual association with one or more measures of obesity, but none survived correction for multiple testing. However, gene-family analysis revealed significant associations with waist circumference (p = 0.0001) and waist-to-hip ratio (p = 0.0001), but not body mass index (p = 0.20) and percent body fat (p = 0.29), indicating that genetic variants are jointly associated with abdominal, but not general, obesity among American Indians. The observed combined genetic effect is independent of cigarette smoking per se. In conclusion, multiple variants in the nAChR gene family are jointly associated with abdominal obesity in American Indians, independent of general obesity and cigarette smoking per se.

Genetic association analyses of atopic illness and proinflammatory cytokine genes with type 1 diabetes.

PubMed

Saleh, Nada M; Raj, Srilakshmi M; Smyth, Deborah J; Wallace, Chris; Howson, Joanna M M; Bell, Louise; Walker, Neil M; Stevens, Helen E; Todd, John A

2011-11-01

The genetic basis of the autoimmune disease type 1 diabetes (T1D) has now been largely determined, so now we can compare these findings with emerging genetic knowledge of disorders and phenotypes that have been negatively or positively associated with T1D historically. Here, we assessed the role in T1D of variants previously reported to be associated with atopic diseases and epithelial barrier function, profilaggrin (FLG), and those that affect the expression levels of the proinflammatory cytokines tumour necrosis factor (TNF)-α, interleukin (IL)-1β, interferon (IFN)γ and IL-18. We genotyped single nucleotide polymorphisms (SNPs): -105/rs28665122 in SELS or SEPS1 (selenoprotein), three single nucleotide polymorphisms in IL18 (-105/rs360717, +183/rs5744292 and +1467/rs574456) and R501X/rs61816761 in FLG, the major locus associated with atopic dermatitis and predisposing to asthma, in a minimum of 6743 T1D cases and 7864 controls. No evidence of T1D association was found for any of the SNPs we genotyped at FLG, SELS or IL18 (p≥0.03), nor with haplotypes of IL18 (p=0.82). Review of previous T1D genome-wide association results revealed that four (human leucocyte antigen (HLA), gasdermin B/ORM1 (Saccharomyces cerevisiae)-like/gasdermin B/, GSDMB/ORMDL3/GSDMA and IL2RB) of ten loci recently reported to be associated with asthma were associated with T1D (p≤0.005). These results show that there are shared genetic associations for atopy-related traits and T1D, and this might help in the future to understand the mechanisms, pathways and environmental factors that underpin the rapid rise in incidence of both disorders in children. Copyright © 2011 John Wiley & Sons, Ltd.

Genetic Markers Predict Primary Non-Response and Durable Response To Anti-TNF Biologic Therapies in Crohn's Disease.

PubMed

Barber, Grant E; Yajnik, Vijay; Khalili, Hamed; Giallourakis, Cosmas; Garber, John; Xavier, Ramnik; Ananthakrishnan, Ashwin N

2016-12-01

One-fifth of patients with Crohn's disease (CD) are primary non-responders to anti-tumor necrosis factor (anti-TNF) therapy, and an estimated 10-15% will fail therapy annually. Little is known about the genetics of response to anti-TNF therapy. The aim of our study was to identify genetic factors associated with primary non-response (PNR) and loss of response to anti-TNFs in CD. From a prospective registry, we characterized the response of 427 CD patients to their first anti-TNF therapy. Patients were designated as achieving primary response, durable response, and non-durable response based on clinical, endoscopic, and radiologic criteria. Genotyping was performed on the Illumina Immunochip. Separate genetic scores based on presence of predictive genetic alleles were calculated for PNR and durable response and performance of clinical and genetics models were compared. From 359 patients, 36 were adjudged to have PNR (10%), 200 had durable response, and 74 had non-durable response. PNRs had longer disease duration and were more likely to be smokers. Fifteen risk alleles were associated with PNR. Patients with PNR had a significantly higher genetic risk score (GRS) (P =8 × 10 -12 ). A combined clinical-genetic model more accurately predicted PNR when compared with a clinical only model (0.93 vs. 0.70, P <0.001). Sixteen distinct single nucleotide polymorphisms predicted durable response with a higher GRS (P =7 × 10 -13 ). The GRSs for PNR and durable response were not mutually correlated, suggesting distinct mechanisms. Genetic risk alleles can predict primary non-response and durable response to anti-TNF therapy in CD.

Genetic diversity, population structure, and traditional culture of Camellia reticulata.

PubMed

Xin, Tong; Huang, Weijuan; De Riek, Jan; Zhang, Shuang; Ahmed, Selena; Van Huylenbroeck, Johan; Long, Chunlin

2017-11-01

Camellia reticulata is an arbor tree that has been cultivated in southwestern China by various sociolinguistic groups for esthetic purposes as well as to derive an edible seed oil. This study examined the influence of management, socio-economic factors, and religion on the genetic diversity patterns of Camellia reticulata utilizing a combination of ethnobotanical and molecular genetic approaches. Semi-structured interviews and key informant interviews were carried out with local communities in China's Yunnan Province. We collected plant material ( n  = 190 individuals) from five populations at study sites using single-dose AFLP markers in order to access the genetic diversity within and between populations. A total of 387 DNA fragments were produced by four AFLP primer sets. All DNA fragments were found to be polymorphic (100%). A relatively high level of genetic diversity was revealed in C. reticulata samples at both the species ( H sp  = 0.3397, I sp  = 0.5236) and population (percentage of polymorphic loci = 85.63%, H pop  = 0.2937, I pop  = 0.4421) levels. Findings further revealed a relatively high degree of genetic diversity within C. reticulata populations (Analysis of Molecular Variance = 96.31%). The higher genetic diversity within populations than among populations of C. reticulata from different geographies is likely due to the cultural and social influences associated with its long cultivation history for esthetic and culinary purposes by diverse sociolinguistic groups. This study highlights the influence of human management, socio-economic factors, and other cultural variables on the genetic and morphological diversity of C. reticulata at a regional level. Findings emphasize the important role of traditional culture on the conservation and utilization of plant genetic diversity.

Proton Nuclear Magnetic Resonance-Spectroscopic Discrimination of Wines Reflects Genetic Homology of Several Different Grape (V. vinifera L.) Cultivars.

PubMed

Hu, Boran; Yue, Yaqing; Zhu, Yong; Wen, Wen; Zhang, Fengmin; Hardie, Jim W

2015-01-01

Proton nuclear magnetic resonance spectroscopy coupled multivariate analysis (1H NMR-PCA/PLS-DA) is an important tool for the discrimination of wine products. Although 1H NMR has been shown to discriminate wines of different cultivars, a grape genetic component of the discrimination has been inferred only from discrimination of cultivars of undefined genetic homology and in the presence of many confounding environmental factors. We aimed to confirm the influence of grape genotypes in the absence of those factors. We applied 1H NMR-PCA/PLS-DA and hierarchical cluster analysis (HCA) to wines from five, variously genetically-related grapevine (V. vinifera) cultivars; all grown similarly on the same site and vinified similarly. We also compared the semi-quantitative profiles of the discriminant metabolites of each cultivar with previously reported chemical analyses. The cultivars were clearly distinguishable and there was a general correlation between their grouping and their genetic homology as revealed by recent genomic studies. Between cultivars, the relative amounts of several of the cultivar-related discriminant metabolites conformed closely with reported chemical analyses. Differences in grape-derived metabolites associated with genetic differences alone are a major source of 1H NMR-based discrimination of wines and 1H NMR has the capacity to discriminate between very closely related cultivars. The study confirms that genetic variation among grape cultivars alone can account for the discrimination of wine by 1H NMR-PCA/PLS and indicates that 1H NMR spectra of wine of single grape cultivars may in future be used in tandem with hierarchical cluster analysis to elucidate genetic lineages and metabolomic relations of grapevine cultivars. In the absence of genetic information, for example, where predecessor varieties are no longer extant, this may be a particularly useful approach.

A site-specific genetic modification for induction of pluripotency and subsequent isolation of derived lung alveolar epithelial type II cells.

PubMed

Yan, Qing; Quan, Yuan; Sun, Huanhuan; Peng, Xinmiao; Zou, Zhengyun; Alcorn, Joseph L; Wetsel, Rick A; Wang, Dachun

2014-02-01

Human induced pluripotent stem cells (hiPSCs) have great therapeutic potential in repairing defective lung alveoli. However, genetic abnormalities caused by vector integrations and low efficiency in generating hiPSCs, as well as difficulty in obtaining transplantable hiPSC-derived cell types are still major obstacles. Here we report a novel strategy using a single nonviral site-specific targeting vector with a combination of Tet-On inducible gene expression system, Cre/lox P switching gene expression system, and alveolar epithelial type II cell (ATIIC)-specific Neomycin(R) transgene expression system. With this strategy, a single copy of all of the required transgenes can be specifically knocked into a site immediately downstream of β-2-microglobulin (B2M) gene locus at a high frequency, without causing B2M dysfunction. Thus, the expression of reprogramming factors, Oct4, Sox2, cMyc, and Klf4, can be precisely regulated for efficient reprogramming of somatic cells into random integration-free or genetic mutation-free hiPSCs. The exogenous reprogramming factor transgenes can be subsequently removed after reprogramming by transient expression of Cre recombinase, and the resulting random integration-free and exogenous reprogramming factor-free hiPSCs can be selectively differentiated into a homogenous population of ATIICs. In addition, we show that these hiPSC-derived ATIICs exhibit ultrastructural characteristics and biological functions of normal ATIICs. When transplanted into bleomycin-challenged mice lungs, hiPSC-derived ATIICs efficiently remain and re-epithelialize injured alveoli to restore pulmonary function, preventing lung fibrosis and increasing survival without tumorigenic side effect. This strategy allows for the first time efficient generation of patient-specific ATIICs for possible future clinical applications. © 2013 AlphaMed Press.

A site-specific genetic modification for induction of pluripotency and subsequent isolation of derived lung alveolar epithelial type II cells

PubMed Central

Yan, Qing; Quan, Yuan; Sun, Huanhuan; Peng, Xinmiao; Zou, Zhengyun; Alcorn, Joseph L.; Wetsel, Rick A.; Wang, Dachun

2013-01-01

Human induced pluripotent stem cells (hiPSCs) have great therapeutic potential in repairing defective lung alveoli. However, genetic abnormalities caused by vector-integrations and low efficiency in generating hiPSCs, as well as difficulty in obtaining transplantable hiPSC-derived cell types, are still major obstacles. Here we report a novel strategy using a single non-viral site-specific-targeting vector with a combination of Tet-On inducible gene expression system, Cre/lox P switching gene expression system, and alveolar epithelial type II cell (ATIIC)-specific NeomycinR trangene expression system. With this strategy, a single copy of all of the required transgenes can be specifically knocked into a site immediately downstream of beta-2-microglobulin (B2M) gene locus at a high frequency, without causing B2M dysfunction. Thus, the expression of reprogramming factors, Oct4, Sox2, cMyc and Klf4, can be precisely regulated for efficient reprogramming of somatic cells into random-integration-free or genetic mutation-free hiPSCs. The exogenous reprogramming factor transgenes can be subsequently removed after reprogramming by transient expression of Cre recombinase, and the resulting random-integration-free and exogenous reprogramming-factor-free hiPSCs can be selectively differentiated into a homogenous population of ATIICs. In addition, we show that these hiPSC-derived ATIICs exhibit ultra-structural characteristics and biological functions of normal ATIICs. When transplanted into bleomycin-challenged mice lungs, hiPSC-derived ATIICs efficiently remain and re-epithelialize injured alveoli to restore pulmonary function, preventing lung fibrosis and increasing survival without tumorigenic side effect. This strategy allows for the first time efficient generation of patient-specific ATIICs for possible future clinical applications. PMID:24123810

Genome-wide Association Study of Cannabis Dependence Severity, Novel Risk Variants, and Shared Genetic Risks.

PubMed

Sherva, Richard; Wang, Qian; Kranzler, Henry; Zhao, Hongyu; Koesterer, Ryan; Herman, Aryeh; Farrer, Lindsay A; Gelernter, Joel

2016-05-01

Cannabis dependence (CAD) is a serious problem worldwide and is of growing importance in the United States because cannabis is increasingly available legally. Although genetic factors contribute substantially to CAD risk, at present no well-established specific genetic risk factors for CAD have been elucidated. To report findings for DSM-IV CAD criteria from association analyses performed in large cohorts of African American and European American participants from 3 studies of substance use disorder genetics. This genome-wide association study for DSM-IV CAD criterion count was performed in 3 independent substance dependence cohorts (the Yale-Penn Study, Study of Addiction: Genetics and Environment [SAGE], and International Consortium on the Genetics of Heroin Dependence [ICGHD]). A referral sample and volunteers recruited in the community and from substance abuse treatment centers included 6000 African American and 8754 European American participants, including some from small families. Participants from the Yale-Penn Study were recruited from 2000 to 2013. Data were collected for the SAGE trial from 1990 to 2007 and for the ICGHD from 2004 to 2009. Data were analyzed from January 2, 2013, to November 9, 2015. Criterion count for DSM-IV CAD. Among the 14 754 participants, 7879 were male, 6875 were female, and the mean (SD) age was 39.2 (10.2) years. Three independent regions with genome-wide significant single-nucleotide polymorphism associations were identified, considering the largest possible sample. These included rs143244591 (β = 0.54, P = 4.32 × 10-10 for the meta-analysis) in novel antisense transcript RP11-206M11.7;rs146091982 (β = 0.54, P = 1.33 × 10-9 for the meta-analysis) in the solute carrier family 35 member G1 gene (SLC35G1); and rs77378271 (β = 0.29, P = 2.13 × 10-8 for the meta-analysis) in the CUB and Sushi multiple domains 1 gene (CSMD1). Also noted was evidence of genome-level pleiotropy between CAD and major depressive disorder and for an association with single-nucleotide polymorphisms in genes associated with schizophrenia risk. Several of the genes identified have functions related to neuronal calcium homeostasis or central nervous system development. These results are the first, to our knowledge, to identify specific CAD risk alleles and potential genetic factors contributing to the comorbidity of CAD with major depression and schizophrenia.

Associations between Vocal Symptoms and Genetic Variants in the Oxytocin Receptor and Arginine Vasopressin 1A Receptor Gene

ERIC Educational Resources Information Center

Jämsen, Sofia Holmqvist; Johansson, Ada; Westberg, Lars; Santtila, Pekka; von der Pahlen, Bettina; Simberg, Susanna

2017-01-01

Purpose: Oxytocin and arginine vasopressin are associated with different aspects of the stress response. As stress is regarded as a risk factor for vocal symptoms, we wanted to explore the association between the oxytocin receptor gene ("OXTR") and arginine vasopressin 1A receptor gene ("AVPR1A") single-nucleotide polymorphisms…

The contribution of diet and genotype to iron status in women: a classical twin study.

PubMed

Fairweather-Tait, Susan J; Guile, Geoffrey R; Valdes, Ana M; Wawer, Anna A; Hurst, Rachel; Skinner, Jane; Macgregor, Alexander J

2013-01-01

This is the first published report examining the combined effect of diet and genotype on body iron content using a classical twin study design. The aim of this study was to determine the relative contribution of genetic and environmental factors in determining iron status. The population was comprised of 200 BMI- and age-matched pairs of MZ and DZ healthy twins, characterised for habitual diet and 15 iron-related candidate genetic markers. Variance components analysis demonstrated that the heritability of serum ferritin (SF) and soluble transferrin receptor was 44% and 54% respectively. Measured single nucleotide polymorphisms explained 5% and selected dietary factors 6% of the variance in iron status; there was a negative association between calcium intake and body iron (p = 0.02) and SF (p = 0.04).

Data Mining and Pattern Recognition Models for Identifying Inherited Diseases: Challenges and Implications.

PubMed

Iddamalgoda, Lahiru; Das, Partha S; Aponso, Achala; Sundararajan, Vijayaraghava S; Suravajhala, Prashanth; Valadi, Jayaraman K

2016-01-01

Data mining and pattern recognition methods reveal interesting findings in genetic studies, especially on how the genetic makeup is associated with inherited diseases. Although researchers have proposed various data mining models for biomedical approaches, there remains a challenge in accurately prioritizing the single nucleotide polymorphisms (SNP) associated with the disease. In this commentary, we review the state-of-art data mining and pattern recognition models for identifying inherited diseases and deliberate the need of binary classification- and scoring-based prioritization methods in determining causal variants. While we discuss the pros and cons associated with these methods known, we argue that the gene prioritization methods and the protein interaction (PPI) methods in conjunction with the K nearest neighbors' could be used in accurately categorizing the genetic factors in disease causation.

Genome-wide analysis in UK Biobank identifies four loci associated with mood instability and genetic correlation with major depressive disorder, anxiety disorder and schizophrenia.

PubMed

Ward, Joey; Strawbridge, Rona J; Bailey, Mark E S; Graham, Nicholas; Ferguson, Amy; Lyall, Donald M; Cullen, Breda; Pidgeon, Laura M; Cavanagh, Jonathan; Mackay, Daniel F; Pell, Jill P; O'Donovan, Michael; Escott-Price, Valentina; Smith, Daniel J

2017-11-30

Mood instability is a core clinical feature of affective and psychotic disorders. In keeping with the Research Domain Criteria approach, it may be a useful construct for identifying biology that cuts across psychiatric categories. We aimed to investigate the biological validity of a simple measure of mood instability and evaluate its genetic relationship with several psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD), schizophrenia, attention deficit hyperactivity disorder (ADHD), anxiety disorder and post-traumatic stress disorder (PTSD). We conducted a genome-wide association study (GWAS) of mood instability in 53,525 cases and 60,443 controls from UK Biobank, identifying four independently associated loci (on chromosomes 8, 9, 14 and 18), and a common single-nucleotide polymorphism (SNP)-based heritability estimate of ~8%. We found a strong genetic correlation between mood instability and MDD (r g  = 0.60, SE = 0.07, p = 8.95 × 10 -17 ) and a small but significant genetic correlation with both schizophrenia (r g  = 0.11, SE = 0.04, p = 0.01) and anxiety disorders (r g  = 0.28, SE = 0.14, p = 0.04), although no genetic correlation with BD, ADHD or PTSD was observed. Several genes at the associated loci may have a role in mood instability, including the DCC netrin 1 receptor (DCC) gene, eukaryotic translation initiation factor 2B subunit beta (eIF2B2), placental growth factor (PGF) and protein tyrosine phosphatase, receptor type D (PTPRD). Strengths of this study include the very large sample size, but our measure of mood instability may be limited by the use of a single question. Overall, this work suggests a polygenic basis for mood instability. This simple measure can be obtained in very large samples; our findings suggest that doing so may offer the opportunity to illuminate the fundamental biology of mood regulation.

Genome-wide association study for rotator cuff tears identifies two significant single-nucleotide polymorphisms.

PubMed

Tashjian, Robert Z; Granger, Erin K; Farnham, James M; Cannon-Albright, Lisa A; Teerlink, Craig C

2016-02-01

The precise etiology of rotator cuff disease is unknown, but prior evidence suggests a role for genetic factors. Limited data exist identifying specific genes associated with rotator cuff tearing. The purpose of this study was to identify specific genes or genetic variants associated with rotator cuff tearing by a genome-wide association study with an independent set of rotator cuff tear cases. A set of 311 full-thickness rotator cuff tear cases genotyped on the Illumina 5M single-nucleotide polymorphism (SNP) platform were used in a genome-wide association study with 2641 genetically matched white population controls available from the Illumina iControls database. Tests of association were performed with GEMMA software at 257,558 SNPs that compose the intersection of Illumina SNP platforms and that passed general quality control metrics. SNPs were considered significant if P < 1.94 × 10(-7) (Bonferroni correction: 0.05/257,558). Tests of association revealed 2 significantly associated SNPs, one occurring in SAP30BP (rs820218; P = 3.8E-9) on chromosome 17q25 and another occurring in SASH1 (rs12527089; P = 1.9E-7) on chromosome 6q24. This study represents the first attempt to identify genetic factors influencing rotator cuff tearing by a genome-wide association study using a dense/complete set of SNPs. Two SNPs were significantly associated with rotator cuff tearing, residing in SAP30BP on chromosome 17 and SASH1 on chromosome 6. Both genes are associated with the cellular process of apoptosis. Identification of potential genes or genetic variants associated with rotator cuff tearing may help in identifying individuals at risk for the development of rotator cuff tearing. Copyright © 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

Genetic polymorphisms and protein structures in growth hormone, growth hormone receptor, ghrelin, insulin-like growth factor 1 and leptin in Mehraban sheep.

PubMed

Bahrami, A; Behzadi, Sh; Miraei-Ashtiani, S R; Roh, S-G; Katoh, K

2013-09-15

The somatotropic axis, the control system for growth hormone (GH) secretion and its endogenous factors involved in the regulation of metabolism and energy partitioning, has promising potentials for producing economically valuable traits in farm animals. Here we investigated single nucleotide polymorphisms (SNPs) of the genes of factors involved in the somatotropic axis for growth hormone (GH1), growth hormone receptor (GHR), ghrelin (GHRL), insulin-like growth factor 1 (IGF-I) and leptin (LEP), using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and DNA sequencing methods in 452 individual Mehraban sheep. A nonradioactive method to allow SSCP detection was used for genomic DNA and PCR amplification of six fragments: exons 4 and 5 of GH1; exon 10 of GH receptor (GHR); exon 1 of ghrelin (GHRL); exon 1 of insulin-like growth factor-I (IGF-I), and exon 3 of leptin (LEP). Polymorphisms were detected in five of the six PCR products. Two electrophoretic patterns were detected for GH1 exon 4. Five conformational patterns were detected for GH1 exon 5 and LEP exon 3, and three for IGF-I exon 1. Only GHR and GHRL were monomorphic. Changes in protein structures due to variable SNPs were also analyzed. The results suggest that Mehraban sheep, a major breed that is important for the animal industry in Middle East countries, has high genetic variability, opening interesting prospects for future selection programs and preservation strategies. Copyright © 2013 Elsevier B.V. All rights reserved.

Copy Number Variants and Exome Sequencing Analysis in Six Pairs of Chinese Monozygotic Twins Discordant for Congenital Heart Disease.

PubMed

Xu, Yuejuan; Li, Tingting; Pu, Tian; Cao, Ruixue; Long, Fei; Chen, Sun; Sun, Kun; Xu, Rang

2017-12-01

Congenital heart disease (CHD) is one of the most common birth defects. More than 200 susceptibility loci have been identified for CHDs, yet a large part of the genetic risk factors remain unexplained. Monozygotic (MZ) twins are thought to be completely genetically identical; however, discordant phenotypes have been found in MZ twins. Recent studies have demonstrated genetic differences between MZ twins. We aimed to test whether copy number variants (CNVs) and/or genetic mutation differences play a role in the etiology of CHDs by using single nucleotide polymorphism (SNP) genotyping arrays and whole exome sequencing of twin pairs discordant for CHDs. Our goal was to identify mutations present only in the affected twins, which could identify novel candidates for CHD susceptibility loci. We present a comprehensive analysis for the CNVs and genetic mutation results of the selected individuals but detected no consistent differences within the twin pairs. Our study confirms that chromosomal structure or genetic mutation differences do not seem to play a role in the MZ twins discordant for CHD.

Epigenome-wide association study of DNA methylation in narcolepsy: an integrated genetic and epigenetic approach.

PubMed

Shimada, Mihoko; Miyagawa, Taku; Toyoda, Hiromi; Tokunaga, Katsushi; Honda, Makoto

2018-04-01

Narcolepsy with cataplexy, which is a hypersomnia characterized by excessive daytime sleepiness and cataplexy, is a multifactorial disease caused by both genetic and environmental factors. Several genetic factors including HLA-DQB1*06:02 have been identified; however, the disease etiology is still unclear. Epigenetic modifications, such as DNA methylation, have been suggested to play an important role in the pathogenesis of complex diseases. Here, we examined DNA methylation profiles of blood samples from narcolepsy and healthy control individuals and performed an epigenome-wide association study (EWAS) to investigate methylation loci associated with narcolepsy. Moreover, data from the EWAS and a previously performed narcolepsy genome-wide association study were integrated to search for methylation loci with causal links to the disease. We found that (1) genes annotated to the top-ranked differentially methylated positions (DMPs) in narcolepsy were associated with pathways of hormone secretion and monocarboxylic acid metabolism. (2) Top-ranked narcolepsy-associated DMPs were significantly more abundant in non-CpG island regions and more than 95 per cent of such sites were hypomethylated in narcolepsy patients. (3) The integrative analysis identified the CCR3 region where both a single methylation site and multiple single-nucleotide polymorphisms were found to be associated with the disease as a candidate region responsible for narcolepsy. The findings of this study suggest the importance of future replication studies, using methylation technologies with wider genome coverage and/or larger number of samples, to confirm and expand on these results.

Genetic and Functional Evidence Supports LPAR1 as a Susceptibility Gene for Hypertension.

PubMed

Xu, Ke; Ma, Lu; Li, Yang; Wang, Fang; Zheng, Gu-Yan; Sun, Zhijun; Jiang, Feng; Chen, Yundai; Liu, Huirong; Dang, Aimin; Chen, Xi; Chun, Jerold; Tian, Xiao-Li

2015-09-01

Essential hypertension is a complex disease affected by genetic and environmental factors and serves as a major risk factor for cardiovascular diseases. Serum lysophosphatidic acid correlates with an elevated blood pressure in rats, and lysophosphatidic acid interacts with 6 subtypes of receptors. In this study, we assessed the genetic association of lysophosphatidic acid receptors with essential hypertension by genotyping 28 single-nucleotide polymorphisms from genes encoding for lysophosphatidic acid receptors, LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6 and their flanking sequences, in 3 Han Chinese cohorts consisting of 2630 patients and 3171 controls in total. We identified a single-nucleotide polymorphism, rs531003 in the 3'-flanking genomic region of LPAR1, associated with hypertension (the Bonferroni corrected P=1.09×10(-5), odds ratio [95% confidence interval]=1.23 [1.13-1.33]). The risk allele C of rs531003 is associated with the increased expression of LPAR1 and the susceptibility of hypertension, particularly in those with a shortage of sleep (P=4.73×10(-5), odds ratio [95% confidence interval]=1.75 [1.34-2.28]). We further demonstrated that blood pressure elevation caused by sleep deprivation and phenylephrine-induced vasoconstriction was both diminished in LPAR1-deficient mice. Together, we show that LPAR1 is a novel susceptibility gene for human essential hypertension and that stress, such as shortage of sleep, increases the susceptibility of patients with risk allele to essential hypertension. © 2015 American Heart Association, Inc.

The Genetic Architecture of Oral Language, Reading Fluency, and Reading Comprehension: A Twin Study From 7 to 16 Years

PubMed Central

2017-01-01

This study examines the genetic and environmental etiology underlying the development of oral language and reading skills, and the relationship between them, over a long period of developmental time spanning middle childhood and adolescence. It focuses particularly on the differential relationship between language and two different aspects of reading: reading fluency and reading comprehension. Structural equation models were applied to language and reading data at 7, 12, and 16 years from the large-scale TEDS twin study. A series of multivariate twin models show a clear patterning of oral language with reading comprehension, as distinct from reading fluency: significant but moderate genetic overlap between oral language and reading fluency (genetic correlation rg = .46–.58 at 7, 12, and 16) contrasts with very substantial genetic overlap between oral language and reading comprehension (rg = .81–.87, at 12 and 16). This pattern is even clearer in a latent factors model, fit to the data aggregated across ages, in which a single factor representing oral language and reading comprehension is correlated with—but distinct from—a second factor representing reading fluency. A distinction between oral language and reading fluency is also apparent in different developmental trajectories: While the heritability of oral language increases over the period from 7 to 12 to 16 years (from h2 = .27 to .47 to .55), the heritability of reading fluency is high and largely stable over the same period of time (h2 = .73 to .71 to .64). PMID:28541066

The genetic architecture of oral language, reading fluency, and reading comprehension: A twin study from 7 to 16 years.

PubMed

Tosto, Maria G; Hayiou-Thomas, Marianna E; Harlaar, Nicole; Prom-Wormley, Elizabeth; Dale, Philip S; Plomin, Robert

2017-06-01

This study examines the genetic and environmental etiology underlying the development of oral language and reading skills, and the relationship between them, over a long period of developmental time spanning middle childhood and adolescence. It focuses particularly on the differential relationship between language and two different aspects of reading: reading fluency and reading comprehension. Structural equation models were applied to language and reading data at 7, 12, and 16 years from the large-scale TEDS twin study. A series of multivariate twin models show a clear patterning of oral language with reading comprehension, as distinct from reading fluency: significant but moderate genetic overlap between oral language and reading fluency (genetic correlation r g = .46-.58 at 7, 12, and 16) contrasts with very substantial genetic overlap between oral language and reading comprehension (r g = .81-.87, at 12 and 16). This pattern is even clearer in a latent factors model, fit to the data aggregated across ages, in which a single factor representing oral language and reading comprehension is correlated with-but distinct from-a second factor representing reading fluency. A distinction between oral language and reading fluency is also apparent in different developmental trajectories: While the heritability of oral language increases over the period from 7 to 12 to 16 years (from h² = .27 to .47 to .55), the heritability of reading fluency is high and largely stable over the same period of time (h² = .73 to .71 to .64). (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Genome-wide association analysis of pain severity in dysmenorrhea identifies association at chromosome 1p13.2, near the nerve growth factor locus.

PubMed

Jones, Amy V; Hockley, James R F; Hyde, Craig; Gorman, Donal; Sredic-Rhodes, Ana; Bilsland, James; McMurray, Gordon; Furlotte, Nicholas A; Hu, Youna; Hinds, David A; Cox, Peter J; Scollen, Serena

2016-11-01

Dysmenorrhea is a common chronic pelvic pain syndrome affecting women of childbearing potential. Family studies suggest that genetic background influences the severity of dysmenorrhea, but genetic predisposition and molecular mechanisms underlying dysmenorrhea are not understood. In this study, we conduct the first genome-wide association study to identify genetic factors associated with dysmenorrhea pain severity. A cohort of females of European descent (n = 11,891) aged 18 to 45 years rated their average dysmenorrhea pain severity. We used a linear regression model adjusting for age and body mass index, identifying one genome-wide significant (P < 5 × 10) association (rs7523086, P = 4.1 × 10, effect size 0.1 [95% confidence interval, 0.074-0.126]). This single nucleotide polymorphism is colocalising with NGF, encoding nerve growth factor. The presence of one risk allele corresponds to a predicted 0.1-point increase in pain intensity on a 4-point ordinal pain scale. The putative effects on NGF function and/or expression remain unknown. However, genetic variation colocalises with active epigenetic marks in fat and ovary tissues, and expression levels in aorta tissue of a noncoding RNA flanking NGF correlate. Participants reporting extreme dysmenorrhea pain were more likely to report being positive for endometriosis, polycystic ovarian syndrome, depression, and other psychiatric disorders. Our results indicate that dysmenorrhea pain severity is partly genetically determined. NGF already has an established role in chronic pain disorders, and our findings suggest that NGF may be an important mediator for gynaecological/pelvic pain in the viscera.

Genome-wide pleiotropy and shared biological pathways for resistance to bovine pathogens

PubMed Central

Zeng, Y.; Yin, T.; Brügemann, K.

2018-01-01

Host genetic architecture is a major factor in resistance to pathogens and parasites. The collection and analysis of sufficient data on both disease resistance and host genetics has, however, been a major obstacle to dissection the genetics of resistance to single or multiple pathogens. A severe challenge in the estimation of heritabilities and genetic correlations from pedigree-based studies has been the confounding effects of the common environment shared among relatives which are difficult to model in pedigree analyses, especially for health traits with low incidence rates. To circumvent this problem we used genome-wide single-nucleotide polymorphism data and implemented the Genomic-Restricted Maximum Likelihood (G-REML) method to estimate the heritabilities and genetic correlations for resistance to 23 different infectious pathogens in calves and cows in populations undergoing natural pathogen challenge. Furthermore, we conducted gene-based analysis and generalized gene-set analysis to understand the biological background of resistance to infectious diseases. The results showed relatively higher heritabilities of resistance in calves than in cows and significant pleiotropy (both positive and negative) among some calf and cow resistance traits. We also found significant pleiotropy between resistance and performance in both calves and cows. Finally, we confirmed the role of the B-lymphocyte pathway as one of the most important biological pathways associated with resistance to all pathogens. These results both illustrate the potential power of these approaches to illuminate the genetics of pathogen resistance in cattle and provide foundational information for future genomic selection aimed at improving the overall production fitness of cattle. PMID:29608619

Toward a generalized and high-throughput enzyme screening system based on artificial genetic circuits.

PubMed

Choi, Su-Lim; Rha, Eugene; Lee, Sang Jun; Kim, Haseong; Kwon, Kilkoang; Jeong, Young-Su; Rhee, Young Ha; Song, Jae Jun; Kim, Hak-Sung; Lee, Seung-Goo

2014-03-21

Large-scale screening of enzyme libraries is essential for the development of cost-effective biological processes, which will be indispensable for the production of sustainable biobased chemicals. Here, we introduce a genetic circuit termed the Genetic Enzyme Screening System that is highly useful for high-throughput enzyme screening from diverse microbial metagenomes. The circuit consists of two AND logics. The first AND logic, the two inputs of which are the target enzyme and its substrate, is responsible for the accumulation of a phenol compound in cell. Then, the phenol compound and its inducible transcription factor, whose activation turns on the expression of a reporter gene, interact in the other logic gate. We confirmed that an individual cell harboring this genetic circuit can present approximately a 100-fold higher cellular fluorescence than the negative control and can be easily quantified by flow cytometry depending on the amounts of phenolic derivatives. The high sensitivity of the genetic circuit enables the rapid discovery of novel enzymes from metagenomic libraries, even for genes that show marginal activities in a host system. The crucial feature of this approach is that this single system can be used to screen a variety of enzymes that produce a phenol compound from respective synthetic phenyl-substrates, including cellulase, lipase, alkaline phosphatase, tyrosine phenol-lyase, and methyl parathion hydrolase. Consequently, the highly sensitive and quantitative nature of this genetic circuit along with flow cytometry techniques could provide a widely applicable toolkit for discovering and engineering novel enzymes at a single cell level.

Clinical and Genetic Risk Factors for Acute Pancreatitis in Patients With Acute Lymphoblastic Leukemia

PubMed Central

Liu, Chengcheng; Yang, Wenjian; Devidas, Meenakshi; Cheng, Cheng; Pei, Deqing; Smith, Colton; Carroll, William L.; Raetz, Elizabeth A.; Bowman, W. Paul; Larsen, Eric C.; Maloney, Kelly W.; Martin, Paul L.; Mattano, Leonard A.; Winick, Naomi J.; Mardis, Elaine R.; Fulton, Robert S.; Bhojwani, Deepa; Howard, Scott C.; Jeha, Sima; Pui, Ching-Hon; Hunger, Stephen P.; Evans, William E.; Loh, Mignon L.

2016-01-01

Purpose Acute pancreatitis is one of the common causes of asparaginase intolerance. The mechanism is unknown, and genetic predisposition to asparaginase-induced pancreatitis has not been previously identified. Methods To determine clinical risk factors for asparaginase-induced pancreatitis, we studied a cohort of 5,185 children and young adults with acute lymphoblastic leukemia, including 117 (2.3%) who were diagnosed with at least one episode of acute pancreatitis during therapy. A genome-wide association study was performed in the cohort and in an independent case-control group of 213 patients to identify genetic risk factors. Results Risk factors associated with pancreatitis included genetically defined Native American ancestry (P < .001), older age (P < .001), and higher cumulative dose of asparaginase (P < .001). No common variants reached genome-wide significance in the genome-wide association study, but a rare nonsense variant rs199695765 in CPA2, encoding carboxypeptidase A2, was highly associated with pancreatitis (hazard ratio, 587; 95% CI, 66.8 to 5166; P = 9.0 × 10−9). A gene-level analysis showed an excess of additional CPA2 variants in patients who did versus those who did not develop pancreatitis (P = .001). Sixteen CPA2 single-nucleotide polymorphisms were associated (P < .05) with pancreatitis, and 13 of 24 patients who carried at least one of these variants developed pancreatitis. Biologic functions that were overrepresented by common variants modestly associated with pancreatitis included purine metabolism and cytoskeleton regulation. Conclusion Older age, higher exposure to asparaginase, and higher Native American ancestry were independent risk factors for pancreatitis in patients with acute lymphoblastic leukemia. Those who inherit a nonsense rare variant in the CPA2 gene had a markedly increased risk of asparaginase-induced pancreatitis. PMID:27114598

Inflammatory Genes and Psychological Factors Predict Induced Shoulder Pain Phenotype

PubMed Central

George, Steven Z.; Parr, Jeffrey J.; Wallace, Margaret R.; Wu, Samuel S.; Borsa, Paul A.; Dai, Yunfeng; Fillingim, Roger B.

2014-01-01

Purpose The pain experience has multiple influences but little is known about how specific biological and psychological factors interact to influence pain responses. The current study investigated the combined influences of genetic (pro-inflammatory) and psychological factors on several pre-clinical shoulder pain phenotypes. Methods An exercise-induced shoulder injury model was used, and a priori selected genetic (IL1B, TNF/LTA region, IL6 single nucleotide polymorphisms, SNPs) and psychological (anxiety, depressive symptoms, pain catastrophizing, fear of pain, kinesiophobia) factors were included as the predictors of interest. The phenotypes were pain intensity (5-day average and peak reported on numerical rating scale), upper-extremity disability (5-day average and peak reported on the QuickDASH instrument), and duration of shoulder pain (in days). Results After controlling for age, sex, and race, the genetic and psychological predictors were entered separately as main effects and interaction terms in regression models for each pain phenotype. Results from the recruited cohort (n = 190) indicated strong statistical evidence for the interactions between 1) TNF/LTA SNP rs2229094 and depressive symptoms for average pain intensity and duration and 2) IL1B two-SNP diplotype and kinesiophobia for average shoulder pain intensity. Moderate statistical evidence for prediction of additional shoulder pain phenotypes included interactions of kinesiophobia, fear of pain, or depressive symptoms with TNF/LTA rs2229094 and IL1B. Conclusion These findings support the combined predictive ability of specific genetic and psychological factors for shoulder pain phenotypes by revealing novel combinations that may merit further investigation in clinical cohorts, to determine their involvement in the transition from acute to chronic pain conditions. PMID:24598699

Genetic and molecular basis of diabetic foot ulcers: Clinical review.

PubMed

Jhamb, Shaurya; Vangaveti, Venkat N; Malabu, Usman H

2016-11-01

Diabetic Foot Ulcers (DFUs) are major complications associated with diabetes and often correlate with peripheral neuropathy, trauma and peripheral vascular disease. It is necessary to understand the molecular and genetic basis of diabetic foot ulcers in order to tailor patient centred care towards particular patient groups. This review aimed to evaluate whether current literature was indicative of an underlying molecular and genetic basis for DFUs and to discuss clinical applications. From a molecular perspective, wound healing is a process that transpires following breach of the skin barrier and is usually mediated by growth factors and cytokines released by specialised cells activated by the immune response, including fibroblasts, endothelial cells, phagocytes, platelets and keratinocytes. Growth factors and cytokines are fundamental in the organisation of the molecular processes involved in making cutaneous wound healing possible. There is a significant role for single nucleotide polymorphism (SNPs) in the fluctuation of these growth factors and cytokines in DFUs. Furthermore, recent evidence suggests a key role for epigenetic mechanisms such as DNA methylation from long standing hyperglycemia and non-coding RNAs in the complex interplay between genes and the environment. Genetic factors and ethnicity can also play a significant role in the development of diabetic neuropathy leading to DFUs. Clinically, interventions which have improved outcomes for people with DFUs or those at risk of DFUs include some systemic therapeutic drug interventions which improve microvascular blood flow, surgical interventions, human growth factors, and hyperbaric oxygen therapy, negative pressure wound therapy, skin replacement or shockwave therapy and the use of topical treatments. Future treatment modalities including stem cell and gene therapies are promising in the therapeutic approach to prevent the progression of chronic diabetic complications. Copyright © 2016 Tissue Viability Society. Published by Elsevier Ltd. All rights reserved.

Prediction of peripheral neuropathy in multiple myeloma patients receiving bortezomib and thalidomide: a genetic study based on a single nucleotide polymorphism array.

PubMed

García-Sanz, Ramón; Corchete, Luis Antonio; Alcoceba, Miguel; Chillon, María Carmen; Jiménez, Cristina; Prieto, Isabel; García-Álvarez, María; Puig, Noemi; Rapado, Immaculada; Barrio, Santiago; Oriol, Albert; Blanchard, María Jesús; de la Rubia, Javier; Martínez, Rafael; Lahuerta, Juan José; González Díaz, Marcos; Mateos, María Victoria; San Miguel, Jesús Fernando; Martínez-López, Joaquín; Sarasquete, María Eugenia

2017-12-01

Bortezomib- and thalidomide-based therapies have significantly contributed to improved survival of multiple myeloma (MM) patients. However, treatment-induced peripheral neuropathy (TiPN) is a common adverse event associated with them. Risk factors for TiPN in MM patients include advanced age, prior neuropathy, and other drugs, but there are conflicting results about the role of genetics in predicting the risk of TiPN. Thus, we carried out a genome-wide association study based on more than 300 000 exome single nucleotide polymorphisms in 172 MM patients receiving therapy involving bortezomib and thalidomide. We compared patients developing and not developing TiPN under similar treatment conditions (GEM05MAS65, NCT00443235). The highest-ranking single nucleotide polymorphism was rs45443101, located in the PLCG2 gene, but no significant differences were found after multiple comparison correction (adjusted P = .1708). Prediction analyses, cytoband enrichment, and pathway analyses were also performed, but none yielded any significant findings. A copy number approach was also explored, but this gave no significant results either. In summary, our study did not find a consistent genetic component associated with TiPN under bortezomib and thalidomide therapies that could be used for prediction, which makes clinical judgment essential in the practical management of MM treatment. Copyright © 2016 John Wiley & Sons, Ltd.

Studies of Gene Variants Related to Inflammation, Oxidative Stress, Dyslipidemia, and Obesity: Implications for a Nutrigenetic Approach

PubMed Central

Curti, Maira Ladeia R.; Jacob, Patrícia; Borges, Maria Carolina; Rogero, Marcelo Macedo; Ferreira, Sandra Roberta G.

2011-01-01

Obesity is currently considered a serious public health issue due to its strong impact on health, economy, and quality of life. It is considered a chronic low-grade inflammation state and is directly involved in the genesis of metabolic disturbances, such as insulin resistance and dyslipidemia, which are well-known risk factors for cardiovascular disease. Furthermore, there is evidence that genetic variation that predisposes to inflammation and metabolic disturbances could interact with environmental factors, such as diet, modulating individual susceptibility to developing these conditions. This paper aims to review the possible interactions between diet and single-nucleotide polymorphisms (SNPs) in genes implicated on the inflammatory response, lipoprotein metabolism, and oxidative status. Therefore, the impact of genetic variants of the peroxisome proliferator-activated receptor-(PPAR-)gamma, tumor necrosis factor-(TNF-)alpha, interleukin (IL)-1, IL-6, apolipoprotein (Apo) A1, Apo A2, Apo A5, Apo E, glutathione peroxidases 1, 2, and 4, and selenoprotein P exposed to variations on diet composition is described. PMID:21773006

Subcloning the RBL-2H3 mucosal mast cell line reduces Ca2+ response heterogeneity at the single-cell level.

PubMed

Kuchtey, J; Fewtrell, C

1996-03-01

Ca2+ imaging experiments have revealed that for a wide variety of cell types, including RBL-2H3 mucosal mast cells, there are considerable cell-to-cell differences of the Ca2+ responses of individual cells. This heterogeneity is evident in both the shape and latency of the responses. Mast cells within a single microscopic field of view, which have experienced identical culture conditions and experimental preparation, display a wide variety of responses upon antigen stimulation. We have subcloned the RBL-2H3 mucosal mast cell line to test the hypothesis that genetic heterogeneity within the population is the cause of the Ca2+ response heterogeneity. We found that cell-to-cell variability was significantly reduced in four of five clonal lines. The response heterogeneity remaining within the clones was not an experimental artifact caused by differences in the amount of fura-2 loaded by individual cells. Factors other than genetic heterogeneity must partly account for Ca2+ response heterogeneity. It is possible that the complex shapes and variability of the Ca2+ responses are reflections of the fact that there are multiple factors underlying the Ca2-response to antigen stimulation. Small differences from cell to cell in one or more of these factors could be a cause of the remaining Ca2+ response heterogeneity.

Domain-Specific and Domain-General Learning Factors are Expressed in Genetically Heterogeneous CD-1 mice

PubMed Central

Kolata, Stefan; Light, Kenneth; Matzel, Louis D.

2008-01-01

It has been established that both domain-specific (e.g. spatial) as well as domain-general (general intelligence) factors influence human cognition. However, the separation of these processes has rarely been attempted in studies using laboratory animals. Previously, we have found that the performances of outbred mice across a wide range of learning tasks correlate in such a way that a single factor can explain 30– 44% of the variance between animals. This general learning factor is in some ways qualitatively and quantitatively analogous to general intelligence in humans. The complete structure of cognition in mice, however, has not been explored due to the limited sample sizes of our previous analyses. Here we report a combined analysis from 241 CD-1 mice tested in five primary learning tasks, and a subset of mice tested in two additional learning tasks. At least two (possibly three) of the seven learning tasks placed explicit demands on spatial and/or hippocampus-dependent processing abilities. Consistent with previous findings, we report a robust general factor influencing learning in mice that accounted for 38% of the variance across tasks. In addition, a domain-specific factor was found to account for performance on that subset of tasks that shared a dependence on hippocampal and/or spatial processing. These results provide further evidence for a general learning/cognitive factor in genetically heterogeneous mice. Furthermore (and similar to human cognitive performance), these results suggest a hierarchical structure to cognitive processes in this genetically heterogeneous species. PMID:19129932

Common genetic risk factors for coronary artery disease: new opportunities for prevention?

PubMed

Hamrefors, Viktor

2017-05-01

Atherosclerotic cardiovascular disease (CVD) is a leading cause of mortality and morbidity worldwide, with coronary artery disease (CAD) being the single leading cause of death. Better control of risk factors, enhanced diagnostic techniques and improved medical therapies have all substantially decreased the mortality of CAD in developed countries. However, CAD and other forms of atherosclerotic CVD are projected to remain the leading cause of death by 2030 and we face a number of challenges if the outcomes of CAD are to be further improved. The fact that a substantial fraction of high-risk subjects do not reach treatment goals for important risk factors is one of these challenges. At the same time, there is also a non-negotiable fraction of 'concealed' high-risk subjects who are not detected by current risk algorithms and diagnostic modalities. In recent years, we have started to rapidly increase our knowledge of the framework of common genetics underlying CAD and atherosclerotic CVD in the population. In conjunction with modern diagnostic and therapeutic options, this new genetic knowledge may provide a valuable tool for further improvements in prevention. This review summarizes the recent findings from the search for common genetic risk factors for CAD. Furthermore, the author discusses how such recent findings could potentially be used in a number of clinical applications within CAD prevention, including in clinical risk stratification, in prediction of drug treatment response and in the search for targets for novel preventive therapies. © 2015 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A

PubMed Central

Lane, Jérôme; McLaren, Paul J.; Dorrell, Lucy; Shianna, Kevin V.; Stemke, Amanda; Pelak, Kimberly; Moore, Stephen; Oldenburg, Johannes; Alvarez-Roman, Maria Teresa; Angelillo-Scherrer, Anne; Boehlen, Francoise; Bolton-Maggs, Paula H.B.; Brand, Brigit; Brown, Deborah; Chiang, Elaine; Cid-Haro, Ana Rosa; Clotet, Bonaventura; Collins, Peter; Colombo, Sara; Dalmau, Judith; Fogarty, Patrick; Giangrande, Paul; Gringeri, Alessandro; Iyer, Rathi; Katsarou, Olga; Kempton, Christine; Kuriakose, Philip; Lin, Judith; Makris, Mike; Manco-Johnson, Marilyn; Tsakiris, Dimitrios A.; Martinez-Picado, Javier; Mauser-Bunschoten, Evelien; Neff, Anne; Oka, Shinichi; Oyesiku, Lara; Parra, Rafael; Peter-Salonen, Kristiina; Powell, Jerry; Recht, Michael; Shapiro, Amy; Stine, Kimo; Talks, Katherine; Telenti, Amalio; Wilde, Jonathan; Yee, Thynn Thynn; Wolinsky, Steven M.; Martinson, Jeremy; Hussain, Shehnaz K.; Bream, Jay H.; Jacobson, Lisa P.; Carrington, Mary; Goedert, James J.; Haynes, Barton F.; McMichael, Andrew J.; Goldstein, David B.; Fellay, Jacques

2013-01-01

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979–1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population. PMID:23372042

Is the association between posttraumatic stress disorder symptoms and poor health due to a common familial or genetic factor?

PubMed Central

Roy-Byrne, Peter P.; Noonan, Carolyn; Afari, Niloofar; Buchwald, Dedra; Goldberg, Jack

2010-01-01

Objective The objective of this study was to identify genetic, familial and environmental contributions to the association between posttraumatic stress disorder (PTSD) symptoms and poor health. Methods A community sample of 1852 twin pairs was assessed for symptoms of PTSD [with the Impact of Events Scale (IES)] and self-reported global health status using a single five-level question. An ordinal logistic regression model estimated odds ratio/s (OR) for the association between PTSD and health status. Within-pair analysis assessed confounding by familial and genetic factors and adjusted for the possible confounding influence of age, sex, race, education and self-reported physician diagnosis of depression. Results The IES was strongly and significantly associated with self-reported health [OR = 1.8; 95% confidence interval (95% CI) = 1.5–2.2; highest quartile vs. lowest quartile]. This association remained significant in within-pair analysis (OR = 1.3; 95% CI=1.0–1.7), but after further adjustment for sociodemographics and depression, it was no longer significant (Ptrend=.17). Separate analysis by zygosity did not show differential effect in monozygotic or dizygotic pairs. Conclusion These findings suggest that the association between PTSD symptoms and poor health is, in part, due to familial confounding and sociodemographic factors. Little evidence of confounding by genetic factors was found. These findings suggest that early prevention efforts would have the greatest potential for improving poor health in PTSD-prone patients, whereas later intervention efforts directed at treating PTSD may have a more limited impact on improving poor health. PMID:16950376

Context matters: sexual signaling loss in digital organisms

PubMed Central

Weigel, Emily G; Testa, Nicholas D; Peer, Alex; Garnett, Sara C

2015-01-01

Sexual signals are important in attracting and choosing mates; however, these signals and their associated preferences are often costly and frequently lost. Despite the prevalence of signaling system loss in many taxa, the factors leading to signal loss remain poorly understood. Here, we test the hypothesis that complexity in signal loss scenarios is due to the context-dependent nature of the many factors affecting signal loss itself. Using the Avida digital life platform, we evolved 50 replicates of ∼250 lineages, each with a unique combination of parameters, including whether signaling is obligate or facultative; genetic linkage between signaling and receiving genes; population size; and strength of preference for signals. Each of these factors ostensibly plays a crucial role in signal loss, but was found to do so only under specific conditions. Under obligate signaling, genetic linkage, but not population size, influenced signal loss; under facultative signaling, genetic linkage does not have significant influence. Somewhat surprisingly, only a total loss of preference in the obligate signaling populations led to total signal loss, indicating that even a modest amount of preference is enough to maintain signaling systems. Strength of preference proved to be the strongest single force preventing signal loss, as it consistently overcame the potential effects of drift within our study. Our findings suggest that signaling loss is often dependent on not just preference for signals, population size, and genetic linkage, but also whether signals are required to initiate mating. These data provide an understanding of the factors (and their interactions) that may facilitate the maintenance of sexual signals. PMID:26380700

Explanatory Models of Genetics and Genetic Risk among a Selected Group of Students.

PubMed

Goltz, Heather Honoré; Bergman, Margo; Goodson, Patricia

2016-01-01

This exploratory qualitative study focuses on how college students conceptualize genetics and genetic risk, concepts essential for genetic literacy (GL) and genetic numeracy (GN), components of overall health literacy (HL). HL is dependent on both the background knowledge and culture of a patient, and lower HL is linked to increased morbidity and mortality for a number of chronic health conditions (e.g., diabetes and cancer). A purposive sample of 86 students from three Southwestern universities participated in eight focus groups. The sample ranged in age from 18 to 54 years, and comprised primarily of female (67.4%), single (74.4%), and non-White (57%) participants, none of whom were genetics/biology majors. A holistic-content approach revealed broad categories concerning participants' explanatory models (EMs) of genetics and genetic risk. Participants' EMs were grounded in highly contextualized narratives that only partially overlapped with biomedical models. While higher education levels should be associated with predominately knowledge-based EM of genetic risk, this study shows that even in well-educated populations cultural factors can dominate. Study findings reveal gaps in how this sample of young adults obtains, processes, and understands genetic/genomic concepts. Future studies should assess how individuals with low GL and GN obtain and process genetics and genetic risk information and incorporate this information into health decision making. Future work should also address the interaction of communication between health educators, providers, and genetic counselors, to increase patient understanding of genetic risk.

Amygdala functional connectivity, HPA axis genetic variation, and life stress in children and relations to anxiety and emotion regulation

PubMed Central

Pagliaccio, David; Luby, Joan L.; Bogdan, Ryan; Agrawal, Arpana; Gaffrey, Michael S.; Belden, Andrew C.; Botteron, Kelly N.; Harms, Michael P.; Barch, Deanna M.

2015-01-01

Internalizing pathology is related to alterations in amygdala resting state functional connectivity, potentially implicating altered emotional reactivity and/or emotion regulation in the etiological pathway. Importantly, there is accumulating evidence that stress exposure and genetic vulnerability impact amygdala structure/function and risk for internalizing pathology. The present study examined whether early life stress and genetic profile scores (10 single nucleotide polymorphisms within four hypothalamic-pituitary-adrenal axis genes: CRHR1, NR3C2, NR3C1, and FKBP5) predicted individual differences in amygdala functional connectivity in school-age children (9–14 year olds; N=120). Whole-brain regression analyses indicated that increasing genetic ‘risk’ predicted alterations in amygdala connectivity to the caudate and postcentral gyrus. Experience of more stressful and traumatic life events predicted weakened amygdala-anterior cingulate cortex connectivity. Genetic ‘risk’ and stress exposure interacted to predict weakened connectivity between the amygdala and the inferior and middle frontal gyri, caudate, and parahippocampal gyrus in those children with the greatest genetic and environmental risk load. Furthermore, amygdala connectivity longitudinally predicted anxiety symptoms and emotion regulation skills at a later follow-up. Amygdala connectivity mediated effects of life stress on anxiety and of genetic variants on emotion regulation. The current results suggest that considering the unique and interacting effects of biological vulnerability and environmental risk factors may be key to understanding the development of altered amygdala functional connectivity, a potential factor in the risk trajectory for internalizing pathology. PMID:26595470

Amygdala functional connectivity, HPA axis genetic variation, and life stress in children and relations to anxiety and emotion regulation.

PubMed

Pagliaccio, David; Luby, Joan L; Bogdan, Ryan; Agrawal, Arpana; Gaffrey, Michael S; Belden, Andrew C; Botteron, Kelly N; Harms, Michael P; Barch, Deanna M

2015-11-01

Internalizing pathology is related to alterations in amygdala resting state functional connectivity, potentially implicating altered emotional reactivity and/or emotion regulation in the etiological pathway. Importantly, there is accumulating evidence that stress exposure and genetic vulnerability impact amygdala structure/function and risk for internalizing pathology. The present study examined whether early life stress and genetic profile scores (10 single nucleotide polymorphisms within 4 hypothalamic-pituitary-adrenal axis genes: CRHR1, NR3C2, NR3C1, and FKBP5) predicted individual differences in amygdala functional connectivity in school-age children (9- to 14-year-olds; N = 120). Whole-brain regression analyses indicated that increasing genetic "risk" predicted alterations in amygdala connectivity to the caudate and postcentral gyrus. Experience of more stressful and traumatic life events predicted weakened amygdala-anterior cingulate cortex connectivity. Genetic "risk" and stress exposure interacted to predict weakened connectivity between the amygdala and the inferior and middle frontal gyri, caudate, and parahippocampal gyrus in those children with the greatest genetic and environmental risk load. Furthermore, amygdala connectivity longitudinally predicted anxiety symptoms and emotion regulation skills at a later follow-up. Amygdala connectivity mediated effects of life stress on anxiety and of genetic variants on emotion regulation. The current results suggest that considering the unique and interacting effects of biological vulnerability and environmental risk factors may be key to understanding the development of altered amygdala functional connectivity, a potential factor in the risk trajectory for internalizing pathology. (c) 2015 APA, all rights reserved).

Genetic effects influencing risk for major depressive disorder in China and Europe.

PubMed

Bigdeli, T B; Ripke, S; Peterson, R E; Trzaskowski, M; Bacanu, S-A; Abdellaoui, A; Andlauer, T F M; Beekman, A T F; Berger, K; Blackwood, D H R; Boomsma, D I; Breen, G; Buttenschøn, H N; Byrne, E M; Cichon, S; Clarke, T-K; Couvy-Duchesne, B; Craddock, N; de Geus, E J C; Degenhardt, F; Dunn, E C; Edwards, A C; Fanous, A H; Forstner, A J; Frank, J; Gill, M; Gordon, S D; Grabe, H J; Hamilton, S P; Hardiman, O; Hayward, C; Heath, A C; Henders, A K; Herms, S; Hickie, I B; Hoffmann, P; Homuth, G; Hottenga, J-J; Ising, M; Jansen, R; Kloiber, S; Knowles, J A; Lang, M; Li, Q S; Lucae, S; MacIntyre, D J; Madden, P A F; Martin, N G; McGrath, P J; McGuffin, P; McIntosh, A M; Medland, S E; Mehta, D; Middeldorp, C M; Milaneschi, Y; Montgomery, G W; Mors, O; Müller-Myhsok, B; Nauck, M; Nyholt, D R; Nöthen, M M; Owen, M J; Penninx, B W J H; Pergadia, M L; Perlis, R H; Peyrot, W J; Porteous, D J; Potash, J B; Rice, J P; Rietschel, M; Riley, B P; Rivera, M; Schoevers, R; Schulze, T G; Shi, J; Shyn, S I; Smit, J H; Smoller, J W; Streit, F; Strohmaier, J; Teumer, A; Treutlein, J; Van der Auwera, S; van Grootheest, G; van Hemert, A M; Völzke, H; Webb, B T; Weissman, M M; Wellmann, J; Willemsen, G; Witt, S H; Levinson, D F; Lewis, C M; Wray, N R; Flint, J; Sullivan, P F; Kendler, K S

2017-03-28

Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log 10 Bayes Factor=8.08) but failed to replicate in an independent European sample (P=0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.

Genetic effects influencing risk for major depressive disorder in China and Europe

PubMed Central

Bigdeli, T B; Ripke, S; Peterson, R E; Trzaskowski, M; Bacanu, S-A; Abdellaoui, A; Andlauer, T F M; Beekman, A T F; Berger, K; Blackwood, D H R; Boomsma, D I; Breen, G; Buttenschøn, H N; Byrne, E M; Cichon, S; Clarke, T-K; Couvy-Duchesne, B; Craddock, N; de Geus, E J C; Degenhardt, F; Dunn, E C; Edwards, A C; Fanous, A H; Forstner, A J; Frank, J; Gill, M; Gordon, S D; Grabe, H J; Hamilton, S P; Hardiman, O; Hayward, C; Heath, A C; Henders, A K; Herms, S; Hickie, I B; Hoffmann, P; Homuth, G; Hottenga, J-J; Ising, M; Jansen, R; Kloiber, S; Knowles, J A; Lang, M; Li, Q S; Lucae, S; MacIntyre, D J; Madden, P A F; Martin, N G; McGrath, P J; McGuffin, P; McIntosh, A M; Medland, S E; Mehta, D; Middeldorp, C M; Milaneschi, Y; Montgomery, G W; Mors, O; Müller-Myhsok, B; Nauck, M; Nyholt, D R; Nöthen, M M; Owen, M J; Penninx, B W J H; Pergadia, M L; Perlis, R H; Peyrot, W J; Porteous, D J; Potash, J B; Rice, J P; Rietschel, M; Riley, B P; Rivera, M; Schoevers, R; Schulze, T G; Shi, J; Shyn, S I; Smit, J H; Smoller, J W; Streit, F; Strohmaier, J; Teumer, A; Treutlein, J; Van der Auwera, S; van Grootheest, G; van Hemert, A M; Völzke, H; Webb, B T; Weissman, M M; Wellmann, J; Willemsen, G; Witt, S H; Levinson, D F; Lewis, C M; Wray, N R; Flint, J; Sullivan, P F; Kendler, K S

2017-01-01

Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30–40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor=8.08) but failed to replicate in an independent European sample (P=0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies. PMID:28350396

Genetic Approaches to Reveal the Connectivity of Adult-Born Neurons

PubMed Central

Arenkiel, Benjamin R.

2011-01-01

Much has been learned about the environmental and molecular factors that influence the division, migration, and programmed cell death of adult-born neurons in the mammalian brain. However, detailed knowledge of the mechanisms that govern the formation and maintenance of functional circuit connectivity via adult neurogenesis remains elusive. Recent advances in genetic technologies now afford the ability to precisely target discrete brain tissues, neuronal subtypes, and even single neurons for vital reporter expression and controlled activity manipulations. Here, I review current viral tracing methods, heterologous receptor expression systems, and optogenetic technologies that hold promise toward elucidating the wiring diagrams and circuit properties of adult-born neurons. PMID:21519388

Genome-wide association study of clinical dimensions of schizophrenia: polygenic effect on disorganized symptoms.

PubMed

Fanous, Ayman H; Zhou, Baiyu; Aggen, Steven H; Bergen, Sarah E; Amdur, Richard L; Duan, Jubao; Sanders, Alan R; Shi, Jianxin; Mowry, Bryan J; Olincy, Ann; Amin, Farooq; Cloninger, C Robert; Silverman, Jeremy M; Buccola, Nancy G; Byerley, William F; Black, Donald W; Freedman, Robert; Dudbridge, Frank; Holmans, Peter A; Ripke, Stephan; Gejman, Pablo V; Kendler, Kenneth S; Levinson, Douglas F

2012-12-01

Multiple sources of evidence suggest that genetic factors influence variation in clinical features of schizophrenia. The authors present the first genome-wide association study (GWAS) of dimensional symptom scores among individuals with schizophrenia. Based on the Lifetime Dimensions of Psychosis Scale ratings of 2,454 case subjects of European ancestry from the Molecular Genetics of Schizophrenia (MGS) sample, three symptom factors (positive, negative/disorganized, and mood) were identified with exploratory factor analysis. Quantitative scores for each factor from a confirmatory factor analysis were analyzed for association with 696,491 single-nucleotide polymorphisms (SNPs) using linear regression, with correction for age, sex, clinical site, and ancestry. Polygenic score analysis was carried out to determine whether case and comparison subjects in 16 Psychiatric GWAS Consortium (PGC) schizophrenia samples (excluding MGS samples) differed in scores computed by weighting their genotypes by MGS association test results for each symptom factor. No genome-wide significant associations were observed between SNPs and factor scores. Most of the SNPs producing the strongest evidence for association were in or near genes involved in neurodevelopment, neuroprotection, or neurotransmission, including genes playing a role in Mendelian CNS diseases, but no statistically significant effect was observed for any defined gene pathway. Finally, polygenic scores based on MGS GWAS results for the negative/disorganized factor were significantly different between case and comparison subjects in the PGC data set; for MGS subjects, negative/disorganized factor scores were correlated with polygenic scores generated using case-control GWAS results from the other PGC samples. The polygenic signal that has been observed in cross-sample analyses of schizophrenia GWAS data sets could be in part related to genetic effects on negative and disorganized symptoms (i.e., core features of chronic schizophrenia).

The genetics of sports injuries and athletic performance

PubMed Central

Maffulli, Nicola; Margiotti, Katia; Longo, Umile Giuseppe; Loppini, Mattia; Fazio, Vito Michele; Denaro, Vincenzo

2013-01-01

Summary Purpose: in the last two decades, several evidences have been provided to support the relationship between single nucleotide polymorphisms and the susceptibility to develop injuries participating in sport and performance related to sports activity. We report up-to-date review of the genetics factors involved in tendon injuries and athletic performance. Methods: we searched PubMed using the terms “sports injuries”, “athletic performance” and “genetics” over the period 1990 to the present day. We also included non-English journals. Results: most of the currently established or putative tendinopathy susceptibility loci have been analyzed by candidate gene studies. The genes currently associated with tendon injuries include gene encoding for collagen, matrix metallopeptidase, tenascin and growth factors. Several genes have been related to the physical performance phenotypes affecting endurance capacity and muscle performance. The most studied include ACE and ACTN3 genes. Conclusions: genetics determines the response of an individual to the surrounding environment. Recently, some of the individual genetic variations contributing to the athletic performance and the onset of musculoskeletal injuries, particularly in tendon and ligament tissues, have been identified. However, the identification of the genetic background related to susceptibility to injuries and physical performance of the athletes is challenging yet and further studies must be performed to establish the specific role of each gene and the potential effect of the interaction of these. PMID:24367777

Frequency of five disease-causing genetic mutations in a large mixed-breed dog population (2011–2012)

PubMed Central

Zierath, Sharon; Hughes, Angela M.; Fretwell, Neale; Dibley, Mark

2017-01-01

Background A large and growing number of inherited genetic disease mutations are now known in the dog. Frequencies of these mutations are typically examined within the breed of discovery, possibly in related breeds, but nearly always in purebred dogs. No report to date has examined the frequencies of specific genetic disease mutations in a large population of mixed-breed dogs. Further, veterinarians and dog owners typically dismiss inherited/genetic diseases as possibilities for health problems in mixed-breed dogs, assuming hybrid vigor will guarantee that single-gene disease mutations are not a cause for concern. Therefore, the objective of this study was to screen a large mixed-breed canine population for the presence of mutant alleles associated with five autosomal recessive disorders: hyperuricosuria and hyperuricemia (HUU), cystinuria (CYST), factor VII deficiency (FVIID), myotonia congenita (MYC) and phosphofructokinase deficiency (PKFD). Genetic testing was performed in conjunction with breed determination via the commercially-available Wisdom PanelTM test. Results From a population of nearly 35,000 dogs, homozygous mutant dogs were identified for HUU (n = 57) and FVIID (n = 65). Homozygotes for HUU and FVIID were identified even among dogs with highly mixed breed ancestry. Carriers were identified for all disorders except MYC. HUU and FVIID were of high enough frequency to merit consideration in any mixed-breed dog, while CYST, MYC, and PKFD are vanishingly rare. Conclusions The assumption that mixed-breed dogs do not suffer from single-gene genetic disorders is shown here to be false. Within the diseases examined, HUU and FVIID should remain on any practitioner’s rule-out list, when clinically appropriate, for all mixed-breed dogs, and judicious genetic testing should be performed for diagnosis or screening. Future testing of large mixed-breed dog populations that include additional known canine genetic mutations will refine our knowledge of which genetic diseases can strike mixed-breed dogs. PMID:29166669

Frequency of five disease-causing genetic mutations in a large mixed-breed dog population (2011-2012).

PubMed

Zierath, Sharon; Hughes, Angela M; Fretwell, Neale; Dibley, Mark; Ekenstedt, Kari J

2017-01-01

A large and growing number of inherited genetic disease mutations are now known in the dog. Frequencies of these mutations are typically examined within the breed of discovery, possibly in related breeds, but nearly always in purebred dogs. No report to date has examined the frequencies of specific genetic disease mutations in a large population of mixed-breed dogs. Further, veterinarians and dog owners typically dismiss inherited/genetic diseases as possibilities for health problems in mixed-breed dogs, assuming hybrid vigor will guarantee that single-gene disease mutations are not a cause for concern. Therefore, the objective of this study was to screen a large mixed-breed canine population for the presence of mutant alleles associated with five autosomal recessive disorders: hyperuricosuria and hyperuricemia (HUU), cystinuria (CYST), factor VII deficiency (FVIID), myotonia congenita (MYC) and phosphofructokinase deficiency (PKFD). Genetic testing was performed in conjunction with breed determination via the commercially-available Wisdom PanelTM test. From a population of nearly 35,000 dogs, homozygous mutant dogs were identified for HUU (n = 57) and FVIID (n = 65). Homozygotes for HUU and FVIID were identified even among dogs with highly mixed breed ancestry. Carriers were identified for all disorders except MYC. HUU and FVIID were of high enough frequency to merit consideration in any mixed-breed dog, while CYST, MYC, and PKFD are vanishingly rare. The assumption that mixed-breed dogs do not suffer from single-gene genetic disorders is shown here to be false. Within the diseases examined, HUU and FVIID should remain on any practitioner's rule-out list, when clinically appropriate, for all mixed-breed dogs, and judicious genetic testing should be performed for diagnosis or screening. Future testing of large mixed-breed dog populations that include additional known canine genetic mutations will refine our knowledge of which genetic diseases can strike mixed-breed dogs.

CYBRD1 as a modifier gene that modulates iron phenotype in HFE p.C282Y homozygous patients.

PubMed

Pelucchi, Sara; Mariani, Raffaella; Calza, Stefano; Fracanzani, Anna Ludovica; Modignani, Giulia Litta; Bertola, Francesca; Busti, Fabiana; Trombini, Paola; Fraquelli, Mirella; Forni, Gian Luca; Girelli, Domenico; Fargion, Silvia; Specchia, Claudia; Piperno, Alberto

2012-12-01

Most patients with hereditary hemochromatosis in the Caucasian population are homozygous for the p.C282Y mutation in the HFE gene. The penetrance and expression of hereditary hemochromatosis differ largely among cases of homozygous p.C282Y. Genetic factors might be involved in addition to environmental factors. In the present study, we analyzed 50 candidate genes involved in iron metabolism and evaluated the association between 214 single nucleotide polymorphisms in these genes and three phenotypic outcomes of iron overload (serum ferritin, iron removed and transferrin saturation) in a large group of 296 p.C282Y homozygous Italians. Polymorphisms were tested for genetic association with each single outcome using linear regression models adjusted for age, sex and alcohol consumption. We found a series of 17 genetic variants located in different genes with possible additive effects on the studied outcomes. In order to evaluate whether the selected polymorphisms could provide a predictive signature for adverse phenotype, we re-evaluated data by dividing patients in two extreme phenotype classes based on the three phenotypic outcomes. We found that only a small improvement in prediction could be achieved by adding genetic information to clinical data. Among the selected polymorphisms, a significant association was observed between rs3806562, located in the 5'UTR of CYBRD1, and transferrin saturation. This variant belongs to the same haplotype block that contains the CYBRD1 polymorphism rs884409, found to be associated with serum ferritin in another population of p.C282Y homozygotes, and able to modulate promoter activity. A luciferase assay indicated that rs3806562 does not have a significant functional role, suggesting that it is a genetic marker linked to the putative genetic modifier rs884409. While our results support the hypothesis that polymorphisms in genes regulating iron metabolism may modulate penetrance of HFE-hereditary hemochromatosis, with emphasis on CYBRD1, they strengthen the notion that none of these polymorphisms alone is a major modifier of the phenotype of hereditary hemochromatosis.

CYBRD1 as a modifier gene that modulates iron phenotype in HFE p.C282Y homozygous patients

PubMed Central

Pelucchi, Sara; Mariani, Raffaella; Calza, Stefano; Fracanzani, Anna Ludovica; Modignani, Giulia Litta; Bertola, Francesca; Busti, Fabiana; Trombini, Paola; Fraquelli, Mirella; Forni, Gian Luca; Girelli, Domenico; Fargion, Silvia; Specchia, Claudia; Piperno, Alberto

2012-01-01

Background Most patients with hereditary hemochromatosis in the Caucasian population are homozygous for the p.C282Y mutation in the HFE gene. The penetrance and expression of hereditary hemochromatosis differ largely among cases of homozygous p.C282Y. Genetic factors might be involved in addition to environmental factors. Design and Methods: In the present study, we analyzed 50 candidate genes involved in iron metabolism and evaluated the association between 214 single nucleotide polymorphisms in these genes and three phenotypic outcomes of iron overload (serum ferritin, iron removed and transferrin saturation) in a large group of 296 p.C282Y homozygous Italians. Polymorphisms were tested for genetic association with each single outcome using linear regression models adjusted for age, sex and alcohol consumption. Results We found a series of 17 genetic variants located in different genes with possible additive effects on the studied outcomes. In order to evaluate whether the selected polymorphisms could provide a predictive signature for adverse phenotype, we re-evaluated data by dividing patients in two extreme phenotype classes based on the three phenotypic outcomes. We found that only a small improvement in prediction could be achieved by adding genetic information to clinical data. Among the selected polymorphisms, a significant association was observed between rs3806562, located in the 5'UTR of CYBRD1, and transferrin saturation. This variant belongs to the same haplotype block that contains the CYBRD1 polymorphism rs884409, found to be associated with serum ferritin in another population of p.C282Y homozygotes, and able to modulate promoter activity. A luciferase assay indicated that rs3806562 does not have a significant functional role, suggesting that it is a genetic marker linked to the putative genetic modifier rs884409. Conclusions While our results support the hypothesis that polymorphisms in genes regulating iron metabolism may modulate penetrance of HFE-hereditary hemochromatosis, with emphasis on CYBRD1, they strengthen the notion that none of these polymorphisms alone is a major modifier of the phenotype of hereditary hemochromatosis. PMID:22773607

Etiological heterogeneity in the development of antisocial behavior: the Virginia Twin Study of Adolescent Behavioral Development and the Young Adult Follow-Up

PubMed Central

SILBERG, JUDY L.; RUTTER, MICHAEL; TRACY, KELLY; MAES, HERMINE H.; EAVES, LINDON

2014-01-01

Background Longitudinal, genetically informed, prospective data collected on a large population of male twins (n = 1037) were used to examine developmental differences in the etiology of antisocial behavior. Method Analyses were carried out on both mother- and child-reported symptoms of conduct disorder (CD) in 10- to 17-year-old twins from the Virginia Twin Study of Adolescent Behavioral Development (VTSABD) and self-reported antisocial behavior by the twins as young adults from the Young Adult Follow-Up (YAFU) study. Results The following trends were identified: (1) a single genetic factor influencing antisocial behavior beginning at age 10 through young adulthood (‘life-course persistent’); (2) a shared-environmental effect beginning in adolescence (‘adolescent-onset’); (3) a transient genetic effect at puberty; and (4) a genetic influence specific to adult antisocial behavior. Conclusions Overall, these etiological findings are consistent with predictions from Moffitt’s developmental theory of antisocial behavior. The genetic effect at puberty at ages 12–15 is also consistent with a genetically mediated influence on the timing of puberty affecting the expression of genetic differences in antisocial outcomes. PMID:17376258

The Human Salivary Microbiome Is Shaped by Shared Environment Rather than Genetics: Evidence from a Large Family of Closely Related Individuals.

PubMed

Shaw, Liam; Ribeiro, Andre L R; Levine, Adam P; Pontikos, Nikolas; Balloux, Francois; Segal, Anthony W; Roberts, Adam P; Smith, Andrew M

2017-09-12

The human microbiome is affected by multiple factors, including the environment and host genetics. In this study, we analyzed the salivary microbiomes of an extended family of Ashkenazi Jewish individuals living in several cities and investigated associations with both shared household and host genetic similarities. We found that environmental effects dominated over genetic effects. While there was weak evidence of geographical structuring at the level of cities, we observed a large and significant effect of shared household on microbiome composition, supporting the role of the immediate shared environment in dictating the presence or absence of taxa. This effect was also seen when including adults who had grown up in the same household but moved out prior to the time of sampling, suggesting that the establishment of the salivary microbiome earlier in life may affect its long-term composition. We found weak associations between host genetic relatedness and microbiome dissimilarity when using family pedigrees as proxies for genetic similarity. However, this association disappeared when using more-accurate measures of kinship based on genome-wide genetic markers, indicating that the environment rather than host genetics is the dominant factor affecting the composition of the salivary microbiome in closely related individuals. Our results support the concept that there is a consistent core microbiome conserved across global scales but that small-scale effects due to a shared living environment significantly affect microbial community composition. IMPORTANCE Previous research shows that the salivary microbiomes of relatives are more similar than those of nonrelatives, but it remains difficult to distinguish the effects of relatedness and shared household environment. Furthermore, pedigree measures may not accurately measure host genetic similarity. In this study, we include genetic relatedness based on genome-wide single nucleotide polymorphisms (SNPs) (rather than pedigree measures) and shared environment in the same analysis. We quantify the relative importance of these factors by studying the salivary microbiomes in members of a large extended Ashkenazi Jewish family living in different locations. We find that host genetics plays no significant role and that the dominant factor is the shared environment at the household level. We also find that this effect appears to persist in individuals who have moved out of the parental household, suggesting that aspects of salivary microbiome composition established during upbringing can persist over a time scale of years. Copyright © 2017 Shaw et al.

Genetic and environmental influences on the comorbidity between depression, panic disorder, agoraphobia and social phobia: A twin study

PubMed Central

Mosing, Miriam A.; Gordon, Scott D.; Medland, Sarah E.; Statham, Dixie J.; Nelson, Elliot C.; Heath, Andrew C.; Martin, Nicholas G.; Wray, Naomi R.

2011-01-01

Background Major depression (MD) and anxiety disorders such as panic disorder (PD), agoraphobia (AG) and social phobia (SP) are heritable and highly comorbid. However, the relative importance of genetic and environmental aetiology of the covariation between these disorders, particularly the relationship between PD and AG is less clear. Methods The present study measured MD, PD and AG in a population sample of 5440 twin pairs and 1245 single twins, about 45% of whom were also scored for SP. Prevalences, within individual comorbidity and twin odds ratios for comorbidity are reported. A behavioural genetic analysis of the four disorders using the classical twin design was conducted. Results Odds ratios for MD, PD, AG, and SP in twins of individuals diagnosed with one of the four disorders were increased. Heritability estimates under a threshold-liability model for MD, PD, AG, and SP respectively were 0.33 (CI:0.30–0.42), 0.38 (CI:0.24–0.55), 0.48 (CI:0.37–0.65) of, and 0.39 (CI:0.16–0.65), with no evidence for any variance explained by the common environment shared by twins. We find that a common genetic factor explains a moderate proportion of variance in these four disorders. The genetic correlation between PD and AG was 0.83. Conclusion MD, PD, AG, and SP strongly co-aggregate within families and common genetic factors explain a moderate proportion of variance in these four disorders. The high genetic correlation between PD and AG and the increased odds ratio for PD and AG in siblings of those with AG without PD suggests a common genetic aetiology for PD and AG. PMID:19750555

Identifying Multimodal Intermediate Phenotypes between Genetic Risk Factors and Disease Status in Alzheimer’s Disease

PubMed Central

Hao, Xiaoke; Yao, Xiaohui; Yan, Jingwen; Risacher, Shannon L.; Saykin, Andrew J.; Zhang, Daoqiang; Shen, Li

2016-01-01

Neuroimaging genetics has attracted growing attention and interest, which is thought to be a powerful strategy to examine the influence of genetic variants (i.e., single nucleotide polymorphisms (SNPs)) on structures or functions of human brain. In recent studies, univariate or multivariate regression analysis methods are typically used to capture the effective associations between genetic variants and quantitative traits (QTs) such as brain imaging phenotypes. The identified imaging QTs, although associated with certain genetic markers, may not be all disease specific. A useful, but underexplored, scenario could be to discover only those QTs associated with both genetic markers and disease status for revealing the chain from genotype to phenotype to symptom. In addition, multimodal brain imaging phenotypes are extracted from different perspectives and imaging markers consistently showing up in multimodalities may provide more insights for mechanistic understanding of diseases (i.e., Alzheimer’s disease (AD)). In this work, we propose a general framework to exploit multi-modal brain imaging phenotypes as intermediate traits that bridge genetic risk factors and multi-class disease status. We applied our proposed method to explore the relation between the well-known AD risk SNP APOE rs429358 and three baseline brain imaging modalities (i.e., structural magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography (FDG-PET) and F-18 florbetapir PET scans amyloid imaging (AV45)) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. The empirical results demonstrate that our proposed method not only helps improve the performances of imaging genetic associations, but also discovers robust and consistent regions of interests (ROIs) across multi-modalities to guide the disease-induced interpretation. PMID:27277494

Genetic and environmental influences on the co-morbidity between depression, panic disorder, agoraphobia, and social phobia: a twin study.

PubMed

Mosing, Miriam A; Gordon, Scott D; Medland, Sarah E; Statham, Dixie J; Nelson, Elliot C; Heath, Andrew C; Martin, Nicholas G; Wray, Naomi R

2009-01-01

Major depression (MD) and anxiety disorders such as panic disorder (PD), agoraphobia (AG), and social phobia (SP) are heritable and highly co-morbid. However, the relative importance of genetic and environmental etiology of the covariation between these disorders, particularly the relationship between PD and AG, is less clear. This study measured MD, PD, and AG in a population sample of 5,440 twin pairs and 1,245 single twins, about 45% of whom were also scored for SP. Prevalences, within individual co-morbidity and twin odds ratios for co-morbidity, are reported. A behavioral genetic analysis of the four disorders using the classical twin design was conducted. Odds ratios for MD, PD, AG, and SP in twins of individuals diagnosed with one of the four disorders were increased. Heritability estimates under a threshold-liability model for MD, PD, AG, and SP respectively were .33 (CI: 0.30-0.42), .38 (CI: 0.24-0.55), .48 (CI: 0.37-0.65), and .39 (CI: 0.16-0.65), with no evidence for any variance explained by the common environment shared by twins. We find that a common genetic factor explains a moderate proportion of variance in these four disorders. The genetic correlation between PD and AG was .83. MD, PD, AG, and SP strongly co-aggregate within families and common genetic factors explain a moderate proportion of variance in these four disorders. The high genetic correlation between PD and AG and the increased odds ratio for PD and AG in siblings of those with AG without PD suggests a common genetic etiology for PD and AG.

Nephron Deficiency and Predisposition to Renal Injury in a Novel One-Kidney Genetic Model

PubMed Central

Wang, Xuexiang; Johnson, Ashley C.; Williams, Jan M.; White, Tiffani; Chade, Alejandro R.; Zhang, Jie; Liu, Ruisheng; Roman, Richard J.; Lee, Jonathan W.; Kyle, Patrick B.; Solberg-Woods, Leah

2015-01-01

Some studies have reported up to 40% of patients born with a single kidney develop hypertension, proteinuria, and in some cases renal failure. The increased susceptibility to renal injury may be due, in part, to reduced nephron numbers. Notably, children who undergo nephrectomy or adults who serve as kidney donors exhibit little difference in renal function compared with persons who have two kidneys. However, the difference in risk between being born with a single kidney versus being born with two kidneys and then undergoing nephrectomy are unclear. Animal models used previously to investigate this question are not ideal because they require invasive methods to model congenital solitary kidney. In this study, we describe a new genetic animal model, the heterogeneous stock-derived model of unilateral renal agenesis (HSRA) rat, which demonstrates 50%–75% spontaneous incidence of a single kidney. The HSRA model is characterized by reduced nephron number (more than would be expected by loss of one kidney), early kidney/glomerular hypertrophy, and progressive renal injury, which culminates in reduced renal function. Long-term studies of temporal relationships among BP, renal hemodynamics, and renal function demonstrate that spontaneous single-kidney HSRA rats are more likely than uninephrectomized normal littermates to exhibit renal impairment because of the combination of reduced nephron numbers and prolonged exposure to renal compensatory mechanisms (i.e., hyperfiltration). Future studies with this novel animal model may provide additional insight into the genetic contributions to kidney development and agenesis and the factors influencing susceptibility to renal injury in individuals with congenital solitary kidney. PMID:25349207

Nephron Deficiency and Predisposition to Renal Injury in a Novel One-Kidney Genetic Model.

PubMed

Wang, Xuexiang; Johnson, Ashley C; Williams, Jan M; White, Tiffani; Chade, Alejandro R; Zhang, Jie; Liu, Ruisheng; Roman, Richard J; Lee, Jonathan W; Kyle, Patrick B; Solberg-Woods, Leah; Garrett, Michael R

2015-07-01

Some studies have reported up to 40% of patients born with a single kidney develop hypertension, proteinuria, and in some cases renal failure. The increased susceptibility to renal injury may be due, in part, to reduced nephron numbers. Notably, children who undergo nephrectomy or adults who serve as kidney donors exhibit little difference in renal function compared with persons who have two kidneys. However, the difference in risk between being born with a single kidney versus being born with two kidneys and then undergoing nephrectomy are unclear. Animal models used previously to investigate this question are not ideal because they require invasive methods to model congenital solitary kidney. In this study, we describe a new genetic animal model, the heterogeneous stock-derived model of unilateral renal agenesis (HSRA) rat, which demonstrates 50%-75% spontaneous incidence of a single kidney. The HSRA model is characterized by reduced nephron number (more than would be expected by loss of one kidney), early kidney/glomerular hypertrophy, and progressive renal injury, which culminates in reduced renal function. Long-term studies of temporal relationships among BP, renal hemodynamics, and renal function demonstrate that spontaneous single-kidney HSRA rats are more likely than uninephrectomized normal littermates to exhibit renal impairment because of the combination of reduced nephron numbers and prolonged exposure to renal compensatory mechanisms (i.e., hyperfiltration). Future studies with this novel animal model may provide additional insight into the genetic contributions to kidney development and agenesis and the factors influencing susceptibility to renal injury in individuals with congenital solitary kidney. Copyright © 2015 by the American Society of Nephrology.

Genetic Investigation into the Paradoxical Differential Risk of Atrial Fibrillation Among Blacks and Whites

PubMed Central

Roberts, Jason D.; Hu, Donglei; Heckbert, Susan R.; Alonso, Alvaro; Dewland, Thomas A.; Vittinghoff, Eric; Liu, Yongmei; Psaty, Bruce M.; Olgin, Jeffrey E.; Magnani, Jared W.; Huntsman, Scott; Burchard, Esteban G.; Arking, Dan E.; Bibbins-Domingo, Kirsten; Harris, Tamara B.; Perez, Marco V.; Ziv, Elad; Marcus, Gregory M.

2017-01-01

Importance Whites have a higher risk of atrial fibrillation (AF) relative to Blacks, despite a lower prevalence of risk factors. This difference may be due, at least in part, to genetic factors. Objective To determine whether 9 single nucleotide polymorphisms (SNPs) associated with AF account for this paradoxical differential racial risk. We also used admixture mapping to search genome wide for loci that may account for this phenomenon. Design, Setting, and Participants Genome wide admixture analysis and candidate SNP study involving 3 population-based cohort studies initiated between 1987 and 1997, including the Cardiovascular Health Study (CHS; n=3,969), the Atherosclerosis Risk in Communities Study (ARIC; n=12,341), and the Health, Aging, and Body Composition Study (Health ABC; n=1,015). Main Outcomes and Measures Incident AF systematically ascertained using clinic visit ECGs, hospital discharge diagnosis codes, death certificates and Medicare claims data. Results Cox proportional hazards models and the proportion of treatment effect method were utilized to determine the impact of 9 AF-risk SNPs among participants from CHS and ARIC. A single SNP, rs10824026 (chromosome 10: position 73661450), was found to significantly mediate 11.4% (95% CI 2.9–29.9%) and 31.7% (95% CI 16.0–53.0%) of the higher risk in Whites compared to Blacks in CHS and ARIC, respectively. Admixture mapping was performed in a meta-analysis of Black participants within CHS (n=811), ARIC (n=3,112), and Health ABC (n=1,015). No loci that reached the pre-specified statistical threshold for genome-wide significance were identified. Conclusions and Relevance The rs10824026 SNP on chromosome 10q22 mediates a modest proportion of the increased risk of AF among Whites relative to Blacks, potentially through an impact on gene expression levels of MYOZ1. No additional genetic variants accounting for a significant portion of the differential racial risk of AF were identified with genome wide admixture mapping, suggesting that additional genetic or environmental influences beyond single SNPs in isolation may account for the paradoxical racial risk of AF among Whites and Blacks. PMID:27438321

Developmental Stability Covaries with Genome-Wide and Single-Locus Heterozygosity in House Sparrows

PubMed Central

Vangestel, Carl; Mergeay, Joachim; Dawson, Deborah A.; Vandomme, Viki; Lens, Luc

2011-01-01

Fluctuating asymmetry (FA), a measure of developmental instability, has been hypothesized to increase with genetic stress. Despite numerous studies providing empirical evidence for associations between FA and genome-wide properties such as multi-locus heterozygosity, support for single-locus effects remains scant. Here we test if, and to what extent, FA co-varies with single- and multilocus markers of genetic diversity in house sparrow (Passer domesticus) populations along an urban gradient. In line with theoretical expectations, FA was inversely correlated with genetic diversity estimated at genome level. However, this relationship was largely driven by variation at a single key locus. Contrary to our expectations, relationships between FA and genetic diversity were not stronger in individuals from urban populations that experience higher nutritional stress. We conclude that loss of genetic diversity adversely affects developmental stability in P. domesticus, and more generally, that the molecular basis of developmental stability may involve complex interactions between local and genome-wide effects. Further study on the relative effects of single-locus and genome-wide effects on the developmental stability of populations with different genetic properties is therefore needed. PMID:21747940

Genetics and Diet Regulate Vitamin A Production via the Homeobox Transcription Factor ISX*

PubMed Central

Lobo, Glenn P.; Amengual, Jaume; Baus, Diane; Shivdasani, Ramesh A.; Taylor, Derek; von Lintig, Johannes

2013-01-01

Low dietary intake of β-carotene is associated with chronic disease and vitamin A deficiency. β-Carotene is converted to vitamin A in the intestine by the enzyme β-carotene-15,15′-monoxygenase (BCMO1) to support vision, reproduction, immune function, and cell differentiation. Considerable variability for this key step in vitamin A metabolism, as reported in the human population, could be related to genetics and individual vitamin A status, but it is unclear how these factors influence β-carotene metabolism and vitamin A homeostasis. Here we show that the intestine-specific transcription factor ISX binds to the Bcmo1 promoter. Moreover, upon induction by the β-carotene derivative retinoic acid, this ISX binding decreased expression of a luciferase reporter gene in human colonic CaCo-2 cells indicating that ISX acts as a transcriptional repressor of BCMO1 expression. Mice deficient for this transcription factor displayed increased intestinal BCMO1 expression and produced significantly higher amounts of vitamin A from supplemental β-carotene. The ISX binding site in the human BCMO1 promoter contains a common single nucleotide polymorphism that is associated with decreased conversion rates and increased fasting blood levels of β-carotene. Thus, our study establishes ISX as a critical regulator of vitamin A production and provides a mechanistic explanation for how both genetics and diet can affect this process. PMID:23393141

Genetic risk factors for ovarian cancer and their role for endometriosis risk.

PubMed

Burghaus, Stefanie; Fasching, Peter A; Häberle, Lothar; Rübner, Matthias; Büchner, Kathrin; Blum, Simon; Engel, Anne; Ekici, Arif B; Hartmann, Arndt; Hein, Alexander; Beckmann, Matthias W; Renner, Stefan P

2017-04-01

Several genetic variants have been validated as risk factors for ovarian cancer. Endometriosis has also been described as a risk factor for ovarian cancer. Identifying genetic risk factors that are common to the two diseases might help improve our understanding of the molecular pathogenesis potentially linking the two conditions. In a hospital-based case-control analysis, 12 single nucleotide polymorphisms (SNPs), validated by the Ovarian Cancer Association Consortium (OCAC) and the Collaborative Oncological Gene-environment Study (COGS) project, were genotyped using TaqMan® OpenArray™ analysis. The cases consisted of patients with endometriosis, and the controls were healthy individuals without endometriosis. A total of 385 cases and 484 controls were analyzed. Odds ratios and P values were obtained using simple logistic regression models, as well as from multiple logistic regression models with adjustment for clinical predictors. rs11651755 in HNF1B was found to be associated with endometriosis in this case-control study. The OR was 0.66 (95% CI, 0.51 to 0.84) and the P value after correction for multiple testing was 0.01. None of the other genotypes was associated with a risk for endometriosis. As rs11651755 in HNF1B modified both the ovarian cancer risk and also the risk for endometriosis, HNF1B may be causally involved in the pathogenetic pathway leading from endometriosis to ovarian cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

Genetic polymorphisms and skin aging: the identification of population genotypic groups holds potential for personalized treatments.

PubMed

Naval, Jordi; Alonso, Vicente; Herranz, Miquel Angel

2014-01-01

Skin changes are among the most visible signs of aging. Skin properties such as hydration, elasticity, and antioxidant capacity play a key role in the skin aging process. Skin aging is a complex process influenced by heritable and environmental factors. Recent studies on twins have revealed that up to 60% of the skin aging variation between individuals can be attributed to genetic factors, while the remaining 40% is due to non-genetic factors. Recent advances in genomics and bioinformatics approaches have led to the association of certain single nucleotide polymorphisms (SNPs) to skin properties. Our aim was to classify individuals based on an ensemble of multiple polymorphisms associated with certain properties of the skin for providing personalized skin care and anti-aging therapies. We identified the key proteins and SNPs associated with certain properties of the skin that contribute to skin aging. We selected a set of 13 SNPs in gene coding for these proteins which are potentially associated with skin aging. Finally, we classified a sample of 120 female volunteers into ten clusters exhibiting different skin properties according to their genotypic signature. This is the first study that describes the actual frequency of genetic polymorphisms and their distribution in clusters involved in skin aging in a Caucasian population. Individuals can be divided into genetic clusters defined by genotypic variables. These genotypic variables are linked with polymorphisms in one or more genes associated with certain properties of the skin that contribute to a person's perceived age. Therefore, by using this classification, it is possible to characterize human skin care and anti-aging needs on the basis of an individual's genetic signature, thus opening the door to personalized treatments addressed at specific populations. This is part of an ongoing effort towards personalized anti-aging therapies combining genetic signatures with environmental and life style evaluations.

Genetic polymorphisms and skin aging: the identification of population genotypic groups holds potential for personalized treatments

PubMed Central

Naval, Jordi; Alonso, Vicente; Herranz, Miquel Angel

2014-01-01

Introduction Skin changes are among the most visible signs of aging. Skin properties such as hydration, elasticity, and antioxidant capacity play a key role in the skin aging process. Skin aging is a complex process influenced by heritable and environmental factors. Recent studies on twins have revealed that up to 60% of the skin aging variation between individuals can be attributed to genetic factors, while the remaining 40% is due to non-genetic factors. Recent advances in genomics and bioinformatics approaches have led to the association of certain single nucleotide polymorphisms (SNPs) to skin properties. Our aim was to classify individuals based on an ensemble of multiple polymorphisms associated with certain properties of the skin for providing personalized skin care and anti-aging therapies. Methods and results We identified the key proteins and SNPs associated with certain properties of the skin that contribute to skin aging. We selected a set of 13 SNPs in gene coding for these proteins which are potentially associated with skin aging. Finally, we classified a sample of 120 female volunteers into ten clusters exhibiting different skin properties according to their genotypic signature. Conclusion This is the first study that describes the actual frequency of genetic polymorphisms and their distribution in clusters involved in skin aging in a Caucasian population. Individuals can be divided into genetic clusters defined by genotypic variables. These genotypic variables are linked with polymorphisms in one or more genes associated with certain properties of the skin that contribute to a person’s perceived age. Therefore, by using this classification, it is possible to characterize human skin care and anti-aging needs on the basis of an individual’s genetic signature, thus opening the door to personalized treatments addressed at specific populations. This is part of an ongoing effort towards personalized anti-aging therapies combining genetic signatures with environmental and life style evaluations. PMID:25061327

Amyotrophic lateral sclerosis and environmental factors

PubMed Central

Bozzoni, Virginia; Pansarasa, Orietta; Diamanti, Luca; Nosari, Guido; Cereda, Cristina; Ceroni, Mauro

2016-01-01

Summary Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that affects central and peripheral motor neuron cells. Its etiology is unknown, although a relationship between genetic background and environmental factors may play a major role in triggering the neurodegeneration. In this review, we analyze the role of environmental factors in ALS: heavy metals, electromagnetic fields and electric shocks, pesticides, β-N-methylamino-L-alanine, physical activity and the controversial role of sports. The literature on the single issues is analyzed in an attempt to clarify, as clearly as possible, whether each risk factor significantly contributes to the disease pathogenesis. After summarizing conflicting observations and data, the authors provide a final synthetic statement. PMID:27027889

ADAM17_i33780A>G polymorphism interacts with dietary n-6 polyunsaturated fatty acids to modulate obesity risk in the genetics of lipid lowering drugs and diet network study

USDA-ARS?s Scientific Manuscript database

The disintegrin and metalloproteinase ADAM17, also known as tumor necrosis factor alpha converting enzyme, is expressed in adipocytes, and elevated levels of expression have been linked to obesity and insulin resistance. This study evaluated the association of six ADAM17 single nucleotide polymorphi...

Isolation, characterization, and development of WRKY genes as useful genetic markers in Theobroma cacao.

PubMed

Borrone, James W; Kuhn, David N; Schnell, Raymond J

2004-08-01

There is currently an international effort in improving disease resistance and crop yield in Theobroma cacao L., an economically important crop of the tropics, using marker-assisted selection for breeding. We are developing molecular genetic markers focusing upon gene families involved with disease resistance. One such family is the WRKY proteins, which are plant-specific transcriptional factors associated with regulating defense responses to both abiotic and biotic stresses. Degenerate PCR primers were designed to the highly conserved DNA-binding domain and other conserved motifs of group I and group II, subgroups a-c, WRKY genes. Sixteen individual WRKY fragments were isolated from a mixture of T. cacao DNA using one pair of primers. Of the 16 WRKY loci investigated, seven contained single nucleotide polymorphisms within the intron as detected by sequence comparison of the PCR products. Four of these were successfully converted into molecular markers and mapped in an F2 population by capillary electrophoresis-single strand conformation polymorphism analysis. This is the first report of a pair of degenerate primers amplifying WRKY loci directly from genomic DNA and demonstrates a simple method for developing useful genetic markers from members of a large gene family. Copyright 2004 Springer-Verlag

Tissue-Specific Profiling Reveals Transcriptome Alterations in Arabidopsis Mutants Lacking Morphological Phenotypes[C][W

PubMed Central

Simon, Marissa; Bruex, Angela; Kainkaryam, Raghunandan M.; Zheng, Xiaohua; Huang, Ling; Woolf, Peter J.; Schiefelbein, John

2013-01-01

Traditional genetic analysis relies on mutants with observable phenotypes. Mutants lacking visible abnormalities may nevertheless exhibit molecular differences useful for defining gene function. To examine this, we analyzed tissue-specific transcript profiles from Arabidopsis thaliana transcription factor gene mutants with known roles in root epidermis development, but lacking a single-gene mutant phenotype due to genetic redundancy. We discovered substantial transcriptional changes in each mutant, preferentially affecting root epidermal genes in a manner consistent with the known double mutant effects. Furthermore, comparing transcript profiles of single and double mutants, we observed remarkable variation in the sensitivity of target genes to the loss of one or both paralogous genes, including preferential effects on specific branches of the epidermal gene network, likely reflecting the pathways of paralog subfunctionalization during evolution. In addition, we analyzed the root epidermal transcriptome of the transparent testa glabra2 mutant to clarify its role in the network. These findings provide insight into the molecular basis of genetic redundancy and duplicate gene diversification at the level of a specific gene regulatory network, and they demonstrate the usefulness of tissue-specific transcript profiling to define gene function in mutants lacking informative visible changes in phenotype. PMID:24014549

Association analysis identifies 65 new breast cancer risk loci.

PubMed

Michailidou, Kyriaki; Lindström, Sara; Dennis, Joe; Beesley, Jonathan; Hui, Shirley; Kar, Siddhartha; Lemaçon, Audrey; Soucy, Penny; Glubb, Dylan; Rostamianfar, Asha; Bolla, Manjeet K; Wang, Qin; Tyrer, Jonathan; Dicks, Ed; Lee, Andrew; Wang, Zhaoming; Allen, Jamie; Keeman, Renske; Eilber, Ursula; French, Juliet D; Qing Chen, Xiao; Fachal, Laura; McCue, Karen; McCart Reed, Amy E; Ghoussaini, Maya; Carroll, Jason S; Jiang, Xia; Finucane, Hilary; Adams, Marcia; Adank, Muriel A; Ahsan, Habibul; Aittomäki, Kristiina; Anton-Culver, Hoda; Antonenkova, Natalia N; Arndt, Volker; Aronson, Kristan J; Arun, Banu; Auer, Paul L; Bacot, François; Barrdahl, Myrto; Baynes, Caroline; Beckmann, Matthias W; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Bernstein, Leslie; Blomqvist, Carl; Bogdanova, Natalia V; Bojesen, Stig E; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Brand, Judith S; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Brinton, Louise; Broberg, Per; Brock, Ian W; Broeks, Annegien; Brooks-Wilson, Angela; Brucker, Sara Y; Brüning, Thomas; Burwinkel, Barbara; Butterbach, Katja; Cai, Qiuyin; Cai, Hui; Caldés, Trinidad; Canzian, Federico; Carracedo, Angel; Carter, Brian D; Castelao, Jose E; Chan, Tsun L; David Cheng, Ting-Yuan; Seng Chia, Kee; Choi, Ji-Yeob; Christiansen, Hans; Clarke, Christine L; Collée, Margriet; Conroy, Don M; Cordina-Duverger, Emilie; Cornelissen, Sten; Cox, David G; Cox, Angela; Cross, Simon S; Cunningham, Julie M; Czene, Kamila; Daly, Mary B; Devilee, Peter; Doheny, Kimberly F; Dörk, Thilo; Dos-Santos-Silva, Isabel; Dumont, Martine; Durcan, Lorraine; Dwek, Miriam; Eccles, Diana M; Ekici, Arif B; Eliassen, A Heather; Ellberg, Carolina; Elvira, Mingajeva; Engel, Christoph; Eriksson, Mikael; Fasching, Peter A; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Fritschi, Lin; Gaborieau, Valerie; Gabrielson, Marike; Gago-Dominguez, Manuela; Gao, Yu-Tang; Gapstur, Susan M; García-Sáenz, José A; Gaudet, Mia M; Georgoulias, Vassilios; Giles, Graham G; Glendon, Gord; Goldberg, Mark S; Goldgar, David E; González-Neira, Anna; Grenaker Alnæs, Grethe I; Grip, Mervi; Gronwald, Jacek; Grundy, Anne; Guénel, Pascal; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A; Håkansson, Niclas; Hamann, Ute; Hamel, Nathalie; Hankinson, Susan; Harrington, Patricia; Hart, Steven N; Hartikainen, Jaana M; Hartman, Mikael; Hein, Alexander; Heyworth, Jane; Hicks, Belynda; Hillemanns, Peter; Ho, Dona N; Hollestelle, Antoinette; Hooning, Maartje J; Hoover, Robert N; Hopper, John L; Hou, Ming-Feng; Hsiung, Chia-Ni; Huang, Guanmengqian; Humphreys, Keith; Ishiguro, Junko; Ito, Hidemi; Iwasaki, Motoki; Iwata, Hiroji; Jakubowska, Anna; Janni, Wolfgang; John, Esther M; Johnson, Nichola; Jones, Kristine; Jones, Michael; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Kabisch, Maria; Kaczmarek, Katarzyna; Kang, Daehee; Kasuga, Yoshio; Kerin, Michael J; Khan, Sofia; Khusnutdinova, Elza; Kiiski, Johanna I; Kim, Sung-Won; Knight, Julia A; Kosma, Veli-Matti; Kristensen, Vessela N; Krüger, Ute; Kwong, Ava; Lambrechts, Diether; Le Marchand, Loic; Lee, Eunjung; Lee, Min Hyuk; Lee, Jong Won; Neng Lee, Chuen; Lejbkowicz, Flavio; Li, Jingmei; Lilyquist, Jenna; Lindblom, Annika; Lissowska, Jolanta; Lo, Wing-Yee; Loibl, Sibylle; Long, Jirong; Lophatananon, Artitaya; Lubinski, Jan; Luccarini, Craig; Lux, Michael P; Ma, Edmond S K; MacInnis, Robert J; Maishman, Tom; Makalic, Enes; Malone, Kathleen E; Kostovska, Ivana Maleva; Mannermaa, Arto; Manoukian, Siranoush; Manson, JoAnn E; Margolin, Sara; Mariapun, Shivaani; Martinez, Maria Elena; Matsuo, Keitaro; Mavroudis, Dimitrios; McKay, James; McLean, Catriona; Meijers-Heijboer, Hanne; Meindl, Alfons; Menéndez, Primitiva; Menon, Usha; Meyer, Jeffery; Miao, Hui; Miller, Nicola; Taib, Nur Aishah Mohd; Muir, Kenneth; Mulligan, Anna Marie; Mulot, Claire; Neuhausen, Susan L; Nevanlinna, Heli; Neven, Patrick; Nielsen, Sune F; Noh, Dong-Young; Nordestgaard, Børge G; Norman, Aaron; Olopade, Olufunmilayo I; Olson, Janet E; Olsson, Håkan; Olswold, Curtis; Orr, Nick; Pankratz, V Shane; Park, Sue K; Park-Simon, Tjoung-Won; Lloyd, Rachel; Perez, Jose I A; Peterlongo, Paolo; Peto, Julian; Phillips, Kelly-Anne; Pinchev, Mila; Plaseska-Karanfilska, Dijana; Prentice, Ross; Presneau, Nadege; Prokofyeva, Darya; Pugh, Elizabeth; Pylkäs, Katri; Rack, Brigitte; Radice, Paolo; Rahman, Nazneen; Rennert, Gadi; Rennert, Hedy S; Rhenius, Valerie; Romero, Atocha; Romm, Jane; Ruddy, Kathryn J; Rüdiger, Thomas; Rudolph, Anja; Ruebner, Matthias; Rutgers, Emiel J T; Saloustros, Emmanouil; Sandler, Dale P; Sangrajrang, Suleeporn; Sawyer, Elinor J; Schmidt, Daniel F; Schmutzler, Rita K; Schneeweiss, Andreas; Schoemaker, Minouk J; Schumacher, Fredrick; Schürmann, Peter; Scott, Rodney J; Scott, Christopher; Seal, Sheila; Seynaeve, Caroline; Shah, Mitul; Sharma, Priyanka; Shen, Chen-Yang; Sheng, Grace; Sherman, Mark E; Shrubsole, Martha J; Shu, Xiao-Ou; Smeets, Ann; Sohn, Christof; Southey, Melissa C; Spinelli, John J; Stegmaier, Christa; Stewart-Brown, Sarah; Stone, Jennifer; Stram, Daniel O; Surowy, Harald; Swerdlow, Anthony; Tamimi, Rulla; Taylor, Jack A; Tengström, Maria; Teo, Soo H; Beth Terry, Mary; Tessier, Daniel C; Thanasitthichai, Somchai; Thöne, Kathrin; Tollenaar, Rob A E M; Tomlinson, Ian; Tong, Ling; Torres, Diana; Truong, Thérèse; Tseng, Chiu-Chen; Tsugane, Shoichiro; Ulmer, Hans-Ulrich; Ursin, Giske; Untch, Michael; Vachon, Celine; van Asperen, Christi J; Van Den Berg, David; van den Ouweland, Ans M W; van der Kolk, Lizet; van der Luijt, Rob B; Vincent, Daniel; Vollenweider, Jason; Waisfisz, Quinten; Wang-Gohrke, Shan; Weinberg, Clarice R; Wendt, Camilla; Whittemore, Alice S; Wildiers, Hans; Willett, Walter; Winqvist, Robert; Wolk, Alicja; Wu, Anna H; Xia, Lucy; Yamaji, Taiki; Yang, Xiaohong R; Har Yip, Cheng; Yoo, Keun-Young; Yu, Jyh-Cherng; Zheng, Wei; Zheng, Ying; Zhu, Bin; Ziogas, Argyrios; Ziv, Elad; Lakhani, Sunil R; Antoniou, Antonis C; Droit, Arnaud; Andrulis, Irene L; Amos, Christopher I; Couch, Fergus J; Pharoah, Paul D P; Chang-Claude, Jenny; Hall, Per; Hunter, David J; Milne, Roger L; García-Closas, Montserrat; Schmidt, Marjanka K; Chanock, Stephen J; Dunning, Alison M; Edwards, Stacey L; Bader, Gary D; Chenevix-Trench, Georgia; Simard, Jacques; Kraft, Peter; Easton, Douglas F

2017-11-02

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10 -8 . The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

Microfluidics for Single-Cell Genetic Analysis

PubMed Central

Thompson, A. M.; Paguirigan, A. L.; Kreutz, J. E.; Radich, J. P.; Chiu, D. T.

2014-01-01

The ability to correlate single-cell genetic information to cellular phenotypes will provide the kind of detailed insight into human physiology and disease pathways that is not possible to infer from bulk cell analysis. Microfluidic technologies are attractive for single-cell manipulation due to precise handling and low risk of contamination. Additionally, microfluidic single-cell techniques can allow for high-throughput and detailed genetic analyses that increase accuracy and decreases reagent cost compared to bulk techniques. Incorporating these microfluidic platforms into research and clinical laboratory workflows can fill an unmet need in biology, delivering the highly accurate, highly informative data necessary to develop new therapies and monitor patient outcomes. In this perspective, we describe the current and potential future uses of microfluidics at all stages of single-cell genetic analysis, including cell enrichment and capture, single-cell compartmentalization and manipulation, and detection and analyses. PMID:24789374

Single Color Multiplexed ddPCR Copy Number Measurements and Single Nucleotide Variant Genotyping.

PubMed

Wood-Bouwens, Christina M; Ji, Hanlee P

2018-01-01

Droplet digital PCR (ddPCR) allows for accurate quantification of genetic events such as copy number variation and single nucleotide variants. Probe-based assays represent the current "gold-standard" for detection and quantification of these genetic events. Here, we introduce a cost-effective single color ddPCR assay that allows for single genome resolution quantification of copy number and single nucleotide variation.

Gene-Environment Interactions in Asthma: Genetic and Epigenetic Effects.

PubMed

Lee, Jong-Uk; Kim, Jeong Dong; Park, Choon-Sik

2015-07-01

Over the past three decades, a large number of genetic studies have been aimed at finding genetic variants associated with the risk of asthma, applying various genetic and genomic approaches including linkage analysis, candidate gene polymorphism studies, and genome-wide association studies (GWAS). However, contrary to general expectation, even single nucleotide polymorphisms (SNPs) discovered by GWAS failed to fully explain the heritability of asthma. Thus, application of rare allele polymorphisms in well defined phenotypes and clarification of environmental factors have been suggested to overcome the problem of 'missing' heritability. Such factors include allergens, cigarette smoke, air pollutants, and infectious agents during pre- and post-natal periods. The first and simplest interaction between a gene and the environment is a candidate interaction of both a well known gene and environmental factor in a direct physical or chemical interaction such as between CD14 and endotoxin or between HLA and allergens. Several GWAS have found environmental interactions with occupational asthma, aspirin exacerbated respiratory disease, tobacco smoke-related airway dysfunction, and farm-related atopic diseases. As one of the mechanisms behind gene-environment interaction is epigenetics, a few studies on DNA CpG methylation have been reported on subphenotypes of asthma, pitching the exciting idea that it may be possible to intervene at the junction between the genome and the environment. Epigenetic studies are starting to include data from clinical samples, which will make them another powerful tool for re-search on gene-environment interactions in asthma.

A practical guide to environmental association analysis in landscape genomics.

PubMed

Rellstab, Christian; Gugerli, Felix; Eckert, Andrew J; Hancock, Angela M; Holderegger, Rolf

2015-09-01

Landscape genomics is an emerging research field that aims to identify the environmental factors that shape adaptive genetic variation and the gene variants that drive local adaptation. Its development has been facilitated by next-generation sequencing, which allows for screening thousands to millions of single nucleotide polymorphisms in many individuals and populations at reasonable costs. In parallel, data sets describing environmental factors have greatly improved and increasingly become publicly accessible. Accordingly, numerous analytical methods for environmental association studies have been developed. Environmental association analysis identifies genetic variants associated with particular environmental factors and has the potential to uncover adaptive patterns that are not discovered by traditional tests for the detection of outlier loci based on population genetic differentiation. We review methods for conducting environmental association analysis including categorical tests, logistic regressions, matrix correlations, general linear models and mixed effects models. We discuss the advantages and disadvantages of different approaches, provide a list of dedicated software packages and their specific properties, and stress the importance of incorporating neutral genetic structure in the analysis. We also touch on additional important aspects such as sampling design, environmental data preparation, pooled and reduced-representation sequencing, candidate-gene approaches, linearity of allele-environment associations and the combination of environmental association analyses with traditional outlier detection tests. We conclude by summarizing expected future directions in the field, such as the extension of statistical approaches, environmental association analysis for ecological gene annotation, and the need for replication and post hoc validation studies. © 2015 John Wiley & Sons Ltd.

A Transcriptome Atlas of Physcomitrella patens Provides Insights into the Evolution and Development of Land Plants.

PubMed

Ortiz-Ramírez, Carlos; Hernandez-Coronado, Marcela; Thamm, Anna; Catarino, Bruno; Wang, Mingyi; Dolan, Liam; Feijó, José A; Becker, Jörg D

2016-02-01

Identifying the genetic mechanisms that underpin the evolution of new organ and tissue systems is an aim of evolutionary developmental biology. Comparative functional genetic studies between angiosperms and bryophytes can define those genetic changes that were responsible for developmental innovations. Here, we report the generation of a transcriptome atlas covering most phases in the life cycle of the model bryophyte Physcomitrella patens, including detailed sporophyte developmental progression. We identified a comprehensive set of sporophyte-specific transcription factors, and found that many of these genes have homologs in angiosperms that function in developmental processes such as flowering and shoot branching. Deletion of the PpTCP5 transcription factor results in development of supernumerary sporangia attached to a single seta, suggesting that it negatively regulates branching in the moss sporophyte. Given that TCP genes repress branching in angiosperms, we suggest that this activity is ancient. Finally, comparison of P. patens and Arabidopsis thaliana transcriptomes led us to the identification of a conserved core of transcription factors expressed in tip-growing cells. We identified modifications in the expression patterns of these genes that could account for developmental differences between P. patens tip-growing cells and A. thaliana pollen tubes and root hairs. Copyright © 2016 The Author. Published by Elsevier Inc. All rights reserved.

Origins and Evolution of Stomatal Development1[OPEN

PubMed Central

2017-01-01

The fossil record suggests stomata-like pores were present on the surfaces of land plants over 400 million years ago. Whether stomata arose once or whether they arose independently across newly evolving land plant lineages has long been a matter of debate. In Arabidopsis, a genetic toolbox has been identified that tightly controls stomatal development and patterning. This includes the basic helix-loop-helix (bHLH) transcription factors SPEECHLESS (SPCH), MUTE, FAMA, and ICE/SCREAMs (SCRMs), which promote stomatal formation. These factors are regulated via a signaling cascade, which includes mobile EPIDERMAL PATTERNING FACTOR (EPF) peptides to enforce stomatal spacing. Mosses and hornworts, the most ancient extant lineages to possess stomata, possess orthologs of these Arabidopsis (Arabidopsis thaliana) stomatal toolbox genes, and manipulation in the model bryophyte Physcomitrella patens has shown that the bHLH and EPF components are also required for moss stomatal development and patterning. This supports an ancient and tightly conserved genetic origin of stomata. Here, we review recent discoveries and, by interrogating newly available plant genomes, we advance the story of stomatal development and patterning across land plant evolution. Furthermore, we identify potential orthologs of the key toolbox genes in a hornwort, further supporting a single ancient genetic origin of stomata in the ancestor to all stomatous land plants. PMID:28356502

A key ecological trait drove the evolution of biparental care and monogamy in an amphibian.

PubMed

Brown, Jason L; Morales, Victor; Summers, Kyle

2010-04-01

Linking specific ecological factors to the evolution of parental care pattern and mating system is a difficult task of key importance. We provide evidence from comparative analyses that an ecological factor (breeding pool size) is associated with the evolution of parental care across all frogs. We further show that the most intensive form of parental care (trophic egg feeding) evolved in concert with the use of small pools for tadpole deposition and that egg feeding was associated with the evolution of biparental care. Previous research on two Peruvian poison frogs (Ranitomeya imitator and Ranitomeya variabilis) revealed similar life histories, with the exception of breeding pool size. This key ecological difference led to divergence in parental care patterns and mating systems. We present ecological field experiments that demonstrate that biparental care is essential to tadpole survival in small (but not large) pools. Field observations demonstrate social monogamy in R. imitator, the species that uses small pools. Molecular analyses demonstrate genetic monogamy in R. imitator, the first example of genetic monogamy in an amphibian. In total, this evidence constitutes the most complete documentation to date that a single ecological factor drove the evolution of biparental care and genetic and social monogamy in an animal.

Birth defects: Risk factors and consequences

PubMed Central

Oliveira, Camila Ive Ferreira; Fett-Conte, Agnes Cristina

2013-01-01

Birth defects (BDs) or congenital anomalies include all structural and functional alterations in embryonic or fetal development resulting from genetic, environmental or unknown causes, which result in physical and/or mental impairment. BDs occur in about 3% of newborn babies and in most cases of pregnancy loss. BDs are a very complex and heterogeneous group of single or multiple changes that, in most cases, are of unknown etiology. Among the risk factors are advanced maternal and paternal ages, parental consanguinity, teratogenic agents such as infectious agents and drugs, and poor nutrition, in particular folic acid deficiency. One of the consequences of these defects is the high death rate within the first year of life. Information on BDs is becoming increasingly more important throughout the world so that preventive measures can be taken. Knowledge of BDs enables the development of therapeutic and preventive strategies besides adequate genetic counseling. PMID:27625844

Ecological effects on arbovirus-mosquito cycles of transmission.

PubMed

Tabachnick, Walter J

2016-12-01

Mosquitoes transmit many viruses to a variety of hosts. Cycles of mosquito borne arbovirus transmission are the result of complex interactions between the mosquito, the arbovirus and the host that are influenced by genetic variations in a variety of traits in each that are all influenced by many environmental factors. R 0 , the basic reproduction number or mean number of individuals infected from a single infected individual, is a measure of mosquito borne arbovirus transmission. Understanding the causes for the distribution of R 0 in any transmission cycle is a daunting challenge due to the lack of information on the genetic and environmental variances that influence R 0 . Information about the major factors influencing R 0 for specific transmission cycles is essential to develop efficient and effective strategies to reduce transmission in different cycles and locations. Copyright © 2016 Elsevier B.V. All rights reserved.

Genetic Influences on Physiological and Subjective Responses to an Aerobic Exercise Session among Sedentary Adults

PubMed Central

Karoly, Hollis C.; Stevens, Courtney J.; Magnan, Renee E.; Harlaar, Nicole; Hutchison, Kent E.; Bryan, Angela D.

2012-01-01

Objective. To determine whether genetic variants suggested by the literature to be associated with physiology and fitness phenotypes predicted differential physiological and subjective responses to a bout of aerobic exercise among inactive but otherwise healthy adults. Method. Participants completed a 30-minute submaximal aerobic exercise session. Measures of physiological and subjective responding were taken before, during, and after exercise. 14 single nucleotide polymorphisms (SNPs) that have been previously associated with various exercise phenotypes were tested for associations with physiological and subjective response to exercise phenotypes. Results. We found that two SNPs in the FTO gene (rs8044769 and rs3751812) were related to positive affect change during exercise. Two SNPs in the CREB1 gene (rs2253206 and 2360969) were related to change in temperature during exercise and with maximal oxygen capacity (VO2 max). The SLIT2 SNP rs1379659 and the FAM5C SNP rs1935881 were associated with norepinephrine change during exercise. Finally, the OPRM1 SNP rs1799971 was related to changes in norepinephrine, lactate, and rate of perceived exertion (RPE) during exercise. Conclusion. Genetic factors influence both physiological and subjective responses to exercise. A better understanding of genetic factors underlying physiological and subjective responses to aerobic exercise has implications for development and potential tailoring of exercise interventions. PMID:22899923

Characterization and genetic mapping of a Photoperiod-sensitive dwarf 1 locus in rice (Oryza sativa L.).

PubMed

Li, Riqing; Xia, Jixing; Xu, Yiwei; Zhao, Xiucai; Liu, Yao-Guang; Chen, Yuanling

2014-01-01

Plant height is an important agronomic trait for crop architecture and yield. Most known factors determining plant height function in gibberellin or brassinosteroid biosynthesis or signal transduction. Here, we report a japonica rice (Oryza sativa ssp. japonica) dominant dwarf mutant, Photoperiod-sensitive dwarf 1 (Psd1). The Psd1 mutant showed impaired cell division and elongation, and a severe dwarf phenotype under long-day conditions, but nearly normal growth in short-day. The plant height of Psd1 mutant could not be rescued by gibberellin or brassinosteroid treatment. Genetic analysis with R1 and F2 populations determined that Psd1 phenotype was controlled by a single dominant locus. Linkage analysis with 101 tall F2 plants grown in a long-day season, which were derived from a cross between Psd1 and an indica cultivar, located Psd1 locus on chromosome 1. Further fine-mapping with 1017 tall F2 plants determined this locus on an 11.5-kb region. Sequencing analysis of this region detected a mutation site in a gene encoding a putative lipid transfer protein; the mutation produces a truncated C-terminus of the protein. This study establishes the genetic foundation for understanding the molecular mechanisms regulating plant cell division and elongation mediated by interaction between genetic and environmental factors.

The etiology of essential tremor: Genes versus environment.

PubMed

Hopfner, Franziska; Helmich, Rick C

2018-01-01

Essential tremor (ET) is characterized by bilateral upper limb action tremor. Here we review the pathophysiology (cerebral mechanisms) and etiology (genetic and environmental risk factors) of ET. We reviewed the literature (until June 2017) by searching PubMed for relevant papers. The pathophysiology of ET involves oscillatory activity in the cortico-olivo-cerebello-thalamic circuit, evidenced by electrophysiological and metabolic imaging. Possible underlying mechanisms include GABA-ergic dysfunction, cerebellar neurodegeneration, olivary dysfunction, or a combination. Genetic studies have examined affected ET families (linkage studies and whole-exome sequencing studies). These studies revealed several chromosomal regions and genes associated with ET, but the findings have not been replicated across different ET families. Genetic studies also assessed the sporadic occurrence of ET using genome wide genotyping of single nucleotide polymorphisms (SNP's) and candidate gene studies. Several SNP's are associated with ET, and this has been replicated across different cohorts. Interestingly, some of the involved genes are linked to the cerebellum and inferior olive. Environmental studies point to an association between ET and beta-carboline alkaloids (such as harmane), which have been found in the cerebellum. Genetic and environmental risk factors may influence cerebellar and/or olivary function, resulting in abnormal cortico-olivo-cerebello-thalamic activity, and ultimately ET. Copyright © 2017 Elsevier Ltd. All rights reserved.

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

PubMed

Pereyra, Florencia; Jia, Xiaoming; McLaren, Paul J; Telenti, Amalio; de Bakker, Paul I W; Walker, Bruce D; Ripke, Stephan; Brumme, Chanson J; Pulit, Sara L; Carrington, Mary; Kadie, Carl M; Carlson, Jonathan M; Heckerman, David; Graham, Robert R; Plenge, Robert M; Deeks, Steven G; Gianniny, Lauren; Crawford, Gabriel; Sullivan, Jordan; Gonzalez, Elena; Davies, Leela; Camargo, Amy; Moore, Jamie M; Beattie, Nicole; Gupta, Supriya; Crenshaw, Andrew; Burtt, Noël P; Guiducci, Candace; Gupta, Namrata; Gao, Xiaojiang; Qi, Ying; Yuki, Yuko; Piechocka-Trocha, Alicja; Cutrell, Emily; Rosenberg, Rachel; Moss, Kristin L; Lemay, Paul; O'Leary, Jessica; Schaefer, Todd; Verma, Pranshu; Toth, Ildiko; Block, Brian; Baker, Brett; Rothchild, Alissa; Lian, Jeffrey; Proudfoot, Jacqueline; Alvino, Donna Marie L; Vine, Seanna; Addo, Marylyn M; Allen, Todd M; Altfeld, Marcus; Henn, Matthew R; Le Gall, Sylvie; Streeck, Hendrik; Haas, David W; Kuritzkes, Daniel R; Robbins, Gregory K; Shafer, Robert W; Gulick, Roy M; Shikuma, Cecilia M; Haubrich, Richard; Riddler, Sharon; Sax, Paul E; Daar, Eric S; Ribaudo, Heather J; Agan, Brian; Agarwal, Shanu; Ahern, Richard L; Allen, Brady L; Altidor, Sherly; Altschuler, Eric L; Ambardar, Sujata; Anastos, Kathryn; Anderson, Ben; Anderson, Val; Andrady, Ushan; Antoniskis, Diana; Bangsberg, David; Barbaro, Daniel; Barrie, William; Bartczak, J; Barton, Simon; Basden, Patricia; Basgoz, Nesli; Bazner, Suzane; Bellos, Nicholaos C; Benson, Anne M; Berger, Judith; Bernard, Nicole F; Bernard, Annette M; Birch, Christopher; Bodner, Stanley J; Bolan, Robert K; Boudreaux, Emilie T; Bradley, Meg; Braun, James F; Brndjar, Jon E; Brown, Stephen J; Brown, Katherine; Brown, Sheldon T; Burack, Jedidiah; Bush, Larry M; Cafaro, Virginia; Campbell, Omobolaji; Campbell, John; Carlson, Robert H; Carmichael, J Kevin; Casey, Kathleen K; Cavacuiti, Chris; Celestin, Gregory; Chambers, Steven T; Chez, Nancy; Chirch, Lisa M; Cimoch, Paul J; Cohen, Daniel; Cohn, Lillian E; Conway, Brian; Cooper, David A; Cornelson, Brian; Cox, David T; Cristofano, Michael V; Cuchural, George; Czartoski, Julie L; Dahman, Joseph M; Daly, Jennifer S; Davis, Benjamin T; Davis, Kristine; Davod, Sheila M; DeJesus, Edwin; Dietz, Craig A; Dunham, Eleanor; Dunn, Michael E; Ellerin, Todd B; Eron, Joseph J; Fangman, John J W; Farel, Claire E; Ferlazzo, Helen; Fidler, Sarah; Fleenor-Ford, Anita; Frankel, Renee; Freedberg, Kenneth A; French, Neel K; Fuchs, Jonathan D; Fuller, Jon D; Gaberman, Jonna; Gallant, Joel E; Gandhi, Rajesh T; Garcia, Efrain; Garmon, Donald; Gathe, Joseph C; Gaultier, Cyril R; Gebre, Wondwoosen; Gilman, Frank D; Gilson, Ian; Goepfert, Paul A; Gottlieb, Michael S; Goulston, Claudia; Groger, Richard K; Gurley, T Douglas; Haber, Stuart; Hardwicke, Robin; Hardy, W David; Harrigan, P Richard; Hawkins, Trevor N; Heath, Sonya; Hecht, Frederick M; Henry, W Keith; Hladek, Melissa; Hoffman, Robert P; Horton, James M; Hsu, Ricky K; Huhn, Gregory D; Hunt, Peter; Hupert, Mark J; Illeman, Mark L; Jaeger, Hans; Jellinger, Robert M; John, Mina; Johnson, Jennifer A; Johnson, Kristin L; Johnson, Heather; Johnson, Kay; Joly, Jennifer; Jordan, Wilbert C; Kauffman, Carol A; Khanlou, Homayoon; Killian, Robert K; Kim, Arthur Y; Kim, David D; Kinder, Clifford A; Kirchner, Jeffrey T; Kogelman, Laura; Kojic, Erna Milunka; Korthuis, P Todd; Kurisu, Wayne; Kwon, Douglas S; LaMar, Melissa; Lampiris, Harry; Lanzafame, Massimiliano; Lederman, Michael M; Lee, David M; Lee, Jean M L; Lee, Marah J; Lee, Edward T Y; Lemoine, Janice; Levy, Jay A; Llibre, Josep M; Liguori, Michael A; Little, Susan J; Liu, Anne Y; Lopez, Alvaro J; Loutfy, Mono R; Loy, Dawn; Mohammed, Debbie Y; Man, Alan; Mansour, Michael K; Marconi, Vincent C; Markowitz, Martin; Marques, Rui; Martin, Jeffrey N; Martin, Harold L; Mayer, Kenneth Hugh; McElrath, M Juliana; McGhee, Theresa A; McGovern, Barbara H; McGowan, Katherine; McIntyre, Dawn; Mcleod, Gavin X; Menezes, Prema; Mesa, Greg; Metroka, Craig E; Meyer-Olson, Dirk; Miller, Andy O; Montgomery, Kate; Mounzer, Karam C; Nagami, Ellen H; Nagin, Iris; Nahass, Ronald G; Nelson, Margret O; Nielsen, Craig; Norene, David L; O'Connor, David H; Ojikutu, Bisola O; Okulicz, Jason; Oladehin, Olakunle O; Oldfield, Edward C; Olender, Susan A; Ostrowski, Mario; Owen, William F; Pae, Eunice; Parsonnet, Jeffrey; Pavlatos, Andrew M; Perlmutter, Aaron M; Pierce, Michael N; Pincus, Jonathan M; Pisani, Leandro; Price, Lawrence Jay; Proia, Laurie; Prokesch, Richard C; Pujet, Heather Calderon; Ramgopal, Moti; Rathod, Almas; Rausch, Michael; Ravishankar, J; Rhame, Frank S; Richards, Constance Shamuyarira; Richman, Douglas D; Rodes, Berta; Rodriguez, Milagros; Rose, Richard C; Rosenberg, Eric S; Rosenthal, Daniel; Ross, Polly E; Rubin, David S; Rumbaugh, Elease; Saenz, Luis; Salvaggio, Michelle R; Sanchez, William C; Sanjana, Veeraf M; Santiago, Steven; Schmidt, Wolfgang; Schuitemaker, Hanneke; Sestak, Philip M; Shalit, Peter; Shay, William; Shirvani, Vivian N; Silebi, Vanessa I; Sizemore, James M; Skolnik, Paul R; Sokol-Anderson, Marcia; Sosman, James M; Stabile, Paul; Stapleton, Jack T; Starrett, Sheree; Stein, Francine; Stellbrink, Hans-Jurgen; Sterman, F Lisa; Stone, Valerie E; Stone, David R; Tambussi, Giuseppe; Taplitz, Randy A; Tedaldi, Ellen M; Telenti, Amalio; Theisen, William; Torres, Richard; Tosiello, Lorraine; Tremblay, Cecile; Tribble, Marc A; Trinh, Phuong D; Tsao, Alice; Ueda, Peggy; Vaccaro, Anthony; Valadas, Emilia; Vanig, Thanes J; Vecino, Isabel; Vega, Vilma M; Veikley, Wenoah; Wade, Barbara H; Walworth, Charles; Wanidworanun, Chingchai; Ward, Douglas J; Warner, Daniel A; Weber, Robert D; Webster, Duncan; Weis, Steve; Wheeler, David A; White, David J; Wilkins, Ed; Winston, Alan; Wlodaver, Clifford G; van't Wout, Angelique; Wright, David P; Yang, Otto O; Yurdin, David L; Zabukovic, Brandon W; Zachary, Kimon C; Zeeman, Beth; Zhao, Meng

2010-12-10

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.

Contextualizing Genetics for Regional Heart Failure Care

PubMed Central

Iyngkaran, Pupalan; Thomas, Merlin C.; Johnson, Renee; French, John; Ilton, Marcus; McDonald, Peter; Hare, David L.; Fatkin, Diane

2016-01-01

Congestive heart failure (CHF) is a chronic and often devastating cardiovascular disorder with no cure. There has been much advancement in the last two decades that has seen improvements in morbidity and mortality. Clinicians have also noted variations in the responses to therapies. More detailed observations also point to clusters of diseases, phenotypic groupings, unusual severity and the rates at which CHF occurs. Medical genetics is playing an increasingly important role in answering some of these observations. This developing field in many respects provides more information than is currently clinically applicable. This includes making sense of the established single gene mutations or uncommon private mutations. In this thematic series which discusses the many factors that could be relevant for CHF care, once established treatments are available in the communities; this section addresses a contextual role for medical genetics. PMID:27280306

Application of a single-objective, hybrid genetic algorithm approach to pharmacokinetic model building.

PubMed

Sherer, Eric A; Sale, Mark E; Pollock, Bruce G; Belani, Chandra P; Egorin, Merrill J; Ivy, Percy S; Lieberman, Jeffrey A; Manuck, Stephen B; Marder, Stephen R; Muldoon, Matthew F; Scher, Howard I; Solit, David B; Bies, Robert R

2012-08-01

A limitation in traditional stepwise population pharmacokinetic model building is the difficulty in handling interactions between model components. To address this issue, a method was previously introduced which couples NONMEM parameter estimation and model fitness evaluation to a single-objective, hybrid genetic algorithm for global optimization of the model structure. In this study, the generalizability of this approach for pharmacokinetic model building is evaluated by comparing (1) correct and spurious covariate relationships in a simulated dataset resulting from automated stepwise covariate modeling, Lasso methods, and single-objective hybrid genetic algorithm approaches to covariate identification and (2) information criteria values, model structures, convergence, and model parameter values resulting from manual stepwise versus single-objective, hybrid genetic algorithm approaches to model building for seven compounds. Both manual stepwise and single-objective, hybrid genetic algorithm approaches to model building were applied, blinded to the results of the other approach, for selection of the compartment structure as well as inclusion and model form of inter-individual and inter-occasion variability, residual error, and covariates from a common set of model options. For the simulated dataset, stepwise covariate modeling identified three of four true covariates and two spurious covariates; Lasso identified two of four true and 0 spurious covariates; and the single-objective, hybrid genetic algorithm identified three of four true covariates and one spurious covariate. For the clinical datasets, the Akaike information criterion was a median of 22.3 points lower (range of 470.5 point decrease to 0.1 point decrease) for the best single-objective hybrid genetic-algorithm candidate model versus the final manual stepwise model: the Akaike information criterion was lower by greater than 10 points for four compounds and differed by less than 10 points for three compounds. The root mean squared error and absolute mean prediction error of the best single-objective hybrid genetic algorithm candidates were a median of 0.2 points higher (range of 38.9 point decrease to 27.3 point increase) and 0.02 points lower (range of 0.98 point decrease to 0.74 point increase), respectively, than that of the final stepwise models. In addition, the best single-objective, hybrid genetic algorithm candidate models had successful convergence and covariance steps for each compound, used the same compartment structure as the manual stepwise approach for 6 of 7 (86 %) compounds, and identified 54 % (7 of 13) of covariates included by the manual stepwise approach and 16 covariate relationships not included by manual stepwise models. The model parameter values between the final manual stepwise and best single-objective, hybrid genetic algorithm models differed by a median of 26.7 % (q₁ = 4.9 % and q₃ = 57.1 %). Finally, the single-objective, hybrid genetic algorithm approach was able to identify models capable of estimating absorption rate parameters for four compounds that the manual stepwise approach did not identify. The single-objective, hybrid genetic algorithm represents a general pharmacokinetic model building methodology whose ability to rapidly search the feasible solution space leads to nearly equivalent or superior model fits to pharmacokinetic data.

Characterizing the genetic influences on risk aversion.

PubMed

Harrati, Amal

2014-01-01

Risk aversion has long been cited as an important factor in retirement decisions, investment behavior, and health. Some of the heterogeneity in individual risk tolerance is well understood, reflecting age gradients, wealth gradients, and similar effects, but much remains unexplained. This study explores genetic contributions to heterogeneity in risk aversion among older Americans. Using over 2 million genetic markers per individual from the U.S. Health and Retirement Study, I report results from a genome-wide association study (GWAS) on risk preferences using a sample of 10,455 adults. None of the single-nucleotide polymorphisms (SNPs) are found to be statistically significant determinants of risk preferences at levels stricter than 5 × 10(-8). These results suggest that risk aversion is a complex trait that is highly polygenic. The analysis leads to upper bounds on the number of genetic effects that could exceed certain thresholds of significance and still remain undetected at the current sample size. The findings suggest that the known heritability in risk aversion is likely to be driven by large numbers of genetic variants, each with a small effect size.

Genotypic and phenotypic predictors of inflammation in patients with chronic kidney disease.

PubMed

Luttropp, Karin; Debowska, Malgorzata; Lukaszuk, Tomasz; Bobrowski, Leon; Carrero, Juan Jesus; Qureshi, Abdul Rashid; Stenvinkel, Peter; Lindholm, Bengt; Waniewski, Jacek; Nordfors, Louise

2016-12-01

In complex diseases such as chronic kidney disease (CKD), the risk of clinical complications is determined by interactions between phenotypic and genotypic factors. However, clinical epidemiological studies rarely attempt to analyse the combined effect of large numbers of phenotype and genotype features. We have recently shown that the relaxed linear separability (RLS) model of feature selection can address such complex issues. Here, it is applied to identify risk factors for inflammation in CKD. The RLS model was applied in 225 CKD stage 5 patients sampled in conjunction with dialysis initiation. Fifty-seven anthropometric or biochemical measurements and 79 genetic polymorphisms were entered into the model. The model was asked to identify phenotypes and genotypes that, when combined, could separate inflamed from non-inflamed patients. Inflammation was defined as a high-sensitivity C-reactive protein concentration above the median (5 mg/L). Among the 60 genotypic and phenotypic features predicting inflammation, 31 were genetic. Among the 10 strongest predictors of inflammation, 8 were single nucleotide polymorphisms located in the NAMPT, CIITA, BMP2 and PIK3CB genes, whereas fibrinogen and bone mineral density were the only phenotypic biomarkers. These results indicate a larger involvement of hereditary factors in inflammation than might have been expected and suggest that inclusion of genotype features in risk assessment studies is critical. The RLS model demonstrates that inflammation in CKD is determined by an extensive panel of factors and may prove to be a suitable tool that could enable a much-needed multifactorial approach as opposed to the commonly utilized single-factor analysis. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Education influences the association between genetic variants and refractive error: a meta-analysis of five Singapore studies

PubMed Central

Fan, Qiao; Wojciechowski, Robert; Kamran Ikram, M.; Cheng, Ching-Yu; Chen, Peng; Zhou, Xin; Pan, Chen-Wei; Khor, Chiea-Chuen; Tai, E-Shyong; Aung, Tin; Wong, Tien-Yin; Teo, Yik-Ying; Saw, Seang-Mei

2014-01-01

Refractive error is a complex ocular trait governed by both genetic and environmental factors and possibly their interplay. Thus far, data on the interaction between genetic variants and environmental risk factors for refractive errors are largely lacking. By using findings from recent genome-wide association studies, we investigated whether the main environmental factor, education, modifies the effect of 40 single nucleotide polymorphisms on refractive error among 8461 adults from five studies including ethnic Chinese, Malay and Indian residents of Singapore. Three genetic loci SHISA6-DNAH9, GJD2 and ZMAT4-SFRP1 exhibited a strong association with myopic refractive error in individuals with higher secondary or university education (SHISA6-DNAH9: rs2969180 A allele, β = −0.33 D, P = 3.6 × 10–6; GJD2: rs524952 A allele, β = −0.31 D, P = 1.68 × 10−5; ZMAT4-SFRP1: rs2137277 A allele, β = −0.47 D, P = 1.68 × 10−4), whereas the association at these loci was non-significant or of borderline significance in those with lower secondary education or below (P for interaction: 3.82 × 10−3–4.78 × 10−4). The evidence for interaction was strengthened when combining the genetic effects of these three loci (P for interaction = 4.40 × 10−8), and significant interactions with education were also observed for axial length and myopia. Our study shows that low level of education may attenuate the effect of risk alleles on myopia. These findings further underline the role of gene–environment interactions in the pathophysiology of myopia. PMID:24014484

Genome-wide association analysis of pain severity in dysmenorrhea identifies association at chromosome 1p13.2, near the nerve growth factor locus

PubMed Central

Jones, Amy V.; Hockley, James R.F.; Hyde, Craig; Gorman, Donal; Sredic-Rhodes, Ana; Bilsland, James; McMurray, Gordon; Furlotte, Nicholas A.; Hu, Youna; Hinds, David A.; Cox, Peter J.; Scollen, Serena

2016-01-01

Abstract Dysmenorrhea is a common chronic pelvic pain syndrome affecting women of childbearing potential. Family studies suggest that genetic background influences the severity of dysmenorrhea, but genetic predisposition and molecular mechanisms underlying dysmenorrhea are not understood. In this study, we conduct the first genome-wide association study to identify genetic factors associated with dysmenorrhea pain severity. A cohort of females of European descent (n = 11,891) aged 18 to 45 years rated their average dysmenorrhea pain severity. We used a linear regression model adjusting for age and body mass index, identifying one genome-wide significant (P < 5 × 10−8) association (rs7523086, P = 4.1 × 10−14, effect size 0.1 [95% confidence interval, 0.074–0.126]). This single nucleotide polymorphism is colocalising with NGF, encoding nerve growth factor. The presence of one risk allele corresponds to a predicted 0.1-point increase in pain intensity on a 4-point ordinal pain scale. The putative effects on NGF function and/or expression remain unknown. However, genetic variation colocalises with active epigenetic marks in fat and ovary tissues, and expression levels in aorta tissue of a noncoding RNA flanking NGF correlate. Participants reporting extreme dysmenorrhea pain were more likely to report being positive for endometriosis, polycystic ovarian syndrome, depression, and other psychiatric disorders. Our results indicate that dysmenorrhea pain severity is partly genetically determined. NGF already has an established role in chronic pain disorders, and our findings suggest that NGF may be an important mediator for gynaecological/pelvic pain in the viscera. PMID:27454463

The association between scalp hair-whorl direction, handedness and hemispheric language dominance: is there a common genetic basis of lateralization?

PubMed

Jansen, Andreas; Lohmann, Hubertus; Scharfe, Stefanie; Sehlmeyer, Christina; Deppe, Michael; Knecht, Stefan

2007-04-01

The hemispheres of the human brain are functionally asymmetric. The left hemisphere tends to be dominant for language and superior in the control of manual dexterity. The mechanisms underlying these asymmetries are not known. Genetic as well as environmental factors are discussed. Recently, atypical anticlockwise hair-whorl direction has been related to an increased probability for non-right-handedness and atypical hemispheric language dominance. These findings are fascinating and important since hair-whorl direction is a structural marker of lateralization and could provide a readily observable anatomical clue to functional brain lateralization. Based on data on handedness and hair-whorl direction, Amar Klar proposed a genetic model ("random-recessive model") in that a single gene with two alleles controls both handedness and hair-whorl orientation (Klar, A.J.S., 2003. Human handedness and scalp hair-whorl direction develop from a common genetic mechanism. Genetics 165, 269-276). The present study was designed to further investigate the relationship between scalp hair-whorl direction with handedness and hemispheric language dominance. 1212 subjects were investigated for scalp hair-whorl direction and handedness. Additionally, we determined hemispheric language dominance (as assessed by a word generation task) in a subgroup of 212 subjects using functional transcranial Doppler sonography (fTCD). As for the single attributes - hair-whorl direction, handedness, and language dominance - we reproduced previously published results. However, we found no association between hair-whorl direction and either language dominance or handedness. These results strongly argue against a common genetic basis of handedness or language lateralization with scalp hair-whorl direction. Inspection of hair patterns will not help us to determine language dominance.

MYH9 genetic variants associated with glomerular disease: what is the role for genetic testing?

PubMed

Kopp, Jeffrey B; Winkler, Cheryl A; Nelson, George W

2010-07-01

Genetic variation in MYH9, encoding nonmuscle myosin IIA heavy chain, has been associated recently with increased risk for kidney disease. Previously, MYH9 missense mutations have been shown to cause the autosomal-dominant MYH9 (ADM9) spectrum, characterized by large platelets, leukocyte Döhle bodies, and, variably, sensorineural deafness, cataracts, and glomerulopathy. Genetic testing is indicated for familial and sporadic cases that fit this spectrum. By contrast, the MYH9 kidney risk variant is characterized by multiple intronic single nucleotide polymorphisms, but the causative variant has not been identified. Disease associations include human immunodeficiency virus-associated collapsing glomerulopathy, focal segmental glomerulosclerosis, hypertension-attributed end-stage kidney disease, and diabetes-attributed end-stage kidney disease. One plausible hypothesis is that the MYH9 kidney risk variant confers a fragile podocyte phenotype. In the case of hypertension-attributed kidney disease, it remains unclear if the hypertension is a contributing cause or a consequence of glomerular injury. The MYH9 kidney risk variant is strikingly more common among individuals of African descent, but only some will develop clinical kidney disease in their lifetime. Thus, it is likely that additional genes and/or environmental factors interact with the MYH9 kidney risk variant to trigger glomerular injury. A preliminary genetic risk stratification scheme, using two single nucleotide polymorphisms, may estimate lifetime risk for kidney disease. Nevertheless, at present, no role has been established for genetic testing as part of personalized medicine, but testing should be considered in clinical studies of glomerular diseases among populations of African descent. Such studies will address critical questions pertaining to MYH9-associated kidney disease, including mechanism, course, and response to therapy. Published by Elsevier Inc.

The split of the Arara population: comparison of genetic drift and founder effect.

PubMed

Ribeiro-dos-Santos, A K; Guerreiro, J F; Santos, S E; Zago, M A

2001-01-01

The total genetic diversity of the Amerindian population is as high as that observed for other continental human populations because a large contribution from variation among tribes makes up for the low variation within tribes. This is attributed mainly to genetic drift acting on small isolated populations. However, a small founder population with a low genetic diversity is another factor that may contribute to the low intratribal diversity. Small founder populations seem to be a frequent event in the formation of new tribes among the Amerindians, but this event is usually not well recorded. In this paper, we analyze the genetic diversity of the Arara of Laranjal village and the Arara of Iriri village, with respect to seven tandem repeat autosomic segments (D1S80, ApoB, D4S43, vW1, vW2, F13A1 and D12S67), two Y-chromosome-specific polymorphisms (DYS19 and DYS199), and mitochondrial DNA (mtDNA) markers (restriction fragment length polymorphisms and sequencing of a segment of the D loop region). The occurrence of a single Y chromosome and mtDNA haplotype, and only 1-4 alleles of the autosomic loci investigated, corroborates historic and demographic records that the Arara of Iriri were founded by a single couple of siblings who came from the Arara of Laranjal, the largest group. Notwithstanding this fact, the genetic distance and the molecular variance between the two Arara villages were greater than those observed between them and other Amazonian tribes, suggesting that the microevolutionary process among Brazilian Amerindians may be misinterpreted if historic demographic data are not considered. Copyright 2000 S. Karger AG, Basel.

Genetic and non-genetic animal models for autism spectrum disorders (ASD).

PubMed

Ergaz, Zivanit; Weinstein-Fudim, Liza; Ornoy, Asher

2016-09-01

Autism spectrum disorder (ASD) is associated, in addition to complex genetic factors, with a variety of prenatal, perinatal and postnatal etiologies. We discuss the known animal models, mostly in mice and rats, of ASD that helps us to understand the etiology, pathogenesis and treatment of human ASD. We describe only models where behavioral testing has shown autistic like behaviors. Some genetic models mimic known human syndromes like fragile X where ASD is part of the clinical picture, and others are without defined human syndromes. Among the environmentally induced ASD models in rodents, the most common model is the one induced by valproic acid (VPA) either prenatally or early postnatally. VPA induces autism-like behaviors following single exposure during different phases of brain development, implying that the mechanism of action is via a general biological mechanism like epigenetic changes. Maternal infection and inflammation are also associated with ASD in man and animal models. Copyright © 2016 Elsevier Inc. All rights reserved.

Short-Term Genetic Selection for Adolescent Locomotor Sensitivity to Delta9-Tetrahydrocannabinol (THC).

PubMed

Kasten, Chelsea R; Zhang, Yanping; Mackie, Ken; Boehm, Stephen L

2018-05-01

Cannabis use is linked to positive and negative outcomes. Identifying genetic targets of susceptibility to the negative effects of cannabinoid use is of growing importance. The current study sought to complete short-term selective breeding for adolescent sensitivity and resistance to the locomotor effects of a single 10 mg/kg THC dose in the open field. Selection for THC-locomotor sensitivity was moderately heritable, with the greatest estimates of heritability seen in females from the F2 to S3 generations. Selection for locomotor sensitivity also resulted in increased anxiety-like activity in the open field. These results are the first to indicate that adolescent THC-locomotor sensitivity can be influenced via selective breeding. Development of lines with a genetic predisposition for THC-sensitivity or resistance to locomotor effects allow for investigation of risk factors, differences in consequences of THC use, identification of correlated behavioral responses, and detection of genetic targets that may contribute to heightened cannabinoid sensitivity.

"Touching Triton": Building Student Understanding of Complex Disease Risk.

PubMed

Loftin, Madelene; East, Kelly; Hott, Adam; Lamb, Neil

2016-01-01

Life science classrooms often emphasize the exception to the rule when it comes to teaching genetics, focusing heavily on rare single-gene and Mendelian traits. By contrast, the vast majority of human traits and diseases are caused by more complicated interactions between genetic and environmental factors. Research indicates that students have a deterministic view of genetics, generalize Mendelian inheritance patterns to all traits, and have unrealistic expectations of genetic technologies. The challenge lies in how to help students analyze complex disease risk with a lack of curriculum materials. Providing open access to both content resources and an engaging storyline can be achieved using a "serious game" model. "Touching Triton" was developed as a serious game in which students are asked to analyze data from a medical record, family history, and genomic report in order to develop an overall lifetime risk estimate of six common, complex diseases. Evaluation of student performance shows significant learning gains in key content areas along with a high level of engagement.

ATG16L1: A multifunctional susceptibility factor in Crohn disease

PubMed Central

Salem, Mohammad; Ammitzboell, Mette; Nys, Kris; Seidelin, Jakob Benedict; Nielsen, Ole Haagen

2015-01-01

Genetic variations in the autophagic pathway influence genetic predispositions to Crohn disease. Autophagy, the major lysosomal pathway for degrading and recycling cytoplasmic material, constitutes an important homeostatic cellular process. Of interest, single-nucleotide polymorphisms in ATG16L1 (autophagy-related 16-like 1 [S. cerevisiae]), a key component in the autophagic response to invading pathogens, have been associated with an increased risk of developing Crohn disease. The most common and well-studied genetic variant of ATG16L1 (rs2241880; leading to a T300A conversion) exhibits a strong association with risk for developing Crohn disease. The rs2241880 variant plays a crucial role in pathogen clearance, resulting in imbalanced cytokine production, and is linked to other biological processes, such as the endoplasmic reticulum stress/unfolded protein response. In this review, we focus on the importance of ATG16L1 and its genetic variant (T300A) within the elementary biological processes linked to Crohn disease. PMID:25906181

ATG16L1: A multifunctional susceptibility factor in Crohn disease.

PubMed

Salem, Mohammad; Ammitzboell, Mette; Nys, Kris; Seidelin, Jakob Benedict; Nielsen, Ole Haagen

2015-04-03

Genetic variations in the autophagic pathway influence genetic predispositions to Crohn disease. Autophagy, the major lysosomal pathway for degrading and recycling cytoplasmic material, constitutes an important homeostatic cellular process. Of interest, single-nucleotide polymorphisms in ATG16L1 (autophagy-related 16-like 1 [S. cerevisiae]), a key component in the autophagic response to invading pathogens, have been associated with an increased risk of developing Crohn disease. The most common and well-studied genetic variant of ATG16L1 (rs2241880; leading to a T300A conversion) exhibits a strong association with risk for developing Crohn disease. The rs2241880 variant plays a crucial role in pathogen clearance, resulting in imbalanced cytokine production, and is linked to other biological processes, such as the endoplasmic reticulum stress/unfolded protein response. In this review, we focus on the importance of ATG16L1 and its genetic variant (T300A) within the elementary biological processes linked to Crohn disease.

Cluster headache and the hypocretin receptor 2 reconsidered: a genetic association study and meta-analysis.

PubMed

Weller, Claudia M; Wilbrink, Leopoldine A; Houwing-Duistermaat, Jeanine J; Koelewijn, Stephany C; Vijfhuizen, Lisanne S; Haan, Joost; Ferrari, Michel D; Terwindt, Gisela M; van den Maagdenberg, Arn M J M; de Vries, Boukje

2015-08-01

Cluster headache is a severe neurological disorder with a complex genetic background. A missense single nucleotide polymorphism (rs2653349; p.Ile308Val) in the HCRTR2 gene that encodes the hypocretin receptor 2 is the only genetic factor that is reported to be associated with cluster headache in different studies. However, as there are conflicting results between studies, we re-evaluated its role in cluster headache. We performed a genetic association analysis for rs2653349 in our large Leiden University Cluster headache Analysis (LUCA) program study population. Systematic selection of the literature yielded three additional studies comprising five study populations, which were included in our meta-analysis. Data were extracted according to predefined criteria. A total of 575 cluster headache patients from our LUCA study and 874 controls were genotyped for HCRTR2 SNP rs2653349 but no significant association with cluster headache was found (odds ratio 0.91 (95% confidence intervals 0.75-1.10), p = 0.319). In contrast, the meta-analysis that included in total 1167 cluster headache cases and 1618 controls from the six study populations, which were part of four different studies, showed association of the single nucleotide polymorphism with cluster headache (random effect odds ratio 0.69 (95% confidence intervals 0.53-0.90), p = 0.006). The association became weaker, as the odds ratio increased to 0.80, when the meta-analysis was repeated without the initial single South European study with the largest effect size. Although we did not find evidence for association of rs2653349 in our LUCA study, which is the largest investigated study population thus far, our meta-analysis provides genetic evidence for a role of HCRTR2 in cluster headache. Regardless, we feel that the association should be interpreted with caution as meta-analyses with individual populations that have limited power have diminished validity. © International Headache Society 2014.

Associations of smoking and age with inflammatory joint signs among first-degree relatives without rheumatoid arthritis: Results from the Studies of the Etiology of RA

PubMed Central

Sparks, Jeffrey A.; Chang, Shun-Chiao; Deane, Kevin D.; Gan, Ryan W.; Demoruelle, M. Kristen; Feser, Marie L.; Moss, LauraKay; Buckner, Jane H.; Keating, Richard M.; Costenbader, Karen H.; Gregersen, Peter K.; Weisman, Michael H.; Mikuls, Ted R.; O’Dell, James R.; Holers, V. Michael; Norris, Jill M.; Karlson, Elizabeth W.

2016-01-01

Objective To examine whether genetic, environmental, and serologic rheumatoid arthritis (RA) risk factors are associated with inflammatory joint signs (IJS) in a cohort of RA first-degree relatives (FDRs). Methods We evaluated RA risk factors and IJS in a prospective cohort of FDRs without RA in the Studies of the Etiology of RA. Genetic factors included five HLA-DRB1 shared epitope alleles and 45 RA-associated single nucleotide polymorphisms; loci were combined using genetic risk scores (GRS) weighted by RA risk. Environmental factors (smoking, body mass index, education, and parity) and RA-related autoantibodies were assessed at baseline. Physical examination at baseline and two-year follow-up by observers blinded to autoantibody status assessed IJS as tender or swollen joints at sites typical for RA. Logistic regression was performed to evaluate associations of genetic, environmental, and serologic factors with IJS. Results We analyzed 966 non-Hispanic white FDRs at baseline and 262 at two-year follow-up after excluding those with IJS at baseline. Mean age was 47.2 years (SD 15.5), 71% were female, and 55% were shared epitope-positive. Smoking >10 pack-years was associated with IJS at baseline (OR 1.59, 95%CI 1.09–2.32) and at 2 years (OR 2.66, 95%CI 1.01–7.03), compared to never smokers. Smoking and age significantly interacted for risk of IJS (p=0.02). FDRs aged <50 years with >10 pack-years had the highest risk of IJS (OR 4.39, 95%CI 2.22–8.66) compared to never smokers aged <50 years). Conclusion In a high-risk cohort of FDRs, smoking and age were associated with both prevalent and incident IJS at sites typical for RA. Further prospective investigations of the factors affecting the transitions between pre-clinical RA phases are warranted. PMID:26866831

Nuclear and mitochondrial genetic structure in the Eurasian beaver (Castor fiber) – implications for future reintroductions

PubMed Central

Senn, Helen; Ogden, Rob; Frosch, Christiane; Syrůčková, Alena; Campbell-Palmer, Roisin; Munclinger, Pavel; Durka, Walter; Kraus, Robert H S; Saveljev, Alexander P; Nowak, Carsten; Stubbe, Annegret; Stubbe, Michael; Michaux, Johan; Lavrov, Vladimir; Samiya, Ravchig; Ulevicius, Alius; Rosell, Frank

2014-01-01

Many reintroduction projects for conservation fail, and there are a large number of factors that may contribute to failure. Genetic analysis can be used to help stack the odds of a reintroduction in favour of success, by conducting assessment of source populations to evaluate the possibility of inbreeding and outbreeding depression and by conducting postrelease monitoring. In this study, we use a panel of 306 SNP (single nucleotide polymorphism) markers and 487–489 base pairs of mitochondrial DNA control region sequence data to examine 321 individuals from possible source populations of the Eurasian beaver for a reintroduction to Scotland. We use this information to reassess the phylogenetic history of the Eurasian beavers, to examine the genetic legacy of past reintroductions on the Eurasian landmass and to assess the future power of the genetic markers to conduct ongoing monitoring via parentage analysis and individual identification. We demonstrate the capacity of medium density genetic data (hundreds of SNPs) to provide information suitable for applied conservation and discuss the difficulty of balancing the need for high genetic diversity against phylogenetic best fit when choosing source population(s) for reintroduction. PMID:25067948

The Genetics of Infertility: Current Status of the Field

PubMed Central

Zorrilla, Michelle; Yatsenko, Alexander N

2013-01-01

Infertility is a relatively common health condition, affecting nearly 7% of all couples. Clinically, it is a highly heterogeneous pathology with a complex etiology that includes environmental and genetic factors. It has been estimated that nearly 50% of infertility cases are due to genetic defects. Hundreds of studies with animal knockout models convincingly showed infertility to be caused by gene defects, single or multiple. However, despite enormous efforts, progress in translating basic research findings into clinical studies has been challenging. The genetic causes remain unexplained for the vast majority of male or female infertility patients. A particular difficulty is the huge number of candidate genes to be studied; there are more than 2,300 genes expressed in the testis alone, and hundreds of those genes influence reproductive function in humans and could contribute to male infertility. At present, there are only a handful of genes or genetic defects that have been shown to cause, or to be strongly associated with, primary infertility. Yet, with completion of the human genome and progress in personalized medicine, the situation is rapidly changing. Indeed, there are 10-15 new gene tests, on average, being added to the clinical genetic testing list annually. PMID:24416713

Epigenetic and genetic variants in the HTR1B gene and clinical improvement in children and adolescents treated with fluoxetine.

PubMed

Gassó, Patricia; Rodríguez, Natalia; Blázquez, Ana; Monteagudo, Ana; Boloc, Daniel; Plana, Maria Teresa; Lafuente, Amalia; Lázaro, Luisa; Arnaiz, Joan Albert; Mas, Sergi

2017-04-03

The serotonin 1B receptor (5-HT 1B ) is important to both the pathogenesis of major depressive disorder and the antidepressant effects of selective serotonin reuptake inhibitors. Although fluoxetine has been shown to be effective and safe in children and adolescents, not all patients experience a proper clinical response, which has led to further study into the main factors involved in this inter-individual variability. Our aim was to study the effect of epigenetic and genetic factors that could affect 5-hydroxytryptamine receptor 1B (HTR1B) gene expression, and thereby response to fluoxetine. A total of 83 children and adolescents were clinically assessed 12weeks after of initiating an antidepressant treatment with fluoxetine for the first time. We evaluated the influence of single nucleotide polymorphisms (SNPs) specifically located in transcription factor binding sites (TFBSs) on their clinical improvement. A combined genetic analysis considering the significant SNPs together with the functional variant rs130058 previously associated in our population was also performed. Moreover, we assessed, for the first time in the literature, whether methylation levels of the HTR1B promoter region could be associated with the pharmacological response. Two, rs9361233 and rs9361235, were significantly associated with clinical improvement after treatment with fluoxetine. The heterozygous genotype combination analysis showed a negative correlation with clinical improvement. The lowest improvement was experienced by patients who were heterozygous for all three SNPs. Moreover, a negative correlation was found between clinical improvement and the average methylation level of the HTR1B promoter. These results give new evidence for the role of epigenetic and genetic factors which could modulate HTR1B expression in the pharmacological response to antidepressants. Copyright © 2016 Elsevier Inc. All rights reserved.

Complete genomic screen in Parkinson disease: evidence for multiple genes.

PubMed

Scott, W K; Nance, M A; Watts, R L; Hubble, J P; Koller, W C; Lyons, K; Pahwa, R; Stern, M B; Colcher, A; Hiner, B C; Jankovic, J; Ondo, W G; Allen, F H; Goetz, C G; Small, G W; Masterman, D; Mastaglia, F; Laing, N G; Stajich, J M; Slotterbeck, B; Booze, M W; Ribble, R C; Rampersaud, E; West, S G; Gibson, R A; Middleton, L T; Roses, A D; Haines, J L; Scott, B L; Vance, J M; Pericak-Vance, M A

2001-11-14

The relative contribution of genes vs environment in idiopathic Parkinson disease (PD) is controversial. Although genetic studies have identified 2 genes in which mutations cause rare single-gene variants of PD and observational studies have suggested a genetic component, twin studies have suggested that little genetic contribution exists in the common forms of PD. To identify genetic risk factors for idiopathic PD. Genetic linkage study conducted 1995-2000 in which a complete genomic screen (n = 344 markers) was performed in 174 families with multiple individuals diagnosed as having idiopathic PD, identified through probands in 13 clinic populations in the continental United States and Australia. A total of 870 family members were studied: 378 diagnosed as having PD, 379 unaffected by PD, and 113 with unclear status. Logarithm of odds (lod) scores generated from parametric and nonparametric genetic linkage analysis. Two-point parametric maximum parametric lod score (MLOD) and multipoint nonparametric lod score (LOD) linkage analysis detected significant evidence for linkage to 5 distinct chromosomal regions: chromosome 6 in the parkin gene (MLOD = 5.07; LOD = 5.47) in families with at least 1 individual with PD onset at younger than 40 years, chromosomes 17q (MLOD = 2.28; LOD = 2.62), 8p (MLOD = 2.01; LOD = 2.22), and 5q (MLOD = 2.39; LOD = 1.50) overall and in families with late-onset PD, and chromosome 9q (MLOD = 1.52; LOD = 2.59) in families with both levodopa-responsive and levodopa-nonresponsive patients. Our data suggest that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic late-onset PD.

Investigating shared aetiology between type 2 diabetes and major depressive disorder in a population based cohort.

PubMed

Clarke, Toni-Kim; Obsteter, Jana; Hall, Lynsey S; Hayward, Caroline; Thomson, Pippa A; Smith, Blair H; Padmanabhan, Sandosh; Hocking, Lynne J; Deary, Ian J; Porteous, David J; McIntosh, Andrew M

2017-04-01

Type II diabetes (T2D) and major depressive disorder (MDD) are often co-morbid. The reasons for this co-morbidity are unclear. Some studies have highlighted the importance of environmental factors and a causal relationship between T2D and MDD has also been postulated. In the present study we set out to investigate the shared aetiology between T2D and MDD using Mendelian randomization in a population based sample, Generation Scotland: the Scottish Family Health Study (N = 21,516). Eleven SNPs found to be associated with T2D were tested for association with MDD and psychological distress (General Health Questionnaire scores). We also assessed causality and genetic overlap between T2D and MDD using polygenic risk scores (PRS) assembled from the largest available GWAS summary statistics to date. No single T2D risk SNP was associated with MDD in the MR analyses and we did not find consistent evidence of genetic overlap between MDD and T2D in the PRS analyses. Linkage disequilibrium score regression analyses supported these findings as no genetic correlation was observed between T2D and MDD (rG = 0.0278 (S.E. 0.11), P-value = 0.79). As suggested by previous studies, T2D and MDD covariance may be better explained by environmental factors. Future studies would benefit from analyses in larger cohorts where stratifying by sex and looking more closely at MDD cases demonstrating metabolic dysregulation is possible. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

The Value of Extended Pedigrees for Next-Generation Analysis of Complex Disease in the Rhesus Macaque

PubMed Central

Vinson, Amanda; Prongay, Kamm; Ferguson, Betsy

2013-01-01

Complex diseases (e.g., cardiovascular disease and type 2 diabetes, among many others) pose the biggest threat to human health worldwide and are among the most challenging to investigate. Susceptibility to complex disease may be caused by multiple genetic variants (GVs) and their interaction, by environmental factors, and by interaction between GVs and environment, and large study cohorts with substantial analytical power are typically required to elucidate these individual contributions. Here, we discuss the advantages of both power and feasibility afforded by the use of extended pedigrees of rhesus macaques (Macaca mulatta) for genetic studies of complex human disease based on next-generation sequence data. We present these advantages in the context of previous research conducted in rhesus macaques for several representative complex diseases. We also describe a single, multigeneration pedigree of Indian-origin rhesus macaques and a sample biobank we have developed for genetic analysis of complex disease, including power of this pedigree to detect causal GVs using either genetic linkage or association methods in a variance decomposition approach. Finally, we summarize findings of significant heritability for a number of quantitative traits that demonstrate that genetic contributions to risk factors for complex disease can be detected and measured in this pedigree. We conclude that the development and application of an extended pedigree to analysis of complex disease traits in the rhesus macaque have shown promising early success and that genome-wide genetic and higher order -omics studies in this pedigree are likely to yield useful insights into the architecture of complex human disease. PMID:24174435

Telomeres and replicative senescence: Is it only length that counts?

PubMed

von Zglinicki, T

2001-07-26

Telomeres are well established as a major 'replicometer', counting the population doublings in primary human cell cultures and ultimately triggering replicative senescence. However, neither is the pace of this biological clock inert, nor is there a fixed threshold telomere length acting as the universal trigger of replicative senescence. The available data suggest that opening of the telomeric loop and unscheduled exposure of the single-stranded G-rich telomeric overhang might act like a semaphore to signal senescent cell cycle arrest. Short telomere length, telomeric single-strand breaks, low levels of loop-stabilizing proteins, or other factors may trigger this opening of the loop. Thus, both telomere shortening and the ultimate signalling into senescence are able to integrate different environmental and genetic factors, especially oxidative stress-mediated damage, which might otherwise become a thread to genomic stability.

Perceived health from biological motion predicts voting behaviour.

PubMed

Kramer, Robin S S; Arend, Isabel; Ward, Robert

2010-04-01

Body motion signals socially relevant traits like the sex, age, and even the genetic quality of actors and may therefore facilitate various social judgements. By examining ratings and voting decisions based solely on body motion of political candidates, we considered how the candidates' motion affected people's judgements and voting behaviour. In two experiments, participants viewed stick figure motion displays made from videos of politicians in public debate. Participants rated the motion displays for a variety of social traits and then indicated their vote preference. In both experiments, perceived physical health was the single best predictor of vote choice, and no two-factor model produced significant improvement. Notably, although attractiveness and leadership correlated with voting behaviour, neither provided additional explanatory power to a single-factor model of health alone. Our results demonstrate for the first time that motion can produce systematic vote preferences.

Studies on the nature and managment of psoriasis.

PubMed

Farber, E M

1971-06-01

Prevalence of psoriasis in Caucasians is estimated as 2 to 3 percent. Sound epidemiologic studies on a worldwide basis are needed to secure accurate prevalence rates for comparative purposes. Utilizing Stanford's psoriasis life histories records, the genetics of psoriasis has been explored by various means: statistical census data, pedigree analysis, and twin studies. This research suggests a multifactorial pattern of inheritance for psoriasis, implying that both genetic and environmental components are responsible for the manifestation of the disease. At present it is not possible to point to any single causative factor. Some of the suggested areas for research include study of uninvolved skin, growth control in the psoriatic lesion, viral causes, immunological aspects, and lipid metabolism.

Advances in research on and diagnosis and treatment of achondroplasia in China

PubMed Central

Wang, Yao; Liu, Zeying; Liu, Zhenxing; Zhao, Heng; Zhou, Xiaoyan; Cui, Yazhou; Han, Jinxiang

2013-01-01

Summary Achondroplasia is a rare autosomal dominant genetic disease. Research on achondroplasia in China, however, has received little emphasis. Around 80–90% of cases of neonatal achondroplasia result from mutations in fibroblast growth factor receptor 3 (FGFR3) according to polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). Recently, genetic research on achondroplasia in China made a major breakthrough by revealing two novel mutations located on the FGFR3 gene, thus helping to complete the pathological molecular map of achondroplasia. There are still, however, unknown aspects of the diagnosis and treatment of achondroplasia. This review will summarize advances in research on and the clinical diagnosis and treatment of achondroplasia in China. PMID:25343101

Rationale, Design, and Methodological Aspects of the BUDAPEST-GLOBAL Study (Burden of Atherosclerotic Plaques Study in Twins-Genetic Loci and the Burden of Atherosclerotic Lesions).

PubMed

Maurovich-Horvat, Pál; Tárnoki, Dávid L; Tárnoki, Ádám D; Horváth, Tamás; Jermendy, Ádám L; Kolossváry, Márton; Szilveszter, Bálint; Voros, Viktor; Kovács, Attila; Molnár, Andrea Á; Littvay, Levente; Lamb, Hildo J; Voros, Szilard; Jermendy, György; Merkely, Béla

2015-12-01

The heritability of coronary atherosclerotic plaque burden, coronary geometry, and phenotypes associated with increased cardiometabolic risk are largely unknown. The primary aim of the Burden of Atherosclerotic Plaques Study in Twins-Genetic Loci and the Burden of Atherosclerotic Lesions (BUDAPEST-GLOBAL) study is to evaluate the influence of genetic and environmental factors on the burden of coronary artery disease. By design this is a prospective, single-center, classical twin study. In total, 202 twins (61 monozygotic pairs, 40 dizygotic same-sex pairs) were enrolled from the Hungarian Twin Registry database. All twins underwent non-contrast-enhanced computed tomography (CT) for the detection and quantification of coronary artery calcium and for the measurement of epicardial fat volumes. In addition, a single non-contrast-enhanced image slice was acquired at the level of L3-L4 to assess abdominal fat distribution. Coronary CT angiography was used for the detection and quantification of plaque, stenosis, and overall coronary artery disease burden. For the primary analysis, we will assess the presence and volume of atherosclerotic plaques. Furthermore, the 3-dimensional coronary geometry will be assessed based on the coronary CT angiography datasets. Additional phenotypic analyses will include per-patient epicardial and abdominal fat quantity measurements. Measurements obtained from monozygotic and dizygotic twin pairs will be compared to evaluate the genetic or environmental effects of the given phenotype. The BUDAPEST-GLOBAL study provides a unique framework to shed some light on the genetic and environmental influences of cardiometabolic disorders. © 2015 Wiley Periodicals, Inc.

Application of Carbon Nanotubes for Plant Genetic Transformation

NASA Astrophysics Data System (ADS)

Burlaka, Olga M.; Pirko, Yaroslav V.; Yemets, Alla I.; Blume, Yaroslav B.

In this chapter, the current state of using carbon nanotubes (CNTs; single- and multi-walled) that have attracted great interdisciplinary interest in recent decades due to their peculiar properties for genetic transformation of prokaryotic and eukaryotic cells will be enlightened. The covalent and non-covalent surface chemistry for the CNT functionalization with focus on the potential applications of surface modifications in design of biocompatible CNTs will be discussed. The properties of CNTs that are favorable for biotechnological use and current status of technical approaches that allow the increase in biocompatibility and lower nanotoxicity of engineered CNTs will be described. Decisions proposed by non-covalent surface modification of CNTs will be discussed. Existing data concerning mechanisms of CNT cell entry and factors governing toxicity, cellular uptake, intracellular traffic, and biodegradation of CNTs along with bioavailability of molecular cargoes of loaded CNTs will be discussed. Eco-friendly production of water dispersions of biologically functionalized multi-walled and single-walled CNTs for use as nano-vehicles for the DNA delivery in plant genetic transformation of plants will be described. The background, advantages, and problems of using CNTs in developing of novel methods of genetic transformation, including plant genetic transformation, will be highlighted. Special attention will be paid to the limitations of conventional gene transfer techniques and promising features of CNT-based strategies having improved efficacy, reproducibility, and accuracy along with less time consumption. Issues impeding manipulation of CNTs such as entangled bundle formation, low water solubility, inert properties of pristine CNTs, etc., and ways to solve arising tasks will be overviewed.

Tumour Heterogeneity: The Key Advantages of Single-Cell Analysis

PubMed Central

Tellez-Gabriel, Marta; Ory, Benjamin; Lamoureux, Francois; Heymann, Marie-Francoise; Heymann, Dominique

2016-01-01

Tumour heterogeneity refers to the fact that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation and metastatic potential. This phenomenon occurs both between tumours (inter-tumour heterogeneity) and within tumours (intra-tumour heterogeneity), and it is caused by genetic and non-genetic factors. The heterogeneity of cancer cells introduces significant challenges in using molecular prognostic markers as well as for classifying patients that might benefit from specific therapies. Thus, research efforts for characterizing heterogeneity would be useful for a better understanding of the causes and progression of disease. It has been suggested that the study of heterogeneity within Circulating Tumour Cells (CTCs) could also reflect the full spectrum of mutations of the disease more accurately than a single biopsy of a primary or metastatic tumour. In previous years, many high throughput methodologies have raised for the study of heterogeneity at different levels (i.e., RNA, DNA, protein and epigenetic events). The aim of the current review is to stress clinical implications of tumour heterogeneity, as well as current available methodologies for their study, paying specific attention to those able to assess heterogeneity at the single cell level. PMID:27999407

Association between a polymorphism in the IL-12p40 gene and cytomegalovirus reactivation after kidney transplantation.

PubMed

Hoffmann, Thomas W; Halimi, Jean-Michel; Büchler, Mathias; Velge-Roussel, Florence; Goudeau, Alain; Al Najjar, Azmi; Boulanger, Marie-Denise; Houssaini, Tarik Sqalli; Marliere, Jean-Frédéric; Lebranchu, Yvon; Baron, Christophe

2008-05-27

Cytomegalovirus (CMV) infection is associated with a significant rate of morbidity after organ transplantation. The genetic factors influencing its occurrence have been little investigated. IL-12 plays a crucial role in anti-infectious immune responses, especially by stimulating IFNgamma production. An A-to-C single nucleotide polymorphism (SNP) within the 3'-untranslated region of the IL-12p40 gene has been characterized and was reported to be both functionally and clinically relevant. However, the impact of this single nucleotide polymorphism on events after organ transplantation has never been reported. In this study, we investigated the impact of the 3'-untranslated region polymorphism on the occurrence of CMV infection in 469 kidney recipients transplanted at the University Hospital of Tours between 1995 and 2005. The polymorphism was genotyped using the restriction fragment length polymorphism method and CMV infection was determined by pp65 antigenemia. Multifactorial Cox regression analysis demonstrated that the presence of the C allele was an independent risk factor for CMV infection (OR=1.52, P=0.043), the risk being even higher when study was restricted to patients with positive CMV serological status before the graft and who did not receive any CMV prophylaxis (OR=1.88, P=0.028). This study identified a new genetic risk factor for CMV reactivation after kidney transplantation. The results of our study suggest that C carriers might especially benefit from CMV prophylaxis.

Proton Nuclear Magnetic Resonance-Spectroscopic Discrimination of Wines Reflects Genetic Homology of Several Different Grape (V. vinifera L.) Cultivars

PubMed Central

Zhu, Yong; Wen, Wen; Zhang, Fengmin; Hardie, Jim W.

2015-01-01

Background and Aims Proton nuclear magnetic resonance spectroscopy coupled multivariate analysis (1H NMR-PCA/PLS-DA) is an important tool for the discrimination of wine products. Although 1H NMR has been shown to discriminate wines of different cultivars, a grape genetic component of the discrimination has been inferred only from discrimination of cultivars of undefined genetic homology and in the presence of many confounding environmental factors. We aimed to confirm the influence of grape genotypes in the absence of those factors. Methods and Results We applied 1H NMR-PCA/PLS-DA and hierarchical cluster analysis (HCA) to wines from five, variously genetically-related grapevine (V. vinifera) cultivars; all grown similarly on the same site and vinified similarly. We also compared the semi-quantitative profiles of the discriminant metabolites of each cultivar with previously reported chemical analyses. The cultivars were clearly distinguishable and there was a general correlation between their grouping and their genetic homology as revealed by recent genomic studies. Between cultivars, the relative amounts of several of the cultivar-related discriminant metabolites conformed closely with reported chemical analyses. Conclusions Differences in grape-derived metabolites associated with genetic differences alone are a major source of 1H NMR-based discrimination of wines and 1H NMR has the capacity to discriminate between very closely related cultivars. Significance of the Study The study confirms that genetic variation among grape cultivars alone can account for the discrimination of wine by 1H NMR-PCA/PLS and indicates that 1H NMR spectra of wine of single grape cultivars may in future be used in tandem with hierarchical cluster analysis to elucidate genetic lineages and metabolomic relations of grapevine cultivars. In the absence of genetic information, for example, where predecessor varieties are no longer extant, this may be a particularly useful approach. PMID:26658757

Testing the genetic predictions of a biogeographical model in a dominant endemic Eastern Pacific coral (Porites panamensis) using a genetic seascape approach

PubMed Central

Saavedra-Sotelo, Nancy C; Calderon-Aguilera, Luis E; Reyes-Bonilla, Héctor; Paz-García, David A; López-Pérez, Ramón A; Cupul-Magaña, Amilcar; Cruz-Barraza, José A; Rocha-Olivares, Axayácatl

2013-01-01

The coral fauna of the Eastern Tropical Pacific (ETP) is depauperate and peripheral; hence, it has drawn attention to the factors allowing its survival. Here, we use a genetic seascape approach and ecological niche modeling to unravel the environmental factors correlating with the genetic variation of Porites panamensis, a hermatypic coral endemic to the ETP. Specifically, we test if levels of diversity and connectivity are higher among abundant than among depauperate populations, as expected by a geographically relaxed version of the Abundant Center Hypothesis (rel-ACH). Unlike the original ACH, referring to a geographical center of distribution of maximal abundance, the rel-ACH refers only to a center of maximum abundance, irrespective of its geographic position. The patterns of relative abundance of P. panamensis in the Mexican Pacific revealed that northern populations from Baja California represent its center of abundance; and southern depauperate populations along the continental margin are peripheral relative to it. Genetic patterns of diversity and structure of nuclear DNA sequences (ribosomal DNA and a single copy open reading frame) and five alloenzymatic loci partially agreed with rel-ACH predictions. We found higher diversity levels in peninsular populations and significant differentiation between peninsular and continental colonies. In addition, continental populations showed higher levels of differentiation and lower connectivity than peninsular populations in the absence of isolation by distance in each region. Some discrepancies with model expectations may relate to the influence of significant habitat discontinuities in the face of limited dispersal potential. Environmental data analyses and niche modeling allowed us to identify temperature, water clarity, and substrate availability as the main factors correlating with patterns of abundance, genetic diversity, and structure, which may hold the key to the survival of P. panamensis in the face of widespread environmental degradation. PMID:24324860

Gene-environment interactions and construct validity in preclinical models of psychiatric disorders.

PubMed

Burrows, Emma L; McOmish, Caitlin E; Hannan, Anthony J

2011-08-01

The contributions of genetic risk factors to susceptibility for brain disorders are often so closely intertwined with environmental factors that studying genes in isolation cannot provide the full picture of pathogenesis. With recent advances in our understanding of psychiatric genetics and environmental modifiers we are now in a position to develop more accurate animal models of psychiatric disorders which exemplify the complex interaction of genes and environment. Here, we consider some of the insights that have emerged from studying the relationship between defined genetic alterations and environmental factors in rodent models. A key issue in such animal models is the optimization of construct validity, at both genetic and environmental levels. Standard housing of laboratory mice and rats generally includes ad libitum food access and limited opportunity for physical exercise, leading to metabolic dysfunction under control conditions, and thus reducing validity of animal models with respect to clinical populations. A related issue, of specific relevance to neuroscientists, is that most standard-housed rodents have limited opportunity for sensory and cognitive stimulation, which in turn provides reduced incentive for complex motor activity. Decades of research using environmental enrichment has demonstrated beneficial effects on brain and behavior in both wild-type and genetically modified rodent models, relative to standard-housed littermate controls. One interpretation of such studies is that environmentally enriched animals more closely approximate average human levels of cognitive and sensorimotor stimulation, whereas the standard housing currently used in most laboratories models a more sedentary state of reduced mental and physical activity and abnormal stress levels. The use of such standard housing as a single environmental variable may limit the capacity for preclinical models to translate into successful clinical trials. Therefore, there is a need to optimize 'environmental construct validity' in animal models, while maintaining comparability between laboratories, so as to ensure optimal scientific and medical outcomes. Utilizing more sophisticated models to elucidate the relative contributions of genetic and environmental factors will allow for improved construct, face and predictive validity, thus facilitating the identification of novel therapeutic targets. Copyright © 2010 Elsevier Inc. All rights reserved.

Anatomy of the Skin and the Pathogenesis of Nonmelanoma Skin Cancer.

PubMed

Losquadro, William D

2017-08-01

Skin is composed of the epidermis, dermis, and adnexal structures. The epidermis is composed of 4 layers-the stratums basale, spinosum, granulosum, and corneum. The dermis is divided into a superficial papillary dermis and deeper reticular dermis. Collagen and elastin within the reticular dermis are responsible for skin tensile strength and elasticity, respectively. The 2 most common kinds of nonmelanoma skin cancers are basal cell and squamous cell carcinoma. Both are caused by a host of environmental and genetic factors, although UV light exposure is the single greatest predisposing factor. Copyright © 2017 Elsevier Inc. All rights reserved.

Population structure and landscape genetics of two endangered frog species of genus Odorrana: different scenarios on two islands

PubMed Central

Igawa, T; Oumi, S; Katsuren, S; Sumida, M

2013-01-01

Isolation by distance and landscape connectivity are fundamental factors underlying speciation and evolution. To understand how landscapes affect gene flow and shape population structures, island species provide intrinsic study objects. We investigated the effects of landscapes on the population structure of the endangered frog species, Odorrana ishikawae and O. splendida, which each inhabit an island in southwest Japan. This was done by examining population structure, gene flow and demographic history of each species by analyzing 12 microsatellite loci and exploring causal environmental factors through ecological niche modeling (ENM) and the cost-distance approach. Our results revealed that the limited gene flow and multiple-population structure in O. splendida and the single-population structure in O. ishikawae were maintained after divergence of the species through ancient vicariance between islands. We found that genetic distance correlated with geographic distance between populations of both species. Our landscape genetic analysis revealed that the connectivity of suitable habitats influences gene flow and leads to the formation of specific population structures. In particular, different degrees of topographical complexity between islands are the major determining factor for shaping contrasting population structures of two species. In conclusion, our results illustrate the diversification mechanism of organisms through the interaction with space and environment. Our results also present an ENM approach for identifying the key factors affecting demographic history and population structures of target species, especially endangered species. PMID:22990312

The Major Genetic Determinants of HIV-1 Control Affect HLA Class I Peptide Presentation

PubMed Central

Pereyra, Florencia; Jia, Xiaoming; McLaren, Paul J.; Telenti, Amalio; de Bakker, Paul I.W.; Walker, Bruce D.; Jia, Xiaoming; McLaren, Paul J.; Ripke, Stephan; Brumme, Chanson J.; Pulit, Sara L.; Telenti, Amalio; Carrington, Mary; Kadie, Carl M.; Carlson, Jonathan M.; Heckerman, David; de Bakker, Paul I.W.; Pereyra, Florencia; de Bakker, Paul I.W.; Graham, Robert R.; Plenge, Robert M.; Deeks, Steven G.; Walker, Bruce D.; Gianniny, Lauren; Crawford, Gabriel; Sullivan, Jordan; Gonzalez, Elena; Davies, Leela; Camargo, Amy; Moore, Jamie M.; Beattie, Nicole; Gupta, Supriya; Crenshaw, Andrew; Burtt, Noël P.; Guiducci, Candace; Gupta, Namrata; Carrington, Mary; Gao, Xiaojiang; Qi, Ying; Yuki, Yuko; Pereyra, Florencia; Piechocka-Trocha, Alicja; Cutrell, Emily; Rosenberg, Rachel; Moss, Kristin L.; Lemay, Paul; O’Leary, Jessica; Schaefer, Todd; Verma, Pranshu; Toth, Ildiko; Block, Brian; Baker, Brett; Rothchild, Alissa; Lian, Jeffrey; Proudfoot, Jacqueline; Alvino, Donna Marie L.; Vine, Seanna; Addo, Marylyn M.; Allen, Todd M.; Altfeld, Marcus; Henn, Matthew R.; Le Gall, Sylvie; Streeck, Hendrik; Walker, Bruce D.; Haas, David W.; Kuritzkes, Daniel R.; Robbins, Gregory K.; Shafer, Robert W.; Gulick, Roy M.; Shikuma, Cecilia M.; Haubrich, Richard; Riddler, Sharon; Sax, Paul E.; Daar, Eric S.; Ribaudo, Heather J.; Agan, Brian; Agarwal, Shanu; Ahern, Richard L.; Allen, Brady L.; Altidor, Sherly; Altschuler, Eric L.; Ambardar, Sujata; Anastos, Kathryn; Anderson, Ben; Anderson, Val; Andrady, Ushan; Antoniskis, Diana; Bangsberg, David; Barbaro, Daniel; Barrie, William; Bartczak, J.; Barton, Simon; Basden, Patricia; Basgoz, Nesli; Bazner, Suzane; Bellos, Nicholaos C.; Benson, Anne M.; Berger, Judith; Bernard, Nicole F.; Bernard, Annette M.; Birch, Christopher; Bodner, Stanley J.; Bolan, Robert K.; Boudreaux, Emilie T.; Bradley, Meg; Braun, James F.; Brndjar, Jon E.; Brown, Stephen J.; Brown, Katherine; Brown, Sheldon T.; Burack, Jedidiah; Bush, Larry M.; Cafaro, Virginia; Campbell, Omobolaji; Campbell, John; Carlson, Robert H.; Carmichael, J. Kevin; Casey, Kathleen K.; Cavacuiti, Chris; Celestin, Gregory; Chambers, Steven T.; Chez, Nancy; Chirch, Lisa M.; Cimoch, Paul J.; Cohen, Daniel; Cohn, Lillian E.; Conway, Brian; Cooper, David A.; Cornelson, Brian; Cox, David T.; Cristofano, Michael V.; Cuchural, George; Czartoski, Julie L.; Dahman, Joseph M.; Daly, Jennifer S.; Davis, Benjamin T.; Davis, Kristine; Davod, Sheila M.; Deeks, Steven G.; DeJesus, Edwin; Dietz, Craig A.; Dunham, Eleanor; Dunn, Michael E.; Ellerin, Todd B.; Eron, Joseph J.; Fangman, John J.W.; Farel, Claire E.; Ferlazzo, Helen; Fidler, Sarah; Fleenor-Ford, Anita; Frankel, Renee; Freedberg, Kenneth A.; French, Neel K.; Fuchs, Jonathan D.; Fuller, Jon D.; Gaberman, Jonna; Gallant, Joel E.; Gandhi, Rajesh T.; Garcia, Efrain; Garmon, Donald; Gathe, Joseph C.; Gaultier, Cyril R.; Gebre, Wondwoosen; Gilman, Frank D.; Gilson, Ian; Goepfert, Paul A.; Gottlieb, Michael S.; Goulston, Claudia; Groger, Richard K.; Gurley, T. Douglas; Haber, Stuart; Hardwicke, Robin; Hardy, W. David; Harrigan, P. Richard; Hawkins, Trevor N.; Heath, Sonya; Hecht, Frederick M.; Henry, W. Keith; Hladek, Melissa; Hoffman, Robert P.; Horton, James M.; Hsu, Ricky K.; Huhn, Gregory D.; Hunt, Peter; Hupert, Mark J.; Illeman, Mark L.; Jaeger, Hans; Jellinger, Robert M.; John, Mina; Johnson, Jennifer A.; Johnson, Kristin L.; Johnson, Heather; Johnson, Kay; Joly, Jennifer; Jordan, Wilbert C.; Kauffman, Carol A.; Khanlou, Homayoon; Killian, Robert K.; Kim, Arthur Y.; Kim, David D.; Kinder, Clifford A.; Kirchner, Jeffrey T.; Kogelman, Laura; Kojic, Erna Milunka; Korthuis, P. Todd; Kurisu, Wayne; Kwon, Douglas S.; LaMar, Melissa; Lampiris, Harry; Lanzafame, Massimiliano; Lederman, Michael M.; Lee, David M.; Lee, Jean M.L.; Lee, Marah J.; Lee, Edward T.Y.; Lemoine, Janice; Levy, Jay A.; Llibre, Josep M.; Liguori, Michael A.; Little, Susan J.; Liu, Anne Y.; Lopez, Alvaro J.; Loutfy, Mono R.; Loy, Dawn; Mohammed, Debbie Y.; Man, Alan; Mansour, Michael K.; Marconi, Vincent C.; Markowitz, Martin; Marques, Rui; Martin, Jeffrey N.; Martin, Harold L.; Mayer, Kenneth Hugh; McElrath, M. Juliana; McGhee, Theresa A.; McGovern, Barbara H.; McGowan, Katherine; McIntyre, Dawn; Mcleod, Gavin X.; Menezes, Prema; Mesa, Greg; Metroka, Craig E.; Meyer-Olson, Dirk; Miller, Andy O.; Montgomery, Kate; Mounzer, Karam C.; Nagami, Ellen H.; Nagin, Iris; Nahass, Ronald G.; Nelson, Margret O.; Nielsen, Craig; Norene, David L.; O’Connor, David H.; Ojikutu, Bisola O.; Okulicz, Jason; Oladehin, Olakunle O.; Oldfield, Edward C.; Olender, Susan A.; Ostrowski, Mario; Owen, William F.; Pae, Eunice; Parsonnet, Jeffrey; Pavlatos, Andrew M.; Perlmutter, Aaron M.; Pierce, Michael N.; Pincus, Jonathan M.; Pisani, Leandro; Price, Lawrence Jay; Proia, Laurie; Prokesch, Richard C.; Pujet, Heather Calderon; Ramgopal, Moti; Rathod, Almas; Rausch, Michael; Ravishankar, J.; Rhame, Frank S.; Richards, Constance Shamuyarira; Richman, Douglas D.; Robbins, Gregory K.; Rodes, Berta; Rodriguez, Milagros; Rose, Richard C.; Rosenberg, Eric S.; Rosenthal, Daniel; Ross, Polly E.; Rubin, David S.; Rumbaugh, Elease; Saenz, Luis; Salvaggio, Michelle R.; Sanchez, William C.; Sanjana, Veeraf M.; Santiago, Steven; Schmidt, Wolfgang; Schuitemaker, Hanneke; Sestak, Philip M.; Shalit, Peter; Shay, William; Shirvani, Vivian N.; Silebi, Vanessa I.; Sizemore, James M.; Skolnik, Paul R.; Sokol-Anderson, Marcia; Sosman, James M.; Stabile, Paul; Stapleton, Jack T.; Starrett, Sheree; Stein, Francine; Stellbrink, Hans-Jurgen; Sterman, F. Lisa; Stone, Valerie E.; Stone, David R.; Tambussi, Giuseppe; Taplitz, Randy A.; Tedaldi, Ellen M.; Telenti, Amalio; Theisen, William; Torres, Richard; Tosiello, Lorraine; Tremblay, Cecile; Tribble, Marc A.; Trinh, Phuong D.; Tsao, Alice; Ueda, Peggy; Vaccaro, Anthony; Valadas, Emilia; Vanig, Thanes J.; Vecino, Isabel; Vega, Vilma M.; Veikley, Wenoah; Wade, Barbara H.; Walworth, Charles; Wanidworanun, Chingchai; Ward, Douglas J.; Warner, Daniel A.; Weber, Robert D.; Webster, Duncan; Weis, Steve; Wheeler, David A.; White, David J.; Wilkins, Ed; Winston, Alan; Wlodaver, Clifford G.; Wout, Angelique van’t; Wright, David P.; Yang, Otto O.; Yurdin, David L.; Zabukovic, Brandon W.; Zachary, Kimon C.; Zeeman, Beth; Zhao, Meng

2011-01-01

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA–viral peptide interaction as the major factor modulating durable control of HIV infection. PMID:21051598

Y-chromosomal insights into the genetic impact of the caste system in India.

PubMed

Zerjal, Tatiana; Pandya, Arpita; Thangaraj, Kumarasamy; Ling, Edmund Y S; Kearley, Jennifer; Bertoneri, Stefania; Paracchini, Silvia; Singh, Lalji; Tyler-Smith, Chris

2007-03-01

The caste system has persisted in Indian Hindu society for around 3,500 years. Like the Y chromosome, caste is defined at birth, and males cannot change their caste. In order to investigate the genetic consequences of this system, we have analysed male-lineage variation in a sample of 227 Indian men of known caste, 141 from the Jaunpur district of Uttar Pradesh and 86 from the rest of India. We typed 131 Y-chromosomal binary markers and 16 microsatellites. We find striking evidence for male substructure: in particular, Brahmins and Kshatriyas (but not other castes) from Jaunpur each show low diversity and the predominance of a single distinct cluster of haplotypes. These findings confirm the genetic isolation and drift within the Jaunpur upper castes, which are likely to result from founder effects and social factors. In the other castes, there may be either larger effective population sizes, or less strict isolation, or both.

Role of genetic variation in docetaxel-induced neutropenia and pharmacokinetics.

PubMed

Nieuweboer, A J M; Smid, M; de Graan, A-J M; Elbouazzaoui, S; de Bruijn, P; Eskens, F A L M; Hamberg, P; Martens, J W M; Sparreboom, A; de Wit, R; van Schaik, R H N; Mathijssen, R H J

2016-11-01

Docetaxel is used for treatment of several solid malignancies. In this study, we aimed for predicting docetaxel clearance and docetaxel-induced neutropenia by developing several genetic models. Therefore, pharmacokinetic data and absolute neutrophil counts (ANCs) of 213 docetaxel-treated cancer patients were collected. Next, patients were genotyped for 1936 single nucleotide polymorphisms (SNPs) in 225 genes using the drug-metabolizing enzymes and transporters platform and thereafter split into two cohorts. The combination of SNPs that best predicted severe neutropenia or low clearance was selected in one cohort and validated in the other. Patients with severe neutropenia had lower docetaxel clearance than patients with ANCs in the normal range (P=0.01). Severe neutropenia was predicted with 70% sensitivity. True low clearance (1 s.d.

Differential sensitivity to the environment: contribution of cognitive biases and genes to psychological wellbeing.

PubMed

Fox, E; Beevers, C G

2016-12-01

Negative cognitive biases and genetic variation have been associated with risk of psychopathology in largely independent lines of research. Here, we discuss ways in which these dynamic fields of research might be fruitfully combined. We propose that gene by environment (G × E) interactions may be mediated by selective cognitive biases and that certain forms of genetic 'reactivity' or 'sensitivity' may represent heightened sensitivity to the learning environment in a 'for better and for worse' manner. To progress knowledge in this field, we recommend including assessments of cognitive processing biases; examining G × E interactions in 'both' negative and positive environments; experimentally manipulating the environment when possible; and moving beyond single-gene effects to assess polygenic sensitivity scores. We formulate a new methodological framework encapsulating cognitive and genetic factors in the development of both psychopathology and optimal wellbeing that holds long-term promise for the development of new personalized therapies.

Frequent inter-species transmission and geographic subdivision in avian influenza viruses from wild birds.

PubMed

Chen, Rubing; Holmes, Edward C

2009-01-05

Revealing the factors that shape the genetic structure of avian influenza viruses (AIVs) in wild bird populations is essential to understanding their evolution. However, the relationship between epidemiological dynamics and patterns of genetic diversity in AIV is not well understood, especially at the continental scale. To address this question, we undertook a phylogeographic analysis of complete genome sequences of AIV sampled from wild birds in North America. In particular, we asked whether host species, geographic location or sampling time played the major role in shaping patterns of viral genetic diversity. Strikingly, our analysis revealed no strong species effect, yet a significant viral clustering by time and place of sampling, as well as the circulation of multiple viral lineages in single locations. These results suggest that AIVs can readily infect many of the bird species that share breeding/feeding areas.

Association genetics in Pinus taeda L. I. wood property traits

Treesearch

Santiago C. Gonzalez-Martinez; Nicholas C. Wheeler; Elhan Ersoz; C. Dana Nelson; David B. Neale

2007-01-01

Genetic association is a powerful method for dissecting complex adaptive traits due to (i) fine-scale mapping resulting from historical recombination, (ii) wide coverage of phenotypic and genotypic variation within a single experiment, and (iii) the simultaneous discovery of loci and alleles. In this article, genetic association among single nucleotide polymorphisms (...

Radiogenomics: a systems biology approach to understanding genetic risk factors for radiotherapy toxicity ?

PubMed Central

Herskind, Carsten; Talbot, Christopher J.; Kerns, Sarah L.; Veldwijk, Marlon R.; Rosenstein, Barry S.; West, Catharine M. L.

2016-01-01

Adverse reactions in normal tissue after radiotherapy (RT) limit the dose that can be given to tumour cells. Since 80% of individual variation in clinical response is estimated to be caused by patient-related factors, identifying these factors might allow prediction of patients with increased risk of developing severe reactions. While inactivation of cell renewal is considered a major cause of toxicity in early-reacting normal tissues, complex interactions involving multiple cell types, cytokines, and hypoxia seem important for late reactions. Here, we review ‘omics’ approaches such as screening of genetic polymorphisms or gene expression analysis, and assess the potential of epigenetic factors, posttranslational modification, signal transduction, and metabolism. Furthermore, functional assays have suggested possible associations with clinical risk of adverse reaction. Pathway analysis incorporating different ‘omics’ approaches may be more efficient in identifying critical pathways than pathway analysis based on single ‘omics’ data sets. Integrating these pathways with functional assays may be powerful in identifying multiple subgroups of RT patients characterized by different mechanisms. Thus ‘omics’ and functional approaches may synergize if they are integrated into radiogenomics ‘systems biology’ to facilitate the goal of individualised radiotherapy. PMID:26944314

Integrative comparison of mRNA expression patterns in breast cancers from Caucasian and Asian Americans with implications for precision medicine

PubMed Central

Wang, Jianan; He, Max M; Li, Liren; Zhang, Jinfeng

2016-01-01

Asian Americans (AS) have significantly lower incidence and mortality rates of breast cancer (BRCA) than Caucasian Americans (CA). While this racial disparity has been documented the underlying pathogenetic factors explaining it are obscure. We addressed this issue by an integrative genomics approach to compare mRNA expression between AS and CA cases of BRCA. RNA-seq data from the Cancer Genome Atlas showed that mRNA expression revealed significant differences at gene and pathway levels. Increased susceptibility and severity in CA patients were likely the result of synergistic environmental and genetic risk factors, with arachidonic acid metabolism and PPAR signaling pathways implicated in linking environmental and genetic factors. An analysis that also added eQTL data from the Genotype-Tissue Expression Project and single nucleotide polymorphism (SNP) data from the 1000 Genomes Project identified several SNPs associated with differentially expressed genes. Overall, the associations we identified may enable a more focused study of genotypic differences that may help explain the disparity in BRCA incidence and mortality rates in CA and AS populations and inform precision medicine. PMID:28069798

Silencing Onion Lachrymatory Factor Synthase Causes a Significant Change in the Sulfur Secondary Metabolite Profile1[W][OA

PubMed Central

Eady, Colin C.; Kamoi, Takahiro; Kato, Masahiro; Porter, Noel G.; Davis, Sheree; Shaw, Martin; Kamoi, Akiko; Imai, Shinsuke

2008-01-01

Through a single genetic transformation in onion (Allium cepa), a crop recalcitrant to genetic transformation, we suppressed the lachrymatory factor synthase gene using RNA interference silencing in six plants. This reduced lachrymatory synthase activity by up to 1,544-fold, so that when wounded the onions produced significantly reduced levels of tear-inducing lachrymatory factor. We then confirmed, through a novel colorimetric assay, that this silencing had shifted the trans-S-1-propenyl-l-cysteine sulfoxide breakdown pathway so that more 1-propenyl sulfenic acid was converted into di-1-propenyl thiosulfinate. A consequence of this raised thiosulfinate level was a marked increase in the downstream production of a nonenzymatically produced zwiebelane isomer and other volatile sulfur compounds, di-1-propenyl disulfide and 2-mercapto-3,4-dimethyl-2,3-dihydrothiophene, which had previously been reported in trace amounts or had not been detected in onion. The consequences of this dramatic simultaneous down- and up-regulation of secondary sulfur products on the health and flavor attributes of the onion are discussed. PMID:18583530

Pediatric Multiple Sclerosis: Genes, Environment, and a Comprehensive Therapeutic Approach.

PubMed

Cappa, Ryan; Theroux, Liana; Brenton, J Nicholas

2017-10-01

Pediatric multiple sclerosis is an increasingly recognized and studied disorder that accounts for 3% to 10% of all patients with multiple sclerosis. The risk for pediatric multiple sclerosis is thought to reflect a complex interplay between environmental and genetic risk factors. Environmental exposures, including sunlight (ultraviolet radiation, vitamin D levels), infections (Epstein-Barr virus), passive smoking, and obesity, have been identified as potential risk factors in youth. Genetic predisposition contributes to the risk of multiple sclerosis, and the major histocompatibility complex on chromosome 6 makes the single largest contribution to susceptibility to multiple sclerosis. With the use of large-scale genome-wide association studies, other non-major histocompatibility complex alleles have been identified as independent risk factors for the disease. The bridge between environment and genes likely lies in the study of epigenetic processes, which are environmentally-influenced mechanisms through which gene expression may be modified. This article will review these topics to provide a framework for discussion of a comprehensive approach to counseling and ultimately treating the pediatric patient with multiple sclerosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Silencing onion lachrymatory factor synthase causes a significant change in the sulfur secondary metabolite profile.

PubMed

Eady, Colin C; Kamoi, Takahiro; Kato, Masahiro; Porter, Noel G; Davis, Sheree; Shaw, Martin; Kamoi, Akiko; Imai, Shinsuke

2008-08-01

Through a single genetic transformation in onion (Allium cepa), a crop recalcitrant to genetic transformation, we suppressed the lachrymatory factor synthase gene using RNA interference silencing in six plants. This reduced lachrymatory synthase activity by up to 1,544-fold, so that when wounded the onions produced significantly reduced levels of tear-inducing lachrymatory factor. We then confirmed, through a novel colorimetric assay, that this silencing had shifted the trans-S-1-propenyl-l-cysteine sulfoxide breakdown pathway so that more 1-propenyl sulfenic acid was converted into di-1-propenyl thiosulfinate. A consequence of this raised thiosulfinate level was a marked increase in the downstream production of a nonenzymatically produced zwiebelane isomer and other volatile sulfur compounds, di-1-propenyl disulfide and 2-mercapto-3,4-dimethyl-2,3-dihydrothiophene, which had previously been reported in trace amounts or had not been detected in onion. The consequences of this dramatic simultaneous down- and up-regulation of secondary sulfur products on the health and flavor attributes of the onion are discussed.

Vision Issues and Space Flight: Evaluation of One-Carbon Metabolism Polymorphisms

NASA Technical Reports Server (NTRS)

Smith, Scott M.; Gregory, Jesse F.; Zeisel, Steven; Ueland, Per; Gibson, C. R.; Mader, Thomas; Kinchen, Jason; Ploutz-Snyder, Robert; Zwart, Sara R.

2015-01-01

Intermediates of the one-carbon metabolic pathway are altered in astronauts who experience vision-related issues during and after space flight. Serum concentrations of homocysteine, cystathionine, 2-methylcitric acid, and methylmalonic acid were higher in astronauts with ophthalmic changes than in those without (Zwart et al., J Nutr, 2012). These differences existed before, during, and after flight. Potential confounding factors did not explain the differences. Genetic polymorphisms could contribute to these differences, and could help explain why crewmembers on the same mission do not all have ophthalmic issues, despite the same environmental factors (e.g., microgravity, exercise, diet). A follow-up study was conducted to evaluate 5 polymorphisms of enzymes in the one-carbon pathway, and to evaluate how these relate to vision and other ophthalmic changes after flight. Preliminary evaluations of the genetic data indicate that all of the crewmembers with the MTRR GG genotype had vision issues to one degree or another. However, not everyone who had vision issues had this genetic polymorphism, so the situation is more complex than the involvement of this single polymorphism. Metabolomic and further data analyses are underway to clarify these findings, but the preliminary assessments are promising.

Genome-Wide Analysis of Mycoplasma bovirhinis GS01 Reveals Potential Virulence Factors and Phylogenetic Relationships.

PubMed

Chen, Shengli; Hao, Huafang; Zhao, Ping; Liu, Yongsheng; Chu, Yuefeng

2018-05-04

Mycoplasma bovirhinis is a significant etiology in bovine pneumonia and mastitis, but our knowledge about the genetic and pathogenic mechanisms of M. bovirhinis is very limited. In this study, we sequenced the complete genome of M. bovirhinis strain GS01 isolated from the nasal swab of pneumonic calves in Gansu, China, and we found that its genome forms a 847,985 bp single circular chromosome with a GC content of 27.57% and with 707 protein-coding genes. The putative virulence determinants of M. bovirhinis were then analyzed. Results showed that three genomic islands and 16 putative virulence genes, including one adhesion gene enolase, seven surface lipoproteins, proteins involved in glycerol metabolism, and cation transporters, might be potential virulence factors. Glycerol and pyruvate metabolic pathways were defective. Comparative analysis revealed remarkable genome variations between GS01 and a recently reported HAZ141_2 strain, and extremely low homology with others mycoplasma species. Phylogenetic analysis demonstrated that M. bovirhinis was most genetically close to M. canis , distant from other bovine Mycoplasma species. Genomic dissection may provide useful information on the pathogenic mechanisms and genetics of M. bovirhinis . Copyright © 2018 Chen et al.

Genome-wide association study identifies 74 loci associated with educational attainment

PubMed Central

Okbay, Aysu; Beauchamp, Jonathan P.; Fontana, Mark A.; Lee, James J.; Pers, Tune H.; Rietveld, Cornelius A.; Turley, Patrick; Chen, Guo-Bo; Emilsson, Valur; Meddens, S. Fleur W.; Oskarsson, Sven; Pickrell, Joseph K.; Thom, Kevin; Timshel, Pascal; de Vlaming, Ronald; Abdellaoui, Abdel; Ahluwalia, Tarunveer S.; Bacelis, Jonas; Baumbach, Clemens; Bjornsdottir, Gyda; Brandsma, Johannes H.; Concas, Maria Pina; Derringer, Jaime; Furlotte, Nicholas A.; Galesloot, Tessel E.; Girotto, Giorgia; Gupta, Richa; Hall, Leanne M.; Harris, Sarah E.; Hofer, Edith; Horikoshi, Momoko; Huffman, Jennifer E.; Kaasik, Kadri; Kalafati, Ioanna P.; Karlsson, Robert; Kong, Augustine; Lahti, Jari; van der Lee, Sven J.; de Leeuw, Christiaan; Lind, Penelope A.; Lindgren, Karl-Oskar; Liu, Tian; Mangino, Massimo; Marten, Jonathan; Mihailov, Evelin; Miller, Michael B.; van der Most, Peter J.; Oldmeadow, Christopher; Payton, Antony; Pervjakova, Natalia; Peyrot, Wouter J.; Qian, Yong; Raitakari, Olli; Rueedi, Rico; Salvi, Erika; Schmidt, Börge; Schraut, Katharina E.; Shi, Jianxin; Smith, Albert V.; Poot, Raymond A.; Pourcain, Beate; Teumer, Alexander; Thorleifsson, Gudmar; Verweij, Niek; Vuckovic, Dragana; Wellmann, Juergen; Westra, Harm-Jan; Yang, Jingyun; Zhao, Wei; Zhu, Zhihong; Alizadeh, Behrooz Z.; Amin, Najaf; Bakshi, Andrew; Baumeister, Sebastian E.; Biino, Ginevra; Bønnelykke, Klaus; Boyle, Patricia A.; Campbell, Harry; Cappuccio, Francesco P.; Davies, Gail; De Neve, Jan-Emmanuel; Deloukas, Panos; Demuth, Ilja; Ding, Jun; Eibich, Peter; Eisele, Lewin; Eklund, Niina; Evans68, David M.; Faul, Jessica D.; Feitosa, Mary F.; Forstner, Andreas J.; Gandin, Ilaria; Gunnarsson, Bjarni; Halldórsson, Bjarni V.; Harris, Tamara B.; Heath, Andrew C.; Hocking, Lynne J.; Holliday, Elizabeth G.; Homuth, Georg; Horan, Michael A.; Hottenga, Jouke-Jan; de Jager, Philip L.; Joshi, Peter K.; Jugessur, Astanand; Kaakinen, Marika A.; Kähönen, Mika; Kanoni, Stavroula; Keltigangas-Järvinen, Liisa; Kiemeney, Lambertus A.L.M.; Kolcic, Ivana; Koskinen, Seppo; Kraja, Aldi T.; Kroh, Martin; Kutalik, Zoltan; Latvala, Antti; Launer, Lenore J.; Lebreton, Maël P.; Levinson, Douglas F.; Lichtenstein, Paul; Lichtner, Peter; Liewald, David C.M.; Loukola, Anu; Madden, Pamela A.; Mägi, Reedik; Mäki-Opas, Tomi; Marioni, Riccardo E.; Marques-Vidal, Pedro; Meddens, Gerardus A.; McMahon, George; Meisinger, Christa; Meitinger, Thomas; Milaneschi, Yusplitri; Milani, Lili; Montgomery, Grant W.; Myhre, Ronny; Nelson, Christopher P.; Nyholt, Dale R.; Ollier, William E.R.; Palotie, Aarno; Paternoster, Lavinia; Pedersen, Nancy L.; Petrovic, Katja E.; Porteous, David J.; Räikkönen, Katri; Ring, Susan M.; Robino, Antonietta; Rostapshova, Olga; Rudan, Igor; Rustichini, Aldo; Salomaa, Veikko; Sanders, Alan R.; Sarin, Antti-Pekka; Schmidt, Helena; Scott, Rodney J.; Smith, Blair H.; Smith, Jennifer A.; Staessen, Jan A.; Steinhagen-Thiessen, Elisabeth; Strauch, Konstantin; Terracciano, Antonio; Tobin, Martin D.; Ulivi, Sheila; Vaccargiu, Simona; Quaye, Lydia; van Rooij, Frank J.A.; Venturini, Cristina; Vinkhuyzen, Anna A.E.; Völker, Uwe; Völzke, Henry; Vonk, Judith M.; Vozzi, Diego; Waage, Johannes; Ware, Erin B.; Willemsen, Gonneke; Attia, John R.; Bennett, David A.; Berger, Klaus; Bertram, Lars; Bisgaard, Hans; Boomsma, Dorret I.; Borecki, Ingrid B.; Bultmann, Ute; Chabris, Christopher F.; Cucca, Francesco; Cusi, Daniele; Deary, Ian J.; Dedoussis, George V.; van Duijn, Cornelia M.; Eriksson, Johan G.; Franke, Barbara; Franke, Lude; Gasparini, Paolo; Gejman, Pablo V.; Gieger, Christian; Grabe, Hans-Jörgen; Gratten, Jacob; Groenen, Patrick J.F.; Gudnason, Vilmundur; van der Harst, Pim; Hayward, Caroline; Hinds, David A.; Hoffmann, Wolfgang; Hyppönen, Elina; Iacono, William G.; Jacobsson, Bo; Järvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Kaprio, Jaakko; Kardia, Sharon L.R.; Lehtimäki, Terho; Lehrer, Steven F.; Magnusson, Patrik K.E.; Martin, Nicholas G.; McGue, Matt; Metspalu, Andres; Pendleton, Neil; Penninx, Brenda W.J.H.; Perola, Markus; Pirastu, Nicola; Pirastu, Mario; Polasek, Ozren; Posthuma, Danielle; Power, Christine; Province, Michael A.; Samani, Nilesh J.; Schlessinger, David; Schmidt, Reinhold; Sørensen, Thorkild I.A.; Spector, Tim D.; Stefansson, Kari; Thorsteinsdottir, Unnur; Thurik, A. Roy; Timpson, Nicholas J.; Tiemeier, Henning; Tung, Joyce Y.; Uitterlinden, André G.; Vitart, Veronique; Vollenweider, Peter; Weir, David R.; Wilson, James F.; Wright, Alan F.; Conley, Dalton C.; Krueger, Robert F.; Smith, George Davey; Hofman, Albert; Laibson, David I.; Medland, Sarah E.; Meyer, Michelle N.; Yang, Jian; Johannesson, Magnus; Visscher, Peter M.; Esko, Tõnu; Koellinger, Philipp D.; Cesarini, David; Benjamin, Daniel J.

2016-01-01

Summary Educational attainment (EA) is strongly influenced by social and other environmental factors, but genetic factors are also estimated to account for at least 20% of the variation across individuals1. We report the results of a genome-wide association study (GWAS) for EA that extends our earlier discovery sample1,2 of 101,069 individuals to 293,723 individuals, and a replication in an independent sample of 111,349 individuals from the UK Biobank. We now identify 74 genome-wide significant loci associated with number of years of schooling completed. Single-nucleotide polymorphisms (SNPs) associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioral phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because EA is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric disease. PMID:27225129

Genome-wide dissection of hybrid sterility in Drosophila confirms a polygenic threshold architecture.

PubMed

Morán, Tomás; Fontdevila, Antonio

2014-01-01

To date, different studies about the genetic basis of hybrid male sterility (HMS), a postzygotic reproductive barrier thoroughly investigated using Drosophila species, have demonstrated that no single major gene can produce hybrid sterility without the cooperation of several genetic factors. Early work using hybrids between Drosophila koepferae (Dk) and Drosophila buzzatii (Db) was consistent with the idea that HMS requires the cooperation of several genetic factors, supporting a polygenic threshold (PT) model. Here we present a genome-wide mapping strategy to test the PT model, analyzing serially backcrossed fertile and sterile males in which the Dk genome was introgressed into the Db background. We identified 32 Dk-specific markers significantly associated with hybrid sterility. Our results demonstrate 1) a strong correlation between the number of segregated sterility markers and males' degree of sterility, 2) the exchangeability among markers, 3) their tendency to cluster into low-recombining chromosomal regions, and 4) the requirement for a minimum number (threshold) of markers to elicit sterility. Although our findings do not contradict a role for occasional major hybrid-sterility genes, they conform more to the view that HMS primarily evolves by the cumulative action of many interacting genes of minor effect in a complex PT architecture.

Genome-wide association study identifies 74 loci associated with educational attainment.

PubMed

Okbay, Aysu; Beauchamp, Jonathan P; Fontana, Mark Alan; Lee, James J; Pers, Tune H; Rietveld, Cornelius A; Turley, Patrick; Chen, Guo-Bo; Emilsson, Valur; Meddens, S Fleur W; Oskarsson, Sven; Pickrell, Joseph K; Thom, Kevin; Timshel, Pascal; de Vlaming, Ronald; Abdellaoui, Abdel; Ahluwalia, Tarunveer S; Bacelis, Jonas; Baumbach, Clemens; Bjornsdottir, Gyda; Brandsma, Johannes H; Pina Concas, Maria; Derringer, Jaime; Furlotte, Nicholas A; Galesloot, Tessel E; Girotto, Giorgia; Gupta, Richa; Hall, Leanne M; Harris, Sarah E; Hofer, Edith; Horikoshi, Momoko; Huffman, Jennifer E; Kaasik, Kadri; Kalafati, Ioanna P; Karlsson, Robert; Kong, Augustine; Lahti, Jari; van der Lee, Sven J; deLeeuw, Christiaan; Lind, Penelope A; Lindgren, Karl-Oskar; Liu, Tian; Mangino, Massimo; Marten, Jonathan; Mihailov, Evelin; Miller, Michael B; van der Most, Peter J; Oldmeadow, Christopher; Payton, Antony; Pervjakova, Natalia; Peyrot, Wouter J; Qian, Yong; Raitakari, Olli; Rueedi, Rico; Salvi, Erika; Schmidt, Börge; Schraut, Katharina E; Shi, Jianxin; Smith, Albert V; Poot, Raymond A; St Pourcain, Beate; Teumer, Alexander; Thorleifsson, Gudmar; Verweij, Niek; Vuckovic, Dragana; Wellmann, Juergen; Westra, Harm-Jan; Yang, Jingyun; Zhao, Wei; Zhu, Zhihong; Alizadeh, Behrooz Z; Amin, Najaf; Bakshi, Andrew; Baumeister, Sebastian E; Biino, Ginevra; Bønnelykke, Klaus; Boyle, Patricia A; Campbell, Harry; Cappuccio, Francesco P; Davies, Gail; De Neve, Jan-Emmanuel; Deloukas, Panos; Demuth, Ilja; Ding, Jun; Eibich, Peter; Eisele, Lewin; Eklund, Niina; Evans, David M; Faul, Jessica D; Feitosa, Mary F; Forstner, Andreas J; Gandin, Ilaria; Gunnarsson, Bjarni; Halldórsson, Bjarni V; Harris, Tamara B; Heath, Andrew C; Hocking, Lynne J; Holliday, Elizabeth G; Homuth, Georg; Horan, Michael A; Hottenga, Jouke-Jan; de Jager, Philip L; Joshi, Peter K; Jugessur, Astanand; Kaakinen, Marika A; Kähönen, Mika; Kanoni, Stavroula; Keltigangas-Järvinen, Liisa; Kiemeney, Lambertus A L M; Kolcic, Ivana; Koskinen, Seppo; Kraja, Aldi T; Kroh, Martin; Kutalik, Zoltan; Latvala, Antti; Launer, Lenore J; Lebreton, Maël P; Levinson, Douglas F; Lichtenstein, Paul; Lichtner, Peter; Liewald, David C M; Loukola, Anu; Madden, Pamela A; Mägi, Reedik; Mäki-Opas, Tomi; Marioni, Riccardo E; Marques-Vidal, Pedro; Meddens, Gerardus A; McMahon, George; Meisinger, Christa; Meitinger, Thomas; Milaneschi, Yusplitri; Milani, Lili; Montgomery, Grant W; Myhre, Ronny; Nelson, Christopher P; Nyholt, Dale R; Ollier, William E R; Palotie, Aarno; Paternoster, Lavinia; Pedersen, Nancy L; Petrovic, Katja E; Porteous, David J; Räikkönen, Katri; Ring, Susan M; Robino, Antonietta; Rostapshova, Olga; Rudan, Igor; Rustichini, Aldo; Salomaa, Veikko; Sanders, Alan R; Sarin, Antti-Pekka; Schmidt, Helena; Scott, Rodney J; Smith, Blair H; Smith, Jennifer A; Staessen, Jan A; Steinhagen-Thiessen, Elisabeth; Strauch, Konstantin; Terracciano, Antonio; Tobin, Martin D; Ulivi, Sheila; Vaccargiu, Simona; Quaye, Lydia; van Rooij, Frank J A; Venturini, Cristina; Vinkhuyzen, Anna A E; Völker, Uwe; Völzke, Henry; Vonk, Judith M; Vozzi, Diego; Waage, Johannes; Ware, Erin B; Willemsen, Gonneke; Attia, John R; Bennett, David A; Berger, Klaus; Bertram, Lars; Bisgaard, Hans; Boomsma, Dorret I; Borecki, Ingrid B; Bültmann, Ute; Chabris, Christopher F; Cucca, Francesco; Cusi, Daniele; Deary, Ian J; Dedoussis, George V; van Duijn, Cornelia M; Eriksson, Johan G; Franke, Barbara; Franke, Lude; Gasparini, Paolo; Gejman, Pablo V; Gieger, Christian; Grabe, Hans-Jörgen; Gratten, Jacob; Groenen, Patrick J F; Gudnason, Vilmundur; van der Harst, Pim; Hayward, Caroline; Hinds, David A; Hoffmann, Wolfgang; Hyppönen, Elina; Iacono, William G; Jacobsson, Bo; Järvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Kaprio, Jaakko; Kardia, Sharon L R; Lehtimäki, Terho; Lehrer, Steven F; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; Metspalu, Andres; Pendleton, Neil; Penninx, Brenda W J H; Perola, Markus; Pirastu, Nicola; Pirastu, Mario; Polasek, Ozren; Posthuma, Danielle; Power, Christine; Province, Michael A; Samani, Nilesh J; Schlessinger, David; Schmidt, Reinhold; Sørensen, Thorkild I A; Spector, Tim D; Stefansson, Kari; Thorsteinsdottir, Unnur; Thurik, A Roy; Timpson, Nicholas J; Tiemeier, Henning; Tung, Joyce Y; Uitterlinden, André G; Vitart, Veronique; Vollenweider, Peter; Weir, David R; Wilson, James F; Wright, Alan F; Conley, Dalton C; Krueger, Robert F; Davey Smith, George; Hofman, Albert; Laibson, David I; Medland, Sarah E; Meyer, Michelle N; Yang, Jian; Johannesson, Magnus; Visscher, Peter M; Esko, Tõnu; Koellinger, Philipp D; Cesarini, David; Benjamin, Daniel J

2016-05-26

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

Pathways to childhood depressive symptoms: the role of social, cognitive, and genetic risk factors.

PubMed

Lau, Jennifer Y F; Rijsdijk, Frühling; Gregory, Alice M; McGuffin, Peter; Eley, Thalia C

2007-11-01

Childhood depressive conditions have been explored from multiple theoretical approaches but with few empirical attempts to address the interrelationships among these different domains and their combined effects. In the present study, the authors examined different pathways through which social, cognitive, and genetic risk factors may be expressed to influence depressive symptoms in 300 pairs of child twins from a longitudinal study. Path analysis supported several indirect routes. First, risks associated with living in a step- or single-parent family and punitive parenting did not directly influence depressive outcome but were instead mediated through maternal depressive symptoms and child negative attributional style. Second, the effects of negative attributional style on depressive outcome were greatly exacerbated in the presence of precipitating negative life events. Third, independent of these social and cognitive risk mechanisms, modest genetic effects were also implicated in symptoms, with some indication that these risks are expressed through exposure to negative stressors. Together, these routes accounted for approximately 13% of total phenotypic variance in depressive symptoms. Theoretical and analytical implications of these results are discussed in the context of several design-related caveats. (c) 2007 APA.

The genetics of feed conversion efficiency traits in a commercial broiler line

PubMed Central

Reyer, Henry; Hawken, Rachel; Murani, Eduard; Ponsuksili, Siriluck; Wimmers, Klaus

2015-01-01

Individual feed conversion efficiency (FCE) is a major trait that influences the usage of energy resources and the ecological footprint of livestock production. The underlying biological processes of FCE are complex and are influenced by factors as diverse as climate, feed properties, gut microbiota, and individual genetic predisposition. To gain an insight to the genetic relationships with FCE traits and to contribute to the improvement of FCE in commercial chicken lines, a genome-wide association study was conducted using a commercial broiler population (n = 859) tested for FCE and weight traits during the finisher period from 39 to 46 days of age. Both single-marker (generalized linear model) and multi-marker (Bayesian approach) analyses were applied to the dataset to detect genes associated with the variability in FCE. The separate analyses revealed 22 quantitative trait loci (QTL) regions on 13 different chromosomes; the integration of both approaches resulted in 7 overlapping QTL regions. The analyses pointed to acylglycerol kinase (AGK) and general transcription factor 2-I (GTF2I) as positional and functional candidate genes. Non-synonymous polymorphisms of both candidate genes revealed evidence for a functional importance of these genes by influencing different biological aspects of FCE. PMID:26552583

Single-tube tetradecaplex panel of highly polymorphic microsatellite markers < 1 Mb from F8 for simplified preimplantation genetic diagnosis of hemophilia A.

PubMed

Zhao, M; Chen, M; Tan, A S C; Cheah, F S H; Mathew, J; Wong, P C; Chong, S S

2017-07-01

Essentials Preimplantation genetic diagnosis (PGD) of severe hemophilia A relies on linkage analysis. Simultaneous multi-marker screening can simplify selection of informative markers in a couple. We developed a single-tube tetradecaplex panel of polymorphic markers for hemophilia A PGD use. Informative markers can be used for linkage analysis alone or combined with mutation detection. Background It is currently not possible to perform single-cell preimplantation genetic diagnosis (PGD) to directly detect the common inversion mutations of the factor VIII (F8) gene responsible for severe hemophilia A (HEMA). As such, PGD for such inversion carriers relies on indirect analysis of linked polymorphic markers. Objectives To simplify linkage-based PGD of HEMA, we aimed to develop a panel of highly polymorphic microsatellite markers located near the F8 gene that could be simultaneously genotyped in a multiplex-PCR reaction. Methods We assessed the polymorphism of various microsatellite markers located ≤ 1 Mb from F8 in 177 female subjects. Highly polymorphic markers were selected for co-amplification with the AMELX/Y indel dimorphism in a single-tube reaction. Results Thirteen microsatellite markers located within 0.6 Mb of F8 were successfully co-amplified with AMELX/Y in a single-tube reaction. Observed heterozygosities of component markers ranged from 0.43 to 0.84, and ∼70-80% of individuals were heterozygous for ≥ 5 markers. The tetradecaplex panel successfully identified fully informative markers in a couple interested in PGD for HEMA because of an intragenic F8 point mutation, with haplotype phasing established through a carrier daughter. In-vitro fertilization (IVF)-PGD involved single-tube co-amplification of fully informative markers with AMELX/Y and the mutation-containing F8 amplicon, followed by microsatellite analysis and amplicon mutation-site minisequencing analysis. Conclusions The single-tube multiplex-PCR format of this highly polymorphic microsatellite marker panel simplifies identification and selection of informative markers for linkage-based PGD of HEMA. Informative markers can also be easily co-amplified with mutation-containing F8 amplicons for combined mutation detection and linkage analysis. © 2017 International Society on Thrombosis and Haemostasis.

Interactive effect of genetic susceptibility with height, body mass index, and hormone replacement therapy on the risk of breast cancer.

PubMed

Harlid, Sophia; Butt, Salma; Ivarsson, Malin I L; Eyfjörd, Jorunn Erla; Lenner, Per; Manjer, Jonas; Dillner, Joakim; Carlson, Joyce

2012-06-22

Breast cancer today has many established risk factors, both genetic and environmental, but these risk factors by themselves explain only part of the total cancer incidence. We have investigated potential interactions between certain known genetic and phenotypic risk factors, specifically nine single nucleotide polymorphisms (SNPs) and height, body mass index (BMI) and hormone replacement therapy (HRT). We analyzed samples from three different study populations: two prospectively followed Swedish cohorts and one Icelandic case-control study. Totally 2884 invasive breast cancer cases and 4508 controls were analysed in the study. Genotypes were determined using Mass spectrometry-Maldi-TOF and phenotypic variables were derived from measurements and/or questionnaires. Odds Ratios and 95% confidence intervals were calculated using unconditional logistic regression with the inclusion of an interaction term in the logistic regression model. One SNP (rs851987 in ESR1) tended to interact with height, with an increasingly protective effect of the major allele in taller women (p = 0.007) and rs13281615 (on 8q24) tended to confer risk only in non users of HRT (p-for interaction = 0.03). There were no significant interactions after correction for multiple testing. We conclude that much larger sample sets would be necessary to demonstrate interactions between low-risk genetic polymorphisms and the phenotypic variables height, BMI and HRT on the risk for breast cancer. However the present hypothesis-generating study has identified tendencies that would be of interest to evaluate for gene-environment interactions in independent materials.

Association between CFH, CFB, ARMS2, SERPINF1, VEGFR1 and VEGF polymorphisms and anatomical and functional response to ranibizumab treatment in neovascular age-related macular degeneration.

PubMed

Cobos, Estefania; Recalde, Sergio; Anter, Jaouad; Hernandez-Sanchez, Maria; Barreales, Carla; Olavarrieta, Leticia; Valverde, Alicia; Suarez-Figueroa, Marta; Cruz, Fernando; Abraldes, Maximino; Pérez-Pérez, Julian; Fernández-Robredo, Patricia; Arias, Luis; García-Layana, Alfredo

2018-03-01

We sought to determine if specific genetic single nucleotide polymorphisms (SNPs) influence vascular endothelial growth factor inhibition response to ranibizumab in neovascular age-related macular degeneration (AMD). A total of 403 Caucasian patients diagnosed with exudative AMD were included. After a three-injection loading phase, a pro re nata regimen was followed. Nine SNPs from six different genes (CFH, CFB, ARMS2, SERPINF1, VEGFR1, VEGF) were genotyped. Non-genetic risk factors (gender, smoking habit and hypertension) were also assessed. Patients were classified as good or poor responders (GR or PR) according to functional (visual acuity), anatomical (foveal thickness measured by OCT) and fluid criteria (fluid/no fluid measured by OCT). Hypertension was the environmental factor with the strongest poor response association with ranibizumab in the anatomical measure after the loading phase (p = 0.0004; OR 3.7; 95% CI, 2.4-5.8) and after 12 months of treatment (p = 10 -5 ; OR 2.3; 95% CI, 1.5-3.4). The genetic variants rs12614 (CFB), rs699947 (VEGFA) and rs7993418 (VEGFR1) predisposed patients to a good response, while rs12603486 and rs1136287 (SERPINF1) were associated with a poor response. The protective genotype of rs800292 variant (CFH) was also associated with a poor anatomical response (p 0.0048). All these data suggest that genetics play an important role in treatment response in AMD patients. © 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Differential Genetic Associations for Systemic Lupus Erythematosus Based on Anti–dsDNA Autoantibody Production

PubMed Central

Chung, Sharon A.; Taylor, Kimberly E.; Graham, Robert R.; Nititham, Joanne; Lee, Annette T.; Ortmann, Ward A.; Jacob, Chaim O.; Alarcón-Riquelme, Marta E.; Tsao, Betty P.; Harley, John B.; Gaffney, Patrick M.; Moser, Kathy L.; Petri, Michelle; Demirci, F. Yesim; Kamboh, M. Ilyas; Manzi, Susan; Gregersen, Peter K.; Langefeld, Carl D.; Behrens, Timothy W.; Criswell, Lindsey A.

2011-01-01

Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti–dsDNA autoantibody production, a SLE–related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti–dsDNA autoantibody positive (anti–dsDNA +, n = 811) and anti–dsDNA autoantibody negative (anti–dsDNA –, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti–dsDNA + SLE. Far fewer and weaker associations were observed for anti–dsDNA – SLE. For example, rs7574865 in STAT4 had an OR for anti–dsDNA + SLE of 1.77 (95% CI 1.57–1.99, p = 2.0E-20) compared to an OR for anti–dsDNA – SLE of 1.26 (95% CI 1.12–1.41, p = 2.4E-04), with pheterogeneity<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti–dsDNA + SLE and were not associated with anti–dsDNA – SLE. In conclusion, we identified differential genetic associations with SLE based on anti–dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti–dsDNA – SLE. PMID:21408207

An evidence-based approach to globally assess the covariate-dependent effect of the MTHFR single nucleotide polymorphism rs1801133 on blood homocysteine: a systematic review and meta-analysis.

PubMed

Jin, Huifeng; Cheng, Haojie; Chen, Wei; Sheng, Xiaoming; Levy, Mark A; Brown, Mark J; Tian, Junqiang

2018-05-01

The single nucleotide polymorphism of the gene 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T (or rs1801133) is the most established genetic factor that increases plasma total homocysteine (tHcy) and consequently results in hyperhomocysteinemia. Yet, given the limited penetrance of this genetic variant, it is necessary to individually predict the risk of hyperhomocysteinemia for an rs1801133 carrier. We hypothesized that variability in this genetic risk is largely due to the presence of factors (covariates) that serve as effect modifiers, confounders, or both, such as folic acid (FA) intake, and aimed to assess this risk in the complex context of these covariates. We systematically extracted from published studies the data on tHcy, rs1801133, and any previously reported rs1801133 covariates. The resulting metadata set was first used to analyze the covariates' modifying effect by meta-regression and other statistical means. Subsequently, we controlled for this modifying effect by genotype-stratifying tHcy data and analyzed the variability in the risk resulting from the confounding of covariates. The data set contains data on 36 rs1801133 covariates that were collected from 114,799 participants and 256 qualified studies, among which 6 covariates (sex, age, race, FA intake, smoking, and alcohol consumption) are the most frequently informed and therefore included for statistical analysis. The effect of rs1801133 on tHcy exhibits significant variability that can be attributed to effect modification as well as confounding by these covariates. Via statistical modeling, we predicted the covariate-dependent risk of tHcy elevation and hyperhomocysteinemia in a systematic manner. We showed an evidence-based approach that globally assesses the covariate-dependent effect of rs1801133 on tHcy. The results should assist clinicians in interpreting the rs1801133 data from genetic testing for their patients. Such information is also important for the public, who increasingly receive genetic data from commercial services without interpretation of its clinical relevance. This study was registered at Research Registry with the registration number reviewregistry328.

The behavioural and neuropathological impact of intranigral AAV-α-synuclein is exacerbated by systemic infusion of the Parkinson's disease-associated pesticide, rotenone, in rats.

PubMed

Mulcahy, Pádraig; O'Doherty, Aideen; Paucard, Alexia; O'Brien, Timothy; Kirik, Deniz; Dowd, Eilís

2013-04-15

Despite the widely held belief that Parkinson's disease is caused by both underlying genetics and exposure to environmental risk factors, it is still widely modelled in preclinical models using a single genetic or neurotoxic insult. This single-insult approach has resulted in a variety of models that are limited with respect to their aetiological, construct, face and/or predictive validity. Thus, the aim of the current study was to investigate the interplay between genes and the environment as an alternative approach to modelling Parkinson's disease. To do so, rats underwent stereotaxic surgery for unilateral delivery of the Parkinson's disease-associated gene, α-synuclein, into the substantia nigra (using AAV vectors). This was followed 13 weeks later by subcutaneous implantation of an osmotic minipump delivering the Parkinson's disease-associated pesticide, rotenone (2.5mgkg(-1)day(-1) for 4 weeks). The effect of the genetic and environmental insults alone or in combination on lateralised motor performance (Corridor, Stepping and Whisker Tests), nigrostriatal integrity (tyrosine hydroxylase immunohistochemistry) and α-synucleinopathy (α-synuclein immunohistochemistry) was assessed. We found that exposing AAV-α-synuclein-treated rats to rotenone led to a model in which the classical Parkinson's disease triad of progressive motor dysfunction, nigrostriatal neurodegeneration and α-synucleinopathy was evident. However, delivering rotenone systemically was also associated with bilateral motor dysfunction and loss of body weight. Thus, although we have shown that Parkinson's disease can be modelled in experimental animals by combined exposure to both genetic and environmental risk factors, this approach is limited by systemic toxicity of the pesticide rotenone. Direct intracerebral delivery of rotenone may be more useful in longer-term studies as we have previously shown that it overcomes this limitation. Copyright © 2013 Elsevier B.V. All rights reserved.

Brief Report: Single-nucleotide polymorphisms in VKORC1 are risk factors for systemic lupus erythematosus in Asians.

PubMed

Kaiser, Rachel; Taylor, Kimberly E; Deng, Yun; Zhao, Jian; Li, Yonghong; Nititham, Joanne; Chang, Monica; Catanese, Joseph; Begovich, Ann B; Brown, Elizabeth E; Edberg, Jeffrey C; McGwin, Gerald; Alarcón, Graciela S; Ramsey-Goldman, Rosalind; Reveille, John D; Vila, Luis M; Petri, Michelle; Kimberly, Robert P; Feng, Xuebing; Sun, Lingyun; Shen, Nan; Li, Wei; Lu, Jian-Xin; Wakeland, Edward K; Li, Quan-Zhen; Yang, Wanling; Lau, Yu-Lung; Liu, Fei-Lan; Chang, Deh-Ming; Yu, Chack-Yung; Song, Yeong W; Tsao, Betty P; Criswell, Lindsey A

2013-01-01

The increased risk of thrombosis in systemic lupus erythematosus (SLE) may be partially explained by interrelated genetic pathways for thrombosis and SLE. The present study was undertaken to investigate whether 33 established and novel single-nucleotide polymorphisms (SNPs) in 20 genes involved in hemostasis pathways that have been associated with deep venous thrombosis (DVT) in the general population are risk factors for SLE among Asian subjects. Patients in the discovery cohort were enrolled in 1 of 2 North American SLE cohorts. Patients in the replication cohort were enrolled in 1 of 4 Asian or 2 North American cohorts. We first genotyped 263 Asian patients with SLE and 357 healthy Asian control subjects for 33 SNPs in the discovery phase, and then genotyped 5 SNPs in up to an additional 1,496 patients and 993 controls in the replication phase. Patients were compared to controls for bivariate association with minor alleles. Principal components analysis was used to control for intra-Asian ancestry in the replication cohort. Two genetic variants in the gene VKORC1 were highly significant in both the discovery and replication cohorts: rs9934438 (in the discovery cohort, odds ratio [OR] 2.45, P=2×10(-9); in the replication cohort, OR 1.54, P=4×10(-6)) and rs9923231 (in the discovery cohort, OR 2.40, P=6×10(-9); in the replication cohort, OR 1.53, P=5×10(-6)). These associations were significant in the replication cohort after adjustment for intra-Asian ancestry: for rs9934438, OR 1.34, P=0.0029; for rs9923231, OR 1.34, P=0.0032. Genetic variants in VKORC1, which are involved in vitamin K reduction and associated with DVT, correlate with SLE development in Asian subjects. These results suggest that there may be intersecting genetic pathways for the development of SLE and thrombosis. Copyright © 2013 by the American College of Rheumatology.

[Impact on environmental factors on the reproductive system and fetal development].

PubMed

Dulskiene, Virginija; Maroziene, Ligita

2002-01-01

A literature review discusses the effect of selected environmental factors on women reproductive system, fetal development and growth. According to recent reports, 2-3% of newborns have congenital malformations. These malformations are caused by interaction of genetic and environmental factors. Exposure of paternal or maternal organisms to environmental hazards may damage germ cells or interfere fetal development, resulting in malformation of various organ systems. Since environmental hazards exposures are complex, it is difficult to establish the primary effect of single factor. Factors, that are known to increase the risk of congenital malformations, preterm delivery or spontaneous abortion, are classified into five groups--psychological, social, biological, physical and chemical factors. The governments of most counties recognize the effect of hazardous environmental factors on public health as global problem. World Health Organization encourages researches, aimed at evaluation of various environmental factors impact on health of pregnant women and their offsprings.

Current outcomes and risk factors for the Norwood procedure.

PubMed

Stasik, Chad N; Gelehrter, S; Goldberg, Caren S; Bove, Edward L; Devaney, Eric J; Ohye, Richard G

2006-02-01

Tremendous strides have been made in the outcomes for hypoplastic left heart syndrome and other functional single-ventricle malformations over the past 25 years. This progress relates primarily to improvements in survival for patients undergoing the Norwood procedure. Previous reports on risk factors have been on smaller groups of patients or collected over relatively long periods of time, during which management has evolved. We analyzed our current results for the Norwood procedure with attention to risk factors for poor outcome. A single-institution review of all patients undergoing a Norwood procedure for a single-ventricle malformation from May 1, 2001, through April 30, 2003, was performed. Patient demographics, anatomy, clinical condition, associated anomalies, operative details, and outcomes were recorded. Of the 111 patients, there were 23 (21%) hospital deaths. Univariate analysis revealed noncardiac abnormalities (genetic or significant extracardiac diagnosis, P = .0018), gestational age (P = .03), diagnosis of unbalanced atrioventricular septal defect (P = .017), and weight of less than 2.5 kg (P = .0072) to be related to hospital death. On multivariate analysis, only weight of less than 2.5 kg and noncardiac abnormalities were found to be independent risk factors. Patients with either of these characteristics had a hospital survival of 52% (12/23), whereas those at standard risk had a survival of 86% (76/88). Although improvements in management might have lessened the effect of some of the traditionally reported risk factors related to variations in the cardiovascular anatomy, noncardiac abnormalities and low birth weight remain as a future challenge for the physician caring for the patient with single-ventricle physiology.

Epidemiology and Heritability of Major Depressive Disorder, Stratified by Age of Onset, Sex, and Illness Course in Generation Scotland: Scottish Family Health Study (GS:SFHS).

PubMed

Fernandez-Pujals, Ana Maria; Adams, Mark James; Thomson, Pippa; McKechanie, Andrew G; Blackwood, Douglas H R; Smith, Blair H; Dominiczak, Anna F; Morris, Andrew D; Matthews, Keith; Campbell, Archie; Linksted, Pamela; Haley, Chris S; Deary, Ian J; Porteous, David J; MacIntyre, Donald J; McIntosh, Andrew M

2015-01-01

The heritability of Major Depressive Disorder (MDD) has been estimated at 37% based largely on twin studies that rely on contested assumptions. More recently, the heritability of MDD has been estimated on large populations from registries such as the Swedish, Finnish, and Chinese cohorts. Family-based designs utilise a number of different relationships and provide an alternative means of estimating heritability. Generation Scotland: Scottish Family Health Study (GS:SFHS) is a large (n = 20,198), family-based population study designed to identify the genetic determinants of common diseases, including Major Depressive Disorder. Two thousand seven hundred and six individuals were SCID diagnosed with MDD, 13.5% of the cohort, from which we inferred a population prevalence of 12.2% (95% credible interval: 11.4% to 13.1%). Increased risk of MDD was associated with being female, unemployed due to a disability, current smokers, former drinkers, and living in areas of greater social deprivation. The heritability of MDD in GS:SFHS was between 28% and 44%, estimated from a pedigree model. The genetic correlation of MDD between sexes, age of onset, and illness course were examined and showed strong genetic correlations. The genetic correlation between males and females with MDD was 0.75 (0.43 to 0.99); between earlier (≤ age 40) and later (> age 40) onset was 0.85 (0.66 to 0.98); and between single and recurrent episodic illness course was 0.87 (0.72 to 0.98). We found that the heritability of recurrent MDD illness course was significantly greater than the heritability of single MDD illness course. The study confirms a moderate genetic contribution to depression, with a small contribution of the common family environment (variance proportion = 0.07, CI: 0.01 to 0.15), and supports the relationship of MDD with previously identified risk factors. This study did not find robust support for genetic differences in MDD due to sex, age of onset, or illness course. However, we found an intriguing difference in heritability between recurrent and single MDD illness course. These findings establish GS:SFHS as a valuable cohort for the genetic investigation of MDD.

Generation and genetic engineering of human induced pluripotent stem cells using designed zinc finger nucleases.

PubMed

Ramalingam, Sivaprakash; London, Viktoriya; Kandavelou, Karthikeyan; Cebotaru, Liudmila; Guggino, William; Civin, Curt; Chandrasegaran, Srinivasan

2013-02-15

Zinc finger nucleases (ZFNs) have become powerful tools to deliver a targeted double-strand break at a pre-determined chromosomal locus in order to insert an exogenous transgene by homology-directed repair. ZFN-mediated gene targeting was used to generate both single-allele chemokine (C-C motif) receptor 5 (CCR5)-modified human induced pluripotent stem cells (hiPSCs) and biallele CCR5-modified hiPSCs from human lung fibroblasts (IMR90 cells) and human primary cord blood mononuclear cells (CBMNCs) by site-specific insertion of stem cell transcription factor genes flanked by LoxP sites into the endogenous CCR5 locus. The Oct4 and Sox2 reprogramming factors, in combination with valproic acid, induced reprogramming of human lung fibroblasts to form CCR5-modified hiPSCs, while 5 factors, Oct4/Sox2/Klf4/Lin28/Nanog, induced reprogramming of CBMNCs. Subsequent Cre recombinase treatment of the CCR5-modified IMR90 hiPSCs resulted in the removal of the Oct4 and Sox2 transgenes. Further genetic engineering of the single-allele CCR5-modified IMR90 hiPSCs was achieved by site-specific addition of the large CFTR transcription unit to the remaining CCR5 wild-type allele, using CCR5-specific ZFNs and a donor construct containing tdTomato and CFTR transgenes flanked by CCR5 homology arms. CFTR was expressed efficiently from the endogenous CCR5 locus of the CCR5-modified tdTomato/CFTR hiPSCs. These results suggest that it might be feasible to use ZFN-evoked strategies to (1) generate precisely targeted genetically well-defined patient-specific hiPSCs, and (2) then to reshape their function by targeted addition and expression of therapeutic genes from the CCR5 chromosomal locus for autologous cell-based transgene-correction therapy to treat various recessive monogenic human diseases in the future.

Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study

PubMed Central

2010-01-01

Introduction Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium. Methods We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects. Results These analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar. Conclusions The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified. PMID:21194473

Uncertainty in BRCA1 cancer susceptibility testing.

PubMed

Baty, Bonnie J; Dudley, William N; Musters, Adrian; Kinney, Anita Y

2006-11-15

This study investigated uncertainty in individuals undergoing genetic counseling/testing for breast/ovarian cancer susceptibility. Sixty-three individuals from a single kindred with a known BRCA1 mutation rated uncertainty about 12 items on a five-point Likert scale before and 1 month after genetic counseling/testing. Factor analysis identified a five-item total uncertainty scale that was sensitive to changes before and after testing. The items in the scale were related to uncertainty about obtaining health care, positive changes after testing, and coping well with results. The majority of participants (76%) rated reducing uncertainty as an important reason for genetic testing. The importance of reducing uncertainty was stable across time and unrelated to anxiety or demographics. Yet, at baseline, total uncertainty was low and decreased after genetic counseling/testing (P = 0.004). Analysis of individual items showed that after genetic counseling/testing, there was less uncertainty about the participant detecting cancer early (P = 0.005) and coping well with their result (P < 0.001). Our findings support the importance to clients of genetic counseling/testing as a means of reducing uncertainty. Testing may help clients to reduce the uncertainty about items they can control, and it may be important to differentiate the sources of uncertainty that are more or less controllable. Genetic counselors can help clients by providing anticipatory guidance about the role of uncertainty in genetic testing. (c) 2006 Wiley-Liss, Inc.

[Genetic variability and differentiation of three Russian populations of yellow potato cyst nematode Globodera rostochiensis as revealed by nuclear markers].

PubMed

Khrisanfova, G G; Kharchevnikov, D A; Popov, I O; Zinov'eva, S V; Semenova, S K

2008-05-01

Genetic variability of yellow potato cyst nematode G. rostochiensis from three Russian populations (Karelia, Vladimir oblast, and Moscow oblast) was investigated using two types of nuclear markers. Using RAPD markers identified with the help of six random primers (P-29, OPA-10, OPT-14, OPA-11, OPB-11, and OPH-20), it was possible to distinguish Karelian population from the group consisting of the populations from two adjacent regions (Moscow oblast and Vladimir oblast). Based on the combined matrix, containing 294 RAPD fragments, dendrogram of genetic differences was constructed, and the indices of genetic divergence and partition (P, H, and G(st)), as well as the gene flow indices N(m) between the nematode samples examined, were calculated. The dendrogram structure, genetic diversity indices, and variations of genetic distances between single individuals in each population from Karelia and Central Russia pointed to genetic isolation and higher genetic diversity of the nematodes from Karelia. Based on polymorphism of rDNA first intergenic spacer ITS1, attribution of all populations examined to the species G. rostochiensis was proved. Small variations of the ITS1 sequence in different geographic populations of nematodes from different regions of the species world range did not allow isolation of separate groups within the species. Possible factors (including interregional transportations of seed potato) affecting nematode population structure in Russia are discussed.

Investigation of Genetic Variants Associated with Alzheimer Disease in Parkinson Disease Cognition.

PubMed

Barrett, Matthew J; Koeppel, Alexander F; Flanigan, Joseph L; Turner, Stephen D; Worrall, Bradford B

2016-01-01

Meta-analysis of genome-wide association studies have implicated multiple single nucleotide polymorphisms (SNPs) and associated genes with Alzheimer disease. The role of these SNPs in cognitive impairment in Parkinson disease (PD) remains incompletely evaluated. The objective of this study was to test alleles associated with risk of Alzheimer disease for association with cognitive impairment in Parkinson disease (PD). Two datasets with PD subjects accessed through the NIH database of Genotypes and Phenotypes contained both single nucleotide polymorphism (SNP) arrays and mini-mental state exam (MMSE) scores. Genetic data underwent rigorous quality control and we selected SNPs for genes associated with AD other than APOE. We constructed logistic regression and ordinal regression models, adjusted for sex, age at MMSE, and duration of PD, to assess the association between selected SNPs and MMSE score. In one dataset, PICALM rs3851179 was associated with cognitive impairment (MMSE <  24) in PD subjects > 70 years old (OR = 2.3; adjusted p-value = 0.017; n = 250) but not in PD subjects ≤ 70 years old. Our finding suggests that PICALM rs3851179 could contribute to cognitive impairment in older patients with PD. It is important that future studies consider the interaction of age and genetic risk factors in the development of cognitive impairment in PD.

Single nucleotide primer extension to detect genetic diseases: Experimental application to hemophilia B (factor IX) and cystic fibrosis genes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuppuswamy, M.N.; Hoffmann, J.W.; Spitzer, S.G.

1991-02-15

In this report, the authors describe an approach to detect the presence of abnormal alleles in those genetic diseases in which frequency of occurrence of the same mutation is high (e.g., hemophilia B). Initially, from each subject, the DNA fragment containing the putative mutation site is amplified by the polymerase chain reaction. For each fragment two reaction mixtures are then prepared. Each contains the amplified fragment, a primer (18-mer or longer) whose sequence is identical to the coding sequence of the normal gene immediately flanking the 5{prime} end of the mutation site, and either an {alpha}-{sup 32}P-labeled nucleotide corresponding tomore » the normal coding sequence at the mutation site or an {alpha}-{sup 32}P-labeled nucleotide corresponding to the mutant sequence. An essential feature of the present methodology is that the base immediately 3{prime} to the template-bound primer is one of those altered in the mutant, since in this way an extension of the primer by a single base will give an extended molecule characteristic of either the mutant or the wild type. The method is rapid and should be useful in carrier detection and prenatal diagnosis of every genetic disease with a known sequence variation.« less

Significant genetic and phenotypic changes arising from clonal growth of a single spore of an arbuscular mycorrhizal fungus over multiple generations.

PubMed

Ehinger, Martine O; Croll, Daniel; Koch, Alexander M; Sanders, Ian R

2012-11-01

Arbuscular mycorrhizal fungi (AMF) are highly successful plant symbionts. They reproduce clonally producing multinucleate spores. It has been suggested that some AMF harbor genetically different nuclei. However, recent advances in sequencing the Glomus irregulare genome have indicated very low within-fungus polymorphism. We tested the null hypothesis that, with no genetic differences among nuclei, no significant genetic or phenotypic variation would occur among clonal single spore lines generated from one initial AMF spore. Furthermore, no additional variation would be expected in the following generations of single spore lines. Genetic diversity contained in one initial spore repeatedly gave rise to genetically different variants of the fungus with novel phenotypes. The genetic changes represented quantitative changes in allele frequencies, most probably as a result of changes in the frequency of genetic variation partitioned on different nuclei. The genetic and phenotypic variation is remarkable, given that it arose repeatedly from one clonal individual. Our results highlight the dynamic nature of AMF genetics. Even though within-fungus genetic variation is low, some is probably partitioned among nuclei and potentially causes changes in the phenotype. Our results are important for understanding AMF genetics, as well as for researchers and biotechnologists hoping to use AMF genetic diversity for the improvement of AMF inoculum. © 2012 The Authors. New Phytologist © 2012 New Phytologist Trust.

[Key morphofunctional transformations in the evolution of chiropterans (Bats, Chiroptera)].

PubMed

Kovaleva, I M

2014-01-01

Study on the morphology and morphogenesis of wing membranes in Bats has revealed some peculiarities in their structure and development. Understanding the embryogenesis of these animals, as well as attraction of data obtained on their molecular genetics and paleontology, allows one to single out some factors that could have initiated evolutionary modifications in development programs. A scenario of the key morphofunctional transformations in the forelimbs during the evolution of chiropterans is given.

How do messenger RNA splicing alterations drive myelodysplasia?

PubMed Central

2017-01-01

Mutations in RNA splicing factors are the single most common class of genetic alterations in myelodysplastic syndrome (MDS) patients. Although much has been learned about how these mutations affect splicing at a global- and transcript-specific level, critical questions about the role of these mutations in MDS development and maintenance remain. Here we present the questions to be addressed in order to understand the unique enrichment of these mutations in MDS. PMID:28348147

The Sociobiological Foundations of Stability and Support Operations

DTIC Science & Technology

1999-01-01

of fatherhood. Parental responsibility is not a factor for the warrior rapist as future proof of paternity is unlikely. In raping the wives and...allows a single parent to replicate his genetic code for as long as the reproductive resources last. If there is a change in the environment or the...aggression. The mammalian brain controls, among other emotions, social behavior and the nurturing of children . The surrounding primate brain gives man

Mendelian randomization with fine-mapped genetic data: Choosing from large numbers of correlated instrumental variables.

PubMed

Burgess, Stephen; Zuber, Verena; Valdes-Marquez, Elsa; Sun, Benjamin B; Hopewell, Jemma C

2017-12-01

Mendelian randomization uses genetic variants to make causal inferences about the effect of a risk factor on an outcome. With fine-mapped genetic data, there may be hundreds of genetic variants in a single gene region any of which could be used to assess this causal relationship. However, using too many genetic variants in the analysis can lead to spurious estimates and inflated Type 1 error rates. But if only a few genetic variants are used, then the majority of the data is ignored and estimates are highly sensitive to the particular choice of variants. We propose an approach based on summarized data only (genetic association and correlation estimates) that uses principal components analysis to form instruments. This approach has desirable theoretical properties: it takes the totality of data into account and does not suffer from numerical instabilities. It also has good properties in simulation studies: it is not particularly sensitive to varying the genetic variants included in the analysis or the genetic correlation matrix, and it does not have greatly inflated Type 1 error rates. Overall, the method gives estimates that are less precise than those from variable selection approaches (such as using a conditional analysis or pruning approach to select variants), but are more robust to seemingly arbitrary choices in the variable selection step. Methods are illustrated by an example using genetic associations with testosterone for 320 genetic variants to assess the effect of sex hormone related pathways on coronary artery disease risk, in which variable selection approaches give inconsistent inferences. © 2017 The Authors Genetic Epidemiology Published by Wiley Periodicals, Inc.

Variation in the miRNA-433 Binding Site of FGF20 Confers Risk for Parkinson Disease by Overexpression of α-Synuclein

PubMed Central

Wang, Gaofeng; van der Walt, Joelle M.; Mayhew, Gregory; Li, Yi-Ju; Züchner, Stephan; Scott, William K.; Martin, Eden R.; Vance, Jeffery M.

2008-01-01

Parkinson disease (PD) is a common neurodegenerative disorder caused by environmental and genetic factors. We have previously shown linkage of PD to chromosome 8p. Subsequently, fibroblast growth factor 20 (FGF20) at 8p21.3–22 was identified as a risk factor in several association studies. To identify the risk-conferring polymorphism in FGF20, we performed genetic and functional analysis of single-nucleotide polymorphisms within the gene. In a sample of 729 nuclear families with 1089 affected and 1165 unaffected individuals, the strongest evidence of association came from rs12720208 in the 3′ untranslated region of FGF20. We show in several functional assays that the risk allele for rs12720208 disrupts a binding site for microRNA-433, increasing translation of FGF20 in vitro and in vivo. In a cell-based system and in PD brains, this increase in translation of FGF20 is correlated with increased α-synuclein expression, which has previously been shown to cause PD through both overexpression and point mutations. We suggest a novel mechanism of action for PD risk in which the modulation of the susceptibility gene's translation by common variations interfere with the regulation mechanisms of microRNA. We propose this is likely to be a common mechanism of genetic modulation of individual susceptibility to complex disease. PMID:18252210

A forward genetic screen reveals essential and non-essential RNAi factors in Paramecium tetraurelia

PubMed Central

Marker, Simone; Carradec, Quentin; Tanty, Véronique; Arnaiz, Olivier; Meyer, Eric

2014-01-01

In most eukaryotes, small RNA-mediated gene silencing pathways form complex interacting networks. In the ciliate Paramecium tetraurelia, at least two RNA interference (RNAi) mechanisms coexist, involving distinct but overlapping sets of protein factors and producing different types of short interfering RNAs (siRNAs). One is specifically triggered by high-copy transgenes, and the other by feeding cells with double-stranded RNA (dsRNA)-producing bacteria. In this study, we designed a forward genetic screen for mutants deficient in dsRNA-induced silencing, and a powerful method to identify the relevant mutations by whole-genome sequencing. We present a set of 47 mutant alleles for five genes, revealing two previously unknown RNAi factors: a novel Paramecium-specific protein (Pds1) and a Cid1-like nucleotidyl transferase. Analyses of allelic diversity distinguish non-essential and essential genes and suggest that the screen is saturated for non-essential, single-copy genes. We show that non-essential genes are specifically involved in dsRNA-induced RNAi while essential ones are also involved in transgene-induced RNAi. One of the latter, the RNA-dependent RNA polymerase RDR2, is further shown to be required for all known types of siRNAs, as well as for sexual reproduction. These results open the way for the dissection of the genetic complexity, interconnection, mechanisms and natural functions of RNAi pathways in P. tetraurelia. PMID:24860163

Lessons learned from international comparative crosscultural studies on dementia.

PubMed

Hendrie, Hugh C

2006-06-01

International and crosscultural comparative studies of Alzheimer disease (AD) offer significant advantages in elucidating risk factors for the disease by providing a wider diversity of environmental exposures as well as greater genetic diversity than do studies confined to a single ethnic group in a developed country. They also present with major methodological problems. The problems and their possible solutions are discussed in this article by describing three projects involving the Cree and English-speaking residents of Manitoba, blacks from Indianapolis, Indiana, and Yoruba from Ibadan and residents of Chinese villages. In this review, the development and harmonization of a culture fair screening instrument for dementia, the CSID, is described. The advantage of a scientific paradigm that can incorporate genetic and environmental factors as well as their interactions to explore the etiology of AD is presented. The importance of developing strategies for recruitment and retention in international community-based studies is emphasized as is the necessity of establishing academic partnerships between the countries. The unique opportunity provided by geopolitical and sociocultural influences to study environmental exposures is exemplified by the ongoing study of the influence of selenium levels on cognition in Chinese villagers. Results from the Indianapolis, Indiana-Ibadan dementia project are presented suggesting that the incidence of AD is lower in Yoruba than in blacks and that this lower rate may be the result of a combination of genetic and environmental factors.

Genetic Deficiency in Neprilysin or Its Pharmacological Inhibition Initiate Excessive Stress-Induced Alcohol Consumption in Mice

PubMed Central

Gembardt, Florian; Becker, Axel; Schultheiss, Heinz-Peter; Siems, Wolf-Eberhard; Walther, Thomas

2012-01-01

Both acquired and inherited genetic factors contribute to excessive alcohol consumption and the corresponding development of addiction. Here we show that the genetic deficiency in neprilysin [NEP] did not change the kinetics of alcohol degradation but led to an increase in alcohol intake in mice in a 2-bottle-free-choice paradigm after one single stress stimulus (intruder). A repetition of such stress led to an irreversible elevated alcohol consumption. This phenomenon could be also observed in wild-type mice receiving an orally active NEP inhibitor. We therefore elucidated the stress behavior in NEP-deficient mice. In an Elevated Plus Maze, NEP knockouts crossed more often the area between the arms, implicating a significant stronger stress response. Furthermore, such animals showed a decreased locomotor activity under intense light in a locomotor activity test, identifying such mice to be more responsive in aversive situations than their wild-type controls. Since the reduction in NEP activity itself does not lead to significant signs of an altered alcohol preference in mice but requires an environmental stimulus, our findings build a bridge between stress components and genetic factors in the development of alcoholism. Therefore, targeting NEP activity might be a very attractive approach for the treatment of alcohol abuse in a society with increasing social and financial stress. PMID:23185571

Association of vWA and TPOX Polymorphisms with Venous Thrombosis in Mexican Mestizos

PubMed Central

Meraz-Ríos, Marco Antonio; Majluf-Cruz, Abraham; Santana, Carla; Noris, Gino; Camacho-Mejorado, Rafael; Acosta-Saavedra, Leonor C.; Calderón-Aranda, Emma S.; Hernández-Juárez, Jesús; Magaña, Jonathan J.; Gómez, Rocío

2014-01-01

Objective. Venous thromboembolism (VTE) is a multifactorial disorder and, worldwide, the most important cause of morbidity and mortality. Genetic factors play a critical role in its aetiology. Microsatellites are the most important source of human genetic variation having more phenotypic effect than many single nucleotide polymorphisms. Hence, we evaluate a possible relationship between VTE and the genetic variants in von Willebrand factor, human alpha fibrinogen, and human thyroid peroxidase microsatellites to identify possible diagnostic markers. Methods. Genotypes were obtained from 177 patients with VTE and 531 nonrelated individuals using validated genotyping methods. The allelic frequencies were compared; Bayesian methods were used to correct population stratification to avoid spurious associations. Results. The vWA-18, TPOX-9, and TPOX-12 alleles were significantly associated with VTE. Moreover, subjects bearing the combination vWA-18/TPOX-12 loci exhibited doubled risk for VTE (95% CI = 1.02–3.64), whereas the combination vWA-18/TPOX-9 showed an OR = 10 (95% CI = 4.93–21.49). Conclusions. The vWA and TPOX microsatellites are good candidate biomarkers in venous thromboembolism diseases and could help to elucidate their origins. Additionally, these polymorphisms could become useful markers for genetic studies of VTE in the Mexican population; however, further studies should be done owing that this data only show preliminary evidence. PMID:25250329

Physical distance, genetic relationship, age, and leprosy classification are independent risk factors for leprosy in contacts of patients with leprosy.

PubMed

Moet, F Johannes; Pahan, David; Schuring, Ron P; Oskam, Linda; Richardus, Jan H

2006-02-01

Close contacts of patients with leprosy have a higher risk of developing leprosy. Several risk factors have been identified, including genetic relationship and physical distance. Their independent contributions to the risk of developing leprosy, however, have never been sufficiently quantified. Logistic-regression analysis was performed on intake data from a prospective cohort study of 1037 patients newly diagnosed as having leprosy and their 21,870 contacts. Higher age showed an increased risk, with a bimodal distribution. Contacts of patients with paucibacillary (PB) leprosy with 2-5 lesions (PB2-5) and those with multibacillary (MB) leprosy had a higher risk than did contacts of patients with single-lesion PB leprosy. The core household group had a higher risk than other contacts living under the same roof and next-door neighbors, who again had a higher risk than neighbors of neighbors. A close genetic relationship indicated an increased risk when blood-related children, parents, and siblings were pooled together. Age of the contact, the disease classification of the index patient, and physical and genetic distance were independently associated with the risk of a contact acquiring leprosy. Contact surveys in leprosy should be not only focused on household contacts but also extended to neighbors and consanguineous relatives, especially when the patient has PB2-5 or MB leprosy.

Postoperative Pain and Analgesia: Is There a Genetic Basis to the Opioid Crisis?

PubMed

Elmallah, Randa K; Ramkumar, Prem N; Khlopas, Anton; Ramkumar, Rathika R; Chughtai, Morad; Sodhi, Nipun; Sultan, Assem A; Mont, Michael A

2018-06-01

Multiple factors have been implicated in determining why certain patients have increased postoperative pain, with the potential to develop chronic pain. The purpose of this study was to: 1) identify and describe genes that affect postoperative pain perception and control; 2) address modifiable risk factors that result in epigenetic altered responses to pain; and 3) characterize differences in pain sensitivity and thresholds between opioid-naïve and opioid-dependent patients. Three electronic databases were used to conduct the literature search: Pubmed, EBSCO host, and SCOPUS. A total of 372 abstracts were reviewed, of which 46 studies were deemed relevant and are included in this review. Specific gene alterations that were shown to affect postoperative pain control included single nucleotide polymorphisms in the mu, kappa, and delta opioid receptors, ion channel genes, cytotoxic T-cells, glutamate receptors and cytokine genes, among others. Alcoholism, obesity, and smoking were all linked with genetic polymorphisms that altered pain sensitivity. Opioid abuse was found to be associated with a poorer response to analgesics postoperatively, as well as a risk for prescription overdose. Although pain perception has multiple complex influences, the greatest variability seen in response to opioids among postoperative patients known to date can be traced to genetic differences in opioid metabolism. Further study is needed to determine the clinical significance of these genetic associations.

Comparative genetic analysis of lint yield and fiber quality among single, three-way, and double crosses in upland cotton

USDA-ARS?s Scientific Manuscript database

Decisions on the appropriate crossing systems to employ for genetic improvement of quantitative traits are critical in cotton breeding. Determination of genetic variance for lint yield and fiber quality in three different crossing schemes, i.e., single cross (SC), three-way cross (TWC), and double ...

Single-Cell Mass Spectrometry Reveals Changes in Lipid and Metabolite Expression in RAW 264.7 Cells upon Lipopolysaccharide Stimulation

NASA Astrophysics Data System (ADS)

Yang, Bo; Patterson, Nathan Heath; Tsui, Tina; Caprioli, Richard M.; Norris, Jeremy L.

2018-05-01

It has been widely recognized that individual cells that exist within a large population of cells, even if they are genetically identical, can have divergent molecular makeups resulting from a variety of factors, including local environmental factors and stochastic processes within each cell. Presently, numerous approaches have been described that permit the resolution of these single-cell expression differences for RNA and protein; however, relatively few techniques exist for the study of lipids and metabolites in this manner. This study presents a methodology for the analysis of metabolite and lipid expression at the level of a single cell through the use of imaging mass spectrometry on a high-performance Fourier transform ion cyclotron resonance mass spectrometer. This report provides a detailed description of the overall experimental approach, including sample preparation as well as the data acquisition and analysis strategy for single cells. Applying this approach to the study of cultured RAW264.7 cells, we demonstrate that this method can be used to study the variation in molecular expression with cell populations and is sensitive to alterations in that expression that occurs upon lipopolysaccharide stimulation. [Figure not available: see fulltext.

Single-Cell Mass Spectrometry Reveals Changes in Lipid and Metabolite Expression in RAW 264.7 Cells upon Lipopolysaccharide Stimulation

NASA Astrophysics Data System (ADS)

Yang, Bo; Patterson, Nathan Heath; Tsui, Tina; Caprioli, Richard M.; Norris, Jeremy L.

2018-03-01

It has been widely recognized that individual cells that exist within a large population of cells, even if they are genetically identical, can have divergent molecular makeups resulting from a variety of factors, including local environmental factors and stochastic processes within each cell. Presently, numerous approaches have been described that permit the resolution of these single-cell expression differences for RNA and protein; however, relatively few techniques exist for the study of lipids and metabolites in this manner. This study presents a methodology for the analysis of metabolite and lipid expression at the level of a single cell through the use of imaging mass spectrometry on a high-performance Fourier transform ion cyclotron resonance mass spectrometer. This report provides a detailed description of the overall experimental approach, including sample preparation as well as the data acquisition and analysis strategy for single cells. Applying this approach to the study of cultured RAW264.7 cells, we demonstrate that this method can be used to study the variation in molecular expression with cell populations and is sensitive to alterations in that expression that occurs upon lipopolysaccharide stimulation. [Figure not available: see fulltext.

Association of Genetic Polymorphisms of Renin–Angiotensin–Aldosterone System-Related Genes with Arterio-Venous Fistula Malfunction in Hemodialysis Patients

PubMed Central

Chen, Yu-Wei; Wu, Yu-Te; Lin, Jhin-Shyaun; Yang, Wu-Chang; Hsu, Yung-Ho; Lee, Kuo-Hua; Ou, Shou-Ming; Chen, Yung-Tai; Shih, Chia-Jen; Lee, Pui-Ching; Chan, Chia-Hao; Chung, Ming-Yi; Lin, Chih-Ching

2016-01-01

Hemodialysis (HD) is the most commonly-used renal replacement therapy for patients with end-stage renal disease worldwide. Arterio-venous fistula (AVF) is the vascular access of choice for HD patients with lowest risk of infection and thrombosis. In addition to environmental factors, genetic factors may also contribute to malfunction of AVF. Previous studies have demonstrated the effect of genotype polymorphisms of angiotensin converting enzyme on vascular access malfunction. We conducted a multicenter, cross-sectional study to evaluate the association between genetic polymorphisms of renin-angiotensin-aldosterone system and AVF malfunction. Totally, 577 patients were enrolled. Their mean age was 60 years old and 53% were male. HD patients with AVF malfunction had longer duration of HD (92.5 ± 68.1 vs. 61.2 ± 51.9 months, p < 0.001), lower prevalence of hypertension (44.8% vs. 55.3%, p = 0.025), right-sided (31.8% vs. 18.4%, p = 0.002) and upper arm AVF (26.6% vs. 9.7%, p < 0.001), and higher mean dynamic venous pressure (DVP) (147.8 ± 28.3 vs. 139.8 ± 30.0, p = 0.021). In subgroup analysis of different genders, location of AVF and DVP remained significant clinical risk factors of AVF malfunction in univariate and multivariate binary logistic regression in female HD patients. Among male HD patients, univariate binary logistic regression analysis revealed that right-side AVF and upper arm location are two important clinical risk factors. In addition, two single nucleotide polymorphisms (SNPs), rs275653 (Odds ratio 1.90, p = 0.038) and rs1492099 (Odds ratio 2.29, p = 0.017) of angiotensin II receptor 1 (AGTR1), were associated with increased risk of AVF malfunction. After adjustment for age and other clinical factors, minor allele-containing genotype polymorphisms (AA and CA) of rs1492099 still remained to be a significant risk factor of AVF malfunction (Odds ratio 3.63, p = 0.005). In conclusion, we demonstrated that rs1492099, a SNP of AGTR1 gene, could be a potential genetic risk factor of AVF malfunction in male HD patients. PMID:27240348

Evaluation of body condition score measured throughout lactation as an indicator of fertility in dairy cattle.

PubMed

Banos, G; Brotherstone, S; Coffey, M P

2004-08-01

Body condition score (BCS) records of primiparous Holstein cows were analyzed both as a single measure per animal and as repeated measures per sire of cow. The former resulted in a single, average, genetic evaluation for each sire, and the latter resulted in separate genetic evaluations per day of lactation. Repeated measure analysis yielded genetic correlations of less than unity between days of lactation, suggesting that BCS may not be the same trait across lactation. Differences between daily genetic evaluations on d 10 or 30 and subsequent daily evaluations were used to assess BCS change at different stages of lactation. Genetic evaluations for BCS level or change were used to estimate genetic correlations between BCS measures and fertility traits in order to assess the capacity of BCS to predict fertility. Genetic correlation estimates with calving interval and non-return rate were consistently higher for daily BCS than single measure BCS evaluations, but results were not always statistically different. Genetic correlations between BCS change and fertility traits were not significantly different from zero. The product of the accuracy of BCS evaluations with their genetic correlation with the UK fertility index, comprising calving interval and non-return rate, was consistently higher for daily than for single BCS evaluations, by 28 to 53%. This product is associated with the conceptual correlated response in fertility from BCS selection and was highest for early (d 10 to 75) evaluations.

Genetic heterogeneity in autism: From single gene to a pathway perspective.

PubMed

An, Joon Yong; Claudianos, Charles

2016-09-01

The extreme genetic heterogeneity of autism spectrum disorder (ASD) represents a major challenge. Recent advances in genetic screening and systems biology approaches have extended our knowledge of the genetic etiology of ASD. In this review, we discuss the paradigm shift from a single gene causation model to pathway perturbation model as a guide to better understand the pathophysiology of ASD. We discuss recent genetic findings obtained through next-generation sequencing (NGS) and examine various integrative analyses using systems biology and complex networks approaches that identify convergent patterns of genetic elements associated with ASD. Copyright © 2016 Elsevier Ltd. All rights reserved.

Relationships between genetic polymorphisms in inflammation-related factor gene and the pathogenesis of nasopharyngeal cancer.

PubMed

Qu, Yan-Li; Yu, Hong; Chen, Yan-Zhi; Zhao, Yu-Xia; Chen, Guang-Jun; Bai, Lu; Liu, Dan; Su, Hong-Xin; Wang, He-Tong

2014-09-01

Our study aims to discuss the association between inflammation-related factors such as single nucleotide polymorphisms (SNPs) with susceptibility and recurrence in nasopharyngeal carcinoma. We used Taqman real-time polymerase chain reaction (PCR) to characterize the genetic variation of five SNPs in 194 nasopharyngeal carcinoma patients and 231 healthy subjects. All statistical analysis is performed with statistical product and service solutions v13.0; odds ratio (OR) value and 95 % confidence interval (CI) were calculated. There is no relationship between TGFβ1 -869 T/C, IL-6 -634C/G, TGFβ1 -509C/T, IL1 -511C/T and nasopharyngeal carcinoma susceptibility. Both single factor and multiple factors analysis showed that IL1a -889 T/T genotype is significantly associated with nasopharyngeal carcinoma in decreasing the risk of nasopharyngeal carcinoma. A highly significant association was found between IL1a -889 T/T genotype and protective genotype as defined by various pathological types. This is more obvious in the protective genotype of the non-keratin-type squamous carcinoma undifferentiated type. We also discovered that genotype G/G and C/G + G/G of IL6 -634 gene are associated with reduced recurrence of nasopharyngeal carcinoma. IL1a -889 gene polymorphism and susceptibility is related to nasopharyngeal carcinoma and can potentially decrease the risk of nasopharyngeal carcinoma in the Han Chinese population in north China. IL1-889 TT genotype is protective genotype for nasopharyngeal carcinoma. We have provided evidence that the GG genotype of the IL6 -634 gene is associated with recurrent risk of nasopharyngeal carcinoma. The G allele is the protective gene of nasopharyngeal carcinoma recurrence.

Long-range gene flow and the effects of climatic and ecological factors on genetic structuring in a large, solitary carnivore: the Eurasian lynx.

PubMed

Ratkiewicz, Mirosław; Matosiuk, Maciej; Saveljev, Alexander P; Sidorovich, Vadim; Ozolins, Janis; Männil, Peep; Balciauskas, Linas; Kojola, Ilpo; Okarma, Henryk; Kowalczyk, Rafał; Schmidt, Krzysztof

2014-01-01

Due to their high mobility, large terrestrial predators are potentially capable of maintaining high connectivity, and therefore low genetic differentiation among populations. However, previous molecular studies have provided contradictory findings in relation to this. To elucidate patterns of genetic structure in large carnivores, we studied the genetic variability of the Eurasian lynx, Lynx lynx throughout north-eastern Europe using microsatellite, mitochondrial DNA control region and Y chromosome-linked markers. Using SAMOVA we found analogous patterns of genetic structure based on both mtDNA and microsatellites, which coincided with a relatively little evidence for male-biased dispersal. No polymorphism for the cytochrome b and ATP6 mtDNA genes and Y chromosome-linked markers were found. Lynx inhabiting a large area encompassing Finland, the Baltic countries and western Russia formed a single genetic unit, while some marginal populations were clearly divergent from others. The existence of a migration corridor was suggested to correspond with distribution of continuous forest cover. The lowest variability (in both markers) was found in lynx from Norway and Białowieża Primeval Forest (BPF), which coincided with a recent demographic bottleneck (Norway) or high habitat fragmentation (BPF). The Carpathian population, being monomorphic for the control region, showed relatively high microsatellite diversity, suggesting the effect of a past bottleneck (e.g. during Last Glacial Maximum) on its present genetic composition. Genetic structuring for the mtDNA control region was best explained by latitude and snow cover depth. Microsatellite structuring correlated with the lynx's main prey, especially the proportion of red deer (Cervus elaphus) in its diet. Eurasian lynx are capable of maintaining panmictic populations across eastern Europe unless they are severely limited by habitat continuity or a reduction in numbers. Different correlations of mtDNA and microsatellite population divergence patterns with climatic and ecological factors may suggest separate selective pressures acting on males and females in this solitary carnivore.

Prevalence, Patterns, and Genetic Association Analysis of Modic Vertebral Endplate Changes.

PubMed

Kanna, Rishi Mugesh; Shanmuganathan, Rajasekaran; Rajagopalan, Veera Ranjani; Natesan, Senthil; Muthuraja, Raveendran; Cheung, Kenneth Man Chee; Chan, Danny; Kao, Patrick Yu Ping; Yee, Anita; Shetty, Ajoy Prasad

2017-08-01

A prospective genetic association study. The etiology of Modic changes (MCs) is unclear. Recently, the role of genetic factors in the etiology of MCs has been evaluated. However, studies with a larger patient subset are lacking, and candidate genes involved in other disc degeneration phenotypes have not been evaluated. We studied the prevalence of MCs and genetic association of 41 candidate genes in a large Indian cohort. MCs are vertebral endplate signal changes predominantly observed in the lumbar spine. A significant association between MCs and lumbar disc degeneration and nonspecific low back pain has been described, with the etiopathogenesis implicating various mechanical, infective, and biochemical factors. We studied 809 patients using 1.5-T magnetic resonance imaging to determine the prevalence, patterns, distribution, and type of lumbar MCs. Genetic association analysis of 71 single nucleotide polymorphisms (SNPs) of 41 candidate genes was performed based on the presence or absence of MCs. SNPs were genotyped using the Sequenome platform, and an association test was performed using PLINK software. The mean age of the study population (n=809) was 36.7±10.8 years. Based on the presence of MCs, the cohort was divided into 702 controls and 107 cases (prevalence, 13%). MCs were more commonly present in the lower (149/251, 59.4%) than in the upper (102/251, 40.6%) endplates. L4-5 endplates were the most commonly affected levels (30.7%). Type 2 MCs were the most commonly observed pattern (n=206, 82%). The rs2228570 SNP of VDR ( p =0.02) and rs17099008 SNP of MMP20 ( p =0.03) were significantly associated with MCs. Genetic polymorphisms of SNPs of VDR and MMP20 were significantly associated with MCs. Understanding the etiopathogenetic mechanisms of MCs is important for planning preventive and therapeutic strategies.

An integrative study of the genetic, social and environmental determinants of chronic kidney disease characterized by tubulointerstitial damages in the North Central Region of Sri Lanka.

PubMed

Nanayakkara, Shanika; Senevirathna, S T M L D; Abeysekera, Tilak; Chandrajith, Rohana; Ratnatunga, Neelakanthi; Gunarathne, E D L; Yan, Junxia; Hitomi, Toshiaki; Muso, Eri; Komiya, Toshiyuki; Harada, Kouji H; Liu, Wanyang; Kobayashi, Hatasu; Okuda, Hiroko; Sawatari, Hideyuki; Matsuda, Fumihiko; Yamada, Ryo; Watanabe, Takao; Miyataka, Hideki; Himeno, Seiichiro; Koizumi, Akio

2014-01-01

Previous investigations on chronic kidney disease of unknown etiology characterized by tubulointerstitial damages (CKDu) in the North Central Region (NCR) of Sri Lanka have supported the involvement of social, environmental and genetic factors in its pathogenesis. We conducted a social-environmental-and-genetic epidemiology study on a male population in NCR to investigate the genetic and environmental contributors. We recruited 311 case-series patients and 504 control candidates. Of the 504 control candidates, 218 (43%) were eliminated because of the presence of hypertension, proteinuria, high HbA1c, high serum creatinine or high alpha-1 microglobulin in urine. None of 18 metals measured (μg//) in urine, including Cd, As and Pb, showed significantly higher concentrations in cases compared with controls. As speciation results showed that 75-80% of total urinary As was in the form of arsenobetaine, which is non-toxic to humans. None of the metal concentrations in drinking water samples exceeded guideline values. A genome-wide association study (GWAS) was conducted to determine the genetic contributors. The GWAS yielded a genome-wide significant association with CKDu for a single nucleotide polymorphism (SNP; rs6066043; p=5.23 × 10(-9) in quantitative trait locus analysis; p=3.73 × 10(-9) in dichotomous analysis) in SLC13A3 (sodium-dependent dicarboxylate transporter member 3). The population attributable fraction and odds ratio for this SNP were 50% and 2.13. Genetic susceptibility was identified as the major risk factor for CKDu. However, 43% of the apparently healthy male population suffers from non-communicable diseases, suggesting their possible influence on CKDu progression.

The genetics of mental illness: implications for practice.

PubMed Central

Hyman, S. E.

2000-01-01

Many of the comfortable and relatively simple models of the nature of mental disorders, their causes and their neural substrates now appear quite frayed. Gone is the idea that symptom clusters, course of illness, family history and treatment response would coalesce in a simple way to yield valid diagnoses. Also too simple was the concept, born of early pharmacological successes, that abnormal levels of one or more neurotransmitters would satisfactorily explain the pathogenesis of depression or schizophrenia. Gone is the notion that there is a single gene that causes any mental disorder or determines any behavioural variant. The concept of the causative gene has been replaced by that of genetic complexity, in which multiple genes act in concert with non-genetic factors to produce a risk of mental disorder. Discoveries in genetics and neuroscience can be expected to lead to better models that provide improved representation of the complexity of the brain and behaviour and the development of both. There are likely to be profound implications for clinical practice. The complex genetics of risk should reinvigorate research on the epidemiology and classification of mental disorders and explain the complex patterns of disease transmission within families. Knowledge of the timing of the expression of risk genes during brain development and of their function should not only contribute to an understanding of gene action and the pathophysiology of disease but should also help to direct the search for modifiable environmental risk factors that convert risk into illness. The function of risk genes can only become comprehensible in the context of advances at the molecular, cellular and systems levels in neuroscience and the behavioural sciences. Genetics should yield new therapies aimed not just at symptoms but also at pathogenic processes, thus permitting the targeting of specific therapies to individual patients. PMID:10885164

Genetic diversity and mating type distribution of Tuber melanosporum and their significance to truffle cultivation in artificially planted truffieres in Australia.

PubMed

Linde, C C; Selmes, H

2012-09-01

Tuber melanosporum is a truffle native to Europe and is cultivated in countries such as Australia for the gastronomic market, where production yields are often lower than expected. We assessed the genetic diversity of T. melanosporum with six microsatellite loci to assess the effect of genetic drift on truffle yield in Australia. Genetic diversity as assessed on 210 ascocarps revealed a higher allelic diversity compared to previous studies from Europe, suggesting a possible genetic expansion and/or multiple and diverse source populations for inoculum. The results also suggest that the single sequence repeat diversity of locus ME2 is adaptive and that, for example, the probability of replication errors is increased for this locus. Loss of genetic diversity in Australian populations is therefore not a likely factor in limiting ascocarp production. A survey of nursery seedlings and trees inoculated with T. melanosporum revealed that <70% of seedlings and host trees were colonized with T. melanosporum and that some trees had been contaminated by Tuber brumale, presumably during the inoculation process. Mating type (MAT1-1-1 and MAT1-2-1) analyses on seedling and four- to ten-year-old host trees found that 100% of seedlings but only approximately half of host trees had both mating types present. Furthermore, MAT1-1-1 was detected significantly more commonly than MAT1-2-1 in established trees, suggesting a competitive advantage for MAT1-1-1 strains. This study clearly shows that there are more factors involved in ascocarp production than just the presence of both mating types on host trees.

Genetic Diversity and Mating Type Distribution of Tuber melanosporum and Their Significance to Truffle Cultivation in Artificially Planted Truffiéres in Australia

PubMed Central

Selmes, H.

2012-01-01

Tuber melanosporum is a truffle native to Europe and is cultivated in countries such as Australia for the gastronomic market, where production yields are often lower than expected. We assessed the genetic diversity of T. melanosporum with six microsatellite loci to assess the effect of genetic drift on truffle yield in Australia. Genetic diversity as assessed on 210 ascocarps revealed a higher allelic diversity compared to previous studies from Europe, suggesting a possible genetic expansion and/or multiple and diverse source populations for inoculum. The results also suggest that the single sequence repeat diversity of locus ME2 is adaptive and that, for example, the probability of replication errors is increased for this locus. Loss of genetic diversity in Australian populations is therefore not a likely factor in limiting ascocarp production. A survey of nursery seedlings and trees inoculated with T. melanosporum revealed that <70% of seedlings and host trees were colonized with T. melanosporum and that some trees had been contaminated by Tuber brumale, presumably during the inoculation process. Mating type (MAT1-1-1 and MAT1-2-1) analyses on seedling and four- to ten-year-old host trees found that 100% of seedlings but only approximately half of host trees had both mating types present. Furthermore, MAT1-1-1 was detected significantly more commonly than MAT1-2-1 in established trees, suggesting a competitive advantage for MAT1-1-1 strains. This study clearly shows that there are more factors involved in ascocarp production than just the presence of both mating types on host trees. PMID:22773652

New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis.

PubMed

Lee, S Hong; Byrne, Enda M; Hultman, Christina M; Kähler, Anna; Vinkhuyzen, Anna A E; Ripke, Stephan; Andreassen, Ole A; Frisell, Thomas; Gusev, Alexander; Hu, Xinli; Karlsson, Robert; Mantzioris, Vasilis X; McGrath, John J; Mehta, Divya; Stahl, Eli A; Zhao, Qiongyi; Kendler, Kenneth S; Sullivan, Patrick F; Price, Alkes L; O'Donovan, Michael; Okada, Yukinori; Mowry, Bryan J; Raychaudhuri, Soumya; Wray, Naomi R; Byerley, William; Cahn, Wiepke; Cantor, Rita M; Cichon, Sven; Cormican, Paul; Curtis, David; Djurovic, Srdjan; Escott-Price, Valentina; Gejman, Pablo V; Georgieva, Lyudmila; Giegling, Ina; Hansen, Thomas F; Ingason, Andrés; Kim, Yunjung; Konte, Bettina; Lee, Phil H; McIntosh, Andrew; McQuillin, Andrew; Morris, Derek W; Nöthen, Markus M; O'Dushlaine, Colm; Olincy, Ann; Olsen, Line; Pato, Carlos N; Pato, Michele T; Pickard, Benjamin S; Posthuma, Danielle; Rasmussen, Henrik B; Rietschel, Marcella; Rujescu, Dan; Schulze, Thomas G; Silverman, Jeremy M; Thirumalai, Srinivasa; Werge, Thomas; Agartz, Ingrid; Amin, Farooq; Azevedo, Maria H; Bass, Nicholas; Black, Donald W; Blackwood, Douglas H R; Bruggeman, Richard; Buccola, Nancy G; Choudhury, Khalid; Cloninger, Robert C; Corvin, Aiden; Craddock, Nicholas; Daly, Mark J; Datta, Susmita; Donohoe, Gary J; Duan, Jubao; Dudbridge, Frank; Fanous, Ayman; Freedman, Robert; Freimer, Nelson B; Friedl, Marion; Gill, Michael; Gurling, Hugh; De Haan, Lieuwe; Hamshere, Marian L; Hartmann, Annette M; Holmans, Peter A; Kahn, René S; Keller, Matthew C; Kenny, Elaine; Kirov, George K; Krabbendam, Lydia; Krasucki, Robert; Lawrence, Jacob; Lencz, Todd; Levinson, Douglas F; Lieberman, Jeffrey A; Lin, Dan-Yu; Linszen, Don H; Magnusson, Patrik K E; Maier, Wolfgang; Malhotra, Anil K; Mattheisen, Manuel; Mattingsdal, Morten; McCarroll, Steven A; Medeiros, Helena; Melle, Ingrid; Milanova, Vihra; Myin-Germeys, Inez; Neale, Benjamin M; Ophoff, Roel A; Owen, Michael J; Pimm, Jonathan; Purcell, Shaun M; Puri, Vinay; Quested, Digby J; Rossin, Lizzy; Ruderfer, Douglas; Sanders, Alan R; Shi, Jianxin; Sklar, Pamela; St Clair, David; Stroup, T Scott; Van Os, Jim; Visscher, Peter M; Wiersma, Durk; Zammit, Stanley; Bridges, S Louis; Choi, Hyon K; Coenen, Marieke J H; de Vries, Niek; Dieud, Philippe; Greenberg, Jeffrey D; Huizinga, Tom W J; Padyukov, Leonid; Siminovitch, Katherine A; Tak, Paul P; Worthington, Jane; De Jager, Philip L; Denny, Joshua C; Gregersen, Peter K; Klareskog, Lars; Mariette, Xavier; Plenge, Robert M; van Laar, Mart; van Riel, Piet

2015-10-01

A long-standing epidemiological puzzle is the reduced rate of rheumatoid arthritis (RA) in those with schizophrenia (SZ) and vice versa. Traditional epidemiological approaches to determine if this negative association is underpinned by genetic factors would test for reduced rates of one disorder in relatives of the other, but sufficiently powered data sets are difficult to achieve. The genomics era presents an alternative paradigm for investigating the genetic relationship between two uncommon disorders. We use genome-wide common single nucleotide polymorphism (SNP) data from independently collected SZ and RA case-control cohorts to estimate the SNP correlation between the disorders. We test a genotype X environment (GxE) hypothesis for SZ with environment defined as winter- vs summer-born. We estimate a small but significant negative SNP-genetic correlation between SZ and RA (-0.046, s.e. 0.026, P = 0.036). The negative correlation was stronger for the SNP set attributed to coding or regulatory regions (-0.174, s.e. 0.071, P = 0.0075). Our analyses led us to hypothesize a gene-environment interaction for SZ in the form of immune challenge. We used month of birth as a proxy for environmental immune challenge and estimated the genetic correlation between winter-born and non-winter born SZ to be significantly less than 1 for coding/regulatory region SNPs (0.56, s.e. 0.14, P = 0.00090). Our results are consistent with epidemiological observations of a negative relationship between SZ and RA reflecting, at least in part, genetic factors. Results of the month of birth analysis are consistent with pleiotropic effects of genetic variants dependent on environmental context.

New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis

PubMed Central

Lee, S Hong; Byrne, Enda M; Hultman, Christina M; Kähler, Anna; Vinkhuyzen, Anna AE; Ripke, Stephan; Andreassen, Ole A; Frisell, Thomas; Gusev, Alexander; Hu, Xinli; Karlsson, Robert; Mantzioris, Vasilis X; McGrath, John J; Mehta, Divya; Stahl, Eli A; Zhao, Qiongyi; Kendler, Kenneth S; Sullivan, Patrick F; Price, Alkes L; O’Donovan, Michael; Okada, Yukinori; Mowry, Bryan J; Raychaudhuri, Soumya; Wray, Naomi R; Byerley, William; Cahn, Wiepke; Cantor, Rita M; Cichon, Sven; Cormican, Paul; Curtis, David; Djurovic, Srdjan; Escott-Price, Valentina; Gejman, Pablo V; Georgieva, Lyudmila; Giegling, Ina; Hansen, Thomas F; Ingason, Andrés; Kim, Yunjung; Konte, Bettina; Lee, Phil H; McIntosh, Andrew; McQuillin, Andrew; Morris, Derek W; Nöthen, Markus M; O’Dushlaine, Colm; Olincy, Ann; Olsen, Line; Pato, Carlos N; Pato, Michele T; Pickard, Benjamin S; Posthuma, Danielle; Rasmussen, Henrik B; Rietschel, Marcella; Rujescu, Dan; Schulze, Thomas G; Silverman, Jeremy M; Thirumalai, Srinivasa; Werge, Thomas; Agartz, Ingrid; Amin, Farooq; Azevedo, Maria H; Bass, Nicholas; Black, Donald W; Blackwood, Douglas H R; Bruggeman, Richard; Buccola, Nancy G; Choudhury, Khalid; Cloninger, Robert C; Corvin, Aiden; Craddock, Nicholas; Daly, Mark J; Datta, Susmita; Donohoe, Gary J; Duan, Jubao; Dudbridge, Frank; Fanous, Ayman; Freedman, Robert; Freimer, Nelson B; Friedl, Marion; Gill, Michael; Gurling, Hugh; De Haan, Lieuwe; Hamshere, Marian L; Hartmann, Annette M; Holmans, Peter A; Kahn, René S; Keller, Matthew C; Kenny, Elaine; Kirov, George K; Krabbendam, Lydia; Krasucki, Robert; Lawrence, Jacob; Lencz, Todd; Levinson, Douglas F; Lieberman, Jeffrey A; Lin, Dan-Yu; Linszen, Don H; Magnusson, Patrik KE; Maier, Wolfgang; Malhotra, Anil K; Mattheisen, Manuel; Mattingsdal, Morten; McCarroll, Steven A; Medeiros, Helena; Melle, Ingrid; Milanova, Vihra; Myin-Germeys, Inez; Neale, Benjamin M; Ophoff, Roel A; Owen, Michael J; Pimm, Jonathan; Purcell, Shaun M; Puri, Vinay; Quested, Digby J; Rossin, Lizzy; Ruderfer, Douglas; Sanders, Alan R; Shi, Jianxin; Sklar, Pamela; St. Clair, David; Stroup, T Scott; Van Os, Jim; Visscher, Peter M; Wiersma, Durk; Zammit, Stanley; Bridges, S Louis; Choi, Hyon K; Coenen, Marieke JH; de Vries, Niek; Dieud, Philippe; Greenberg, Jeffrey D; Huizinga, Tom WJ; Padyukov, Leonid; Siminovitch, Katherine A; Tak, Paul P; Worthington, Jane; De Jager, Philip L; Denny, Joshua C; Gregersen, Peter K; Klareskog, Lars; Mariette, Xavier; Plenge, Robert M; van Laar, Mart; van Riel, Piet

2015-01-01

Background: A long-standing epidemiological puzzle is the reduced rate of rheumatoid arthritis (RA) in those with schizophrenia (SZ) and vice versa. Traditional epidemiological approaches to determine if this negative association is underpinned by genetic factors would test for reduced rates of one disorder in relatives of the other, but sufficiently powered data sets are difficult to achieve. The genomics era presents an alternative paradigm for investigating the genetic relationship between two uncommon disorders. Methods: We use genome-wide common single nucleotide polymorphism (SNP) data from independently collected SZ and RA case-control cohorts to estimate the SNP correlation between the disorders. We test a genotype X environment (GxE) hypothesis for SZ with environment defined as winter- vs summer-born. Results: We estimate a small but significant negative SNP-genetic correlation between SZ and RA (−0.046, s.e. 0.026, P = 0.036). The negative correlation was stronger for the SNP set attributed to coding or regulatory regions (−0.174, s.e. 0.071, P = 0.0075). Our analyses led us to hypothesize a gene-environment interaction for SZ in the form of immune challenge. We used month of birth as a proxy for environmental immune challenge and estimated the genetic correlation between winter-born and non-winter born SZ to be significantly less than 1 for coding/regulatory region SNPs (0.56, s.e. 0.14, P  = 0.00090). Conclusions: Our results are consistent with epidemiological observations of a negative relationship between SZ and RA reflecting, at least in part, genetic factors. Results of the month of birth analysis are consistent with pleiotropic effects of genetic variants dependent on environmental context. PMID:26286434

Translational Mouse Models of Autism: Advancing Toward Pharmacological Therapeutics

PubMed Central

Kazdoba, Tatiana M.; Leach, Prescott T.; Yang, Mu; Silverman, Jill L.; Solomon, Marjorie

2016-01-01

Animal models provide preclinical tools to investigate the causal role of genetic mutations and environmental factors in the etiology of autism spectrum disorder (ASD). Knockout and humanized knock-in mice, and more recently knockout rats, have been generated for many of the de novo single gene mutations and copy number variants (CNVs) detected in ASD and comorbid neurodevelopmental disorders. Mouse models incorporating genetic and environmental manipulations have been employed for preclinical testing of hypothesis-driven pharmacological targets, to begin to develop treatments for the diagnostic and associated symptoms of autism. In this review, we summarize rodent behavioral assays relevant to the core features of autism, preclinical and clinical evaluations of pharmacological interventions, and strategies to improve the translational value of rodent models of autism. PMID:27305922

Pharmacogenomic prediction of anthracycline-induced cardiotoxicity in children.

PubMed

Visscher, Henk; Ross, Colin J D; Rassekh, S Rod; Barhdadi, Amina; Dubé, Marie-Pierre; Al-Saloos, Hesham; Sandor, George S; Caron, Huib N; van Dalen, Elvira C; Kremer, Leontien C; van der Pal, Helena J; Brown, Andrew M K; Rogers, Paul C; Phillips, Michael S; Rieder, Michael J; Carleton, Bruce C; Hayden, Michael R

2012-05-01

Anthracycline-induced cardiotoxicity (ACT) is a serious adverse drug reaction limiting anthracycline use and causing substantial morbidity and mortality. Our aim was to identify genetic variants associated with ACT in patients treated for childhood cancer. We carried out a study of 2,977 single-nucleotide polymorphisms (SNPs) in 220 key drug biotransformation genes in a discovery cohort of 156 anthracycline-treated children from British Columbia, with replication in a second cohort of 188 children from across Canada and further replication of the top SNP in a third cohort of 96 patients from Amsterdam, the Netherlands. We identified a highly significant association of a synonymous coding variant rs7853758 (L461L) within the SLC28A3 gene with ACT (odds ratio, 0.35; P = 1.8 × 10(-5) for all cohorts combined). Additional associations (P < .01) with risk and protective variants in other genes including SLC28A1 and several adenosine triphosphate-binding cassette transporters (ABCB1, ABCB4, and ABCC1) were present. We further explored combining multiple variants into a single-prediction model together with clinical risk factors and classification of patients into three risk groups. In the high-risk group, 75% of patients were accurately predicted to develop ACT, with 36% developing this within the first year alone, whereas in the low-risk group, 96% of patients were accurately predicted not to develop ACT. We have identified multiple genetic variants in SLC28A3 and other genes associated with ACT. Combined with clinical risk factors, genetic risk profiling might be used to identify high-risk patients who can then be provided with safer treatment options.

Detecting genotypic changes associated with selective mortality at sea in Atlantic salmon: polygenic multilocus analysis surpasses genome scan.

PubMed

Bourret, Vincent; Dionne, Mélanie; Bernatchez, Louis

2014-09-01

Wild populations of Atlantic salmon have declined worldwide. While the causes for this decline may be complex and numerous, increased mortality at sea is predicted to be one of the major contributing factors. Examining the potential changes occurring in the genome-wide composition of populations during this migration has the potential to tease apart some of the factors influencing marine mortality. Here, we genotyped 5568 SNPs in Atlantic salmon populations representing two distinct regional genetic groups and across two cohorts to test for differential allelic and genotypic frequencies between juveniles (smolts) migrating to sea and adults (grilses) returning to freshwater after 1 year at sea. Given the complexity of the traits potentially associated with sea mortality, we contrasted the outcomes of a single-locus F(ST) based genome scan method with a new multilocus framework to test for genetically based differential mortality at sea. While numerous outliers were identified by the single-locus analysis, no evidence for parallel, temporally repeated selection was found. In contrast, the multilocus approach detected repeated patterns of selection for a multilocus group of 34 covarying SNPs in one of the two populations. No significant pattern of selective mortality was detected in the other population, suggesting different causes of mortality among populations. These results first support the hypothesis that selection mainly causes small changes in allele frequencies among many covarying loci rather than a small number of changes in loci with large effects. They also point out that moving away from the a strict 'selective sweep paradigm' towards a multilocus genetics framework may be a more useful approach for studying the genomic signatures of natural selection on complex traits in wild populations. © 2014 John Wiley & Sons Ltd.

Combined Medical and Surgical Approach Improves Healing of Septic Perianal Crohn's Disease.

PubMed

Choi, Christine S; Berg, Arthur S; Sangster, William; Schieffer, Kathleen M; Harris, Leonard R; Deiling, Sue M; Koltun, Walter A

2016-09-01

Septic perianal Crohn's disease (SPCD) is a treatment challenge in spite of tumor necrosis factor antagonists (anti-TNF). Our aim was to define the success of SPCD management with a combined medical and surgical approach and to identify clinical and genetic factors predictive of healing. A retrospective chart review of patients with SPCD treated at the Penn State Milton S Hershey Medical Center was done. Primary end point was complete healing (ie normal clinical exam and no pain for at least 6 months). Genetic analysis of 185 single nucleotide polymorphisms associated with Crohn's disease was performed in 78 patients. One hundred and thirty-five episodes of SPCD were identified in 114 patients with a mean follow-up of 77 ± 7.4 months. Overall, 80 of 135 episodes healed (59.3%) and did not differ between those receiving anti-TNF and not (60.4% vs 56.8%). There appeared to be a consistent improved heal rate in each subcategory of surgically managed patients that received anti-TNF. Female sex was significantly predictive of healing in only those receiving anti-TNF agents (63.6% vs 25.0%; p = 0.0005). Twenty-two (19.3%) patients ultimately received a permanent diversion with either a total proctocolectomy or completion proctectomy. Multivariate analysis suggested several single nucleotide polymorphisms in Crohn's disease-associated genes to be possibly associated with healing, but lost significance after Bonferroni correction. Overall, there is an approximate 60% rate of healing SPCD using a combined medical and surgical approach. About 20% of SPCD patients will require a permanent stoma. There were no clear genetic predictors of healing SPCD. Copyright © 2016 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Genetic testing in congenital heart disease: A clinical approach

PubMed Central

Chaix, Marie A; Andelfinger, Gregor; Khairy, Paul

2016-01-01

Congenital heart disease (CHD) is the most common type of birth defect. Traditionally, a polygenic model defined by the interaction of multiple genes and environmental factors was hypothesized to account for different forms of CHD. It is now understood that the contribution of genetics to CHD extends beyond a single unified paradigm. For example, monogenic models and chromosomal abnormalities have been associated with various syndromic and non-syndromic forms of CHD. In such instances, genetic investigation and testing may potentially play an important role in clinical care. A family tree with a detailed phenotypic description serves as the initial screening tool to identify potentially inherited defects and to guide further genetic investigation. The selection of a genetic test is contingent upon the particular diagnostic hypothesis generated by clinical examination. Genetic investigation in CHD may carry the potential to improve prognosis by yielding valuable information with regards to personalized medical care, confidence in the clinical diagnosis, and/or targeted patient follow-up. Moreover, genetic assessment may serve as a tool to predict recurrence risk, define the pattern of inheritance within a family, and evaluate the need for further family screening. In some circumstances, prenatal or preimplantation genetic screening could identify fetuses or embryos at high risk for CHD. Although genetics may appear to constitute a highly specialized sector of cardiology, basic knowledge regarding inheritance patterns, recurrence risks, and available screening and diagnostic tools, including their strengths and limitations, could assist the treating physician in providing sound counsel. PMID:26981213

Determinism and Underdetermination in Genetics: Implications for Students' Engagement in Argumentation and Epistemic Practices

NASA Astrophysics Data System (ADS)

Jiménez-Aleixandre, María Pilar

2014-02-01

In the last two decades science studies and science education research have shifted from an interest in products (of science or of learning), to an interest in processes and practices. The focus of this paper is on students' engagement in epistemic practices (Kelly in Teaching scientific inquiry: Recommendations for research and implementation. Sense Publishers, Rotterdam, pp 99-117, 2008), or on their practical epistemologies (Wickman in Sci Educ 88(3):325-344, 2004). In order to support these practices in genetics classrooms we need to take into account domain-specific features of the epistemology of genetics, in particular issues about determinism and underdetermination. I suggest that certain difficulties may be related to the specific nature of causality in genetics, and in particular to the correspondence between a given set of factors and a range of potential effects, rather than a single one. The paper seeks to bring together recent developments in the epistemology of biology and of genetics, on the one hand, with science education approaches about epistemic practices, on the other. The implications of these perspectives for current challenges in learning genetics are examined, focusing on students' engagement in epistemic practices, as argumentation, understood as using evidence to evaluate knowledge claims. Engaging in argumentation in genetics classrooms is intertwined with practices such as using genetics models to build explanations, or framing genetics issues in their social context. These challenges are illustrated with studies making part of our research program in the USC.

Association of human height-related genetic variants with familial short stature in Han Chinese in Taiwan.

PubMed

Lin, Ying-Ju; Liao, Wen-Ling; Wang, Chung-Hsing; Tsai, Li-Ping; Tang, Chih-Hsin; Chen, Chien-Hsiun; Wu, Jer-Yuarn; Liang, Wen-Miin; Hsieh, Ai-Ru; Cheng, Chi-Fung; Chen, Jin-Hua; Chien, Wen-Kuei; Lin, Ting-Hsu; Wu, Chia-Ming; Liao, Chiu-Chu; Huang, Shao-Mei; Tsai, Fuu-Jen

2017-07-25

Human height can be described as a classical and inherited trait model. Genome-wide association studies (GWAS) have revealed susceptible loci and provided insights into the polygenic nature of human height. Familial short stature (FSS) represents a suitable trait for investigating short stature genetics because disease associations with short stature have been ruled out in this case. In addition, FSS is caused only by genetically inherited factors. In this study, we explored the correlations of FSS risk with the genetic loci associated with human height in previous GWAS, alone and cumulatively. We systematically evaluated 34 known human height single nucleotide polymorphisms (SNPs) in relation to FSS in the additive model (p < 0.00005). A cumulative effect was observed: the odds ratios gradually increased with increasing genetic risk score quartiles (p < 0.001; Cochran-Armitage trend test). Six affected genes-ZBTB38, ZNF638, LCORL, CABLES1, CDK10, and TSEN15-are located in the nucleus and have been implicated in embryonic, organismal, and tissue development. In conclusion, our study suggests that 13 human height GWAS-identified SNPs are associated with FSS risk both alone and cumulatively.

Genetic variants and cognitive aging: destiny or a nudge?

PubMed

Raz, Naftali; Lustig, Cindy

2014-06-01

One would be hard-pressed to find a human trait that is not heritable at least to some extent, and genetics have played an important role in behavioral science for more than half a century. With the advent of high-throughput molecular methods and the increasing availability of genomic analyses, genetics have acquired a firm foothold in public discourse. However, although the proliferation of genetic association studies and ever-expanding library of single-nucleotide polymorphisms have generated some fascinating results, they have thus far fallen short of delivering the anticipated dramatic breakthroughs. In this collection of eight articles, we present a spectrum of efforts aimed at finding more nuanced and meaningful ways of integrating genomic findings into the study of cognitive aging. The articles present examples of Mendelian randomization in the service of investigating difficult-to-manipulate biochemical properties of human participants. Furthermore, in an important step forward, they acknowledge the interactive effects of genes and physiological risk factors on age-related difference and change in cognitive performance, as well as the possibility of modifying the negative effect of genetic variants by lifestyle changes. PsycINFO Database Record (c) 2014 APA, all rights reserved.

TATES: Efficient Multivariate Genotype-Phenotype Analysis for Genome-Wide Association Studies

PubMed Central

van der Sluis, Sophie; Posthuma, Danielle; Dolan, Conor V.

2013-01-01

To date, the genome-wide association study (GWAS) is the primary tool to identify genetic variants that cause phenotypic variation. As GWAS analyses are generally univariate in nature, multivariate phenotypic information is usually reduced to a single composite score. This practice often results in loss of statistical power to detect causal variants. Multivariate genotype–phenotype methods do exist but attain maximal power only in special circumstances. Here, we present a new multivariate method that we refer to as TATES (Trait-based Association Test that uses Extended Simes procedure), inspired by the GATES procedure proposed by Li et al (2011). For each component of a multivariate trait, TATES combines p-values obtained in standard univariate GWAS to acquire one trait-based p-value, while correcting for correlations between components. Extensive simulations, probing a wide variety of genotype–phenotype models, show that TATES's false positive rate is correct, and that TATES's statistical power to detect causal variants explaining 0.5% of the variance can be 2.5–9 times higher than the power of univariate tests based on composite scores and 1.5–2 times higher than the power of the standard MANOVA. Unlike other multivariate methods, TATES detects both genetic variants that are common to multiple phenotypes and genetic variants that are specific to a single phenotype, i.e. TATES provides a more complete view of the genetic architecture of complex traits. As the actual causal genotype–phenotype model is usually unknown and probably phenotypically and genetically complex, TATES, available as an open source program, constitutes a powerful new multivariate strategy that allows researchers to identify novel causal variants, while the complexity of traits is no longer a limiting factor. PMID:23359524

Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk

PubMed Central

Fischer, Annegret; Ellinghaus, David; Nutsua, Marcel; Hofmann, Sylvia; Montgomery, Courtney G.; Iannuzzi, Michael C.; Rybicki, Benjamin A.; Petrek, Martin; Mrazek, Frantisek; Pabst, Stefan; Grohé, Christian; Grunewald, Johan; Ronninger, Marcus; Eklund, Anders; Padyukov, Leonid; Mihailovic-Vucinic, Violeta; Jovanovic, Dragana; Sterclova, Martina; Homolka, Jiri; Nöthen, Markus M.; Herms, Stefan; Gieger, Christian; Strauch, Konstantin; Winkelmann, Juliane; Boehm, Bernhard O.; Brand, Stephan; Büning, Carsten; Schürmann, Manfred; Ellinghaus, Eva; Baurecht, Hansjörg; Lieb, Wolfgang; Nebel, Almut; Müller-Quernheim, Joachim; Franke, Andre

2015-01-01

Rationale: Genetic variation plays a significant role in the etiology of sarcoidosis. However, only a small fraction of its heritability has been explained so far. Objectives: To define further genetic risk loci for sarcoidosis, we used the Immunochip for a candidate gene association study of immune-associated loci. Methods: Altogether the study population comprised over 19,000 individuals. In a two-stage design, 1,726 German sarcoidosis cases and 5,482 control subjects were genotyped for 128,705 single-nucleotide polymorphisms using the Illumina Immunochip for the screening step. The remaining 3,955 cases, 7,514 control subjects, and 684 parents of affected offspring were used for validation and replication of 44 candidate and two established risk single-nucleotide polymorphisms. Measurements and Main Results: Four novel susceptibility loci were identified with genome-wide significance in the European case-control populations, located on chromosomes 12q24.12 (rs653178; ATXN2/SH2B3), 5q33.3 (rs4921492; IL12B), 4q24 (rs223498; MANBA/NFKB1), and 2q33.2 (rs6748088; FAM117B). We further defined three independent association signals in the HLA region with genome-wide significance, peaking in the BTNL2 promoter region (rs5007259), at HLA-B (rs4143332/HLA-B*0801) and at HLA-DPB1 (rs9277542), and found another novel independent signal near IL23R (rs12069782) on chromosome 1p31.3. Conclusions: Functional predictions and protein network analyses suggest a prominent role of the drug-targetable IL23/Th17 signaling pathway in the genetic etiology of sarcoidosis. Our findings reveal a substantial genetic overlap of sarcoidosis with diverse immune-mediated inflammatory disorders, which could be of relevance for the clinical application of modern therapeutics PMID:26051272

High Points of Human Genetics

ERIC Educational Resources Information Center

Stern, Curt

1975-01-01

Discusses such high points of human genetics as the study of chromosomes, somatic cell hybrids, the population formula: the Hardy-Weinberg Law, biochemical genetics, the single-active X Theory, behavioral genetics and finally how genetics can serve humanity. (BR)

Genetic characterization, at the mitochondrial and nuclear DNA levels, of five Canary Island dog breeds.

PubMed

Suárez, N M; Betancor, E; Fregel, R; Pestano, J

2013-08-01

Many studies presenting genetic analysis of dog breeds have been conducted without the inclusion of island dog breeds, although isolation can be one of the main factors in their origin. Here we report the genetic analysis at the nuclear and mitochondrial DNA levels of five Canary Island dog breeds (Canarian Warren Hound, Canary Island Mastiff, Garafiano Shepherd, La Palma Rat-Hunter and El Hierro Wolfhound) to fill this gap and, at the same time, genetically characterize these breeds. We identified 168 alleles in autosomal microsatellites and 16 mitochondrial haplotypes. Observed and expected heterozygosities ranged from 0.556 to 0.783 and from 0.737 to 0.943 respectively. Furthermore, three haplotypes were newly described and exclusive to a particular breed (A17+ in the Canary Island Mastiff; A33+ in the Canarian Warren Hound; Bi in the La Palma Rat-Hunter). The outcome of our analyses also revealed different breed histories consistent with historical documents and hypothetical origin designations. Although mtDNA haplotypes showed poor breed discriminating power, autosomal markers allowed a clear clustering of each single population. We expect that our results, together with further analyses, will help to make the population histories of island dog breeds clearer. © 2013 The Authors, Animal Genetics © 2013 Stichting International Foundation for Animal Genetics.

Complex Adaptive System Models and the Genetic Analysis of Plasma HDL-Cholesterol Concentration

PubMed Central

Rea, Thomas J.; Brown, Christine M.; Sing, Charles F.

2006-01-01

Despite remarkable advances in diagnosis and therapy, ischemic heart disease (IHD) remains a leading cause of morbidity and mortality in industrialized countries. Recent efforts to estimate the influence of genetic variation on IHD risk have focused on predicting individual plasma high-density lipoprotein cholesterol (HDL-C) concentration. Plasma HDL-C concentration (mg/dl), a quantitative risk factor for IHD, has a complex multifactorial etiology that involves the actions of many genes. Single gene variations may be necessary but are not individually sufficient to predict a statistically significant increase in risk of disease. The complexity of phenotype-genotype-environment relationships involved in determining plasma HDL-C concentration has challenged commonly held assumptions about genetic causation and has led to the question of which combination of variations, in which subset of genes, in which environmental strata of a particular population significantly improves our ability to predict high or low risk phenotypes. We document the limitations of inferences from genetic research based on commonly accepted biological models, consider how evidence for real-world dynamical interactions between HDL-C determinants challenges the simplifying assumptions implicit in traditional linear statistical genetic models, and conclude by considering research options for evaluating the utility of genetic information in predicting traits with complex etiologies. PMID:17146134

Extensive long-distance pollen dispersal in a fragmented landscape maintains genetic diversity in white spruce.

PubMed

O'Connell, Lisa M; Mosseler, Alex; Rajora, Om P

2007-01-01

Conifers are among the most genetically diverse plants but show the lowest levels of genetic differentiation, even among geographically distant populations. High gene flow among populations may be one of the most important factors in maintaining these genetic patterns. Here, we provide empirical evidence for extensive pollen-mediated gene dispersal between natural stands of a widespread northern temperate/boreal conifer, Picea glauca. We used 6 polymorphic allozyme loci to quantify the proportion of seeds sired by pollen originating from different sources in a landscape fragmented by agriculture in North Central Ontario, Canada. In 7 stands, a small proportion of seeds were sired by self-pollen or neighboring trees but 87.1% (+/-1.7% standard error [SE]) of seeds were sired by pollen from at least 250 to 3000 m away. In 4 single isolated trees, self-fertilization rates were low and more than 96% (+/-1.3% SE) of seeds were sired by immigrant pollen. The average minimum pollen dispersal distance in outcrossed matings was 619 m. These results provide strong evidence that extensive long-distance pollen dispersal plays a primary role in maintaining low genetic differentiation among natural populations of P. glauca and helps maintain genetic diversity and minimize inbreeding in small stands in a fragmented landscape.

Toxicogenomics and Cancer Susceptibility: Advances with Next-Generation Sequencing

PubMed Central

Ning, Baitang; Su, Zhenqiang; Mei, Nan; Hong, Huixiao; Deng, Helen; Shi, Leming; Fuscoe, James C.; Tolleson, William H.

2017-01-01

The aim of this review is to comprehensively summarize the recent achievements in the field of toxicogenomics and cancer research regarding genetic-environmental interactions in carcinogenesis and detection of genetic aberrations in cancer genomes by next-generation sequencing technology. Cancer is primarily a genetic disease in which genetic factors and environmental stimuli interact to cause genetic and epigenetic aberrations in human cells. Mutations in the germline act as either high-penetrance alleles that strongly increase the risk of cancer development, or as low-penetrance alleles that mildly change an individual’s susceptibility to cancer. Somatic mutations, resulting from either DNA damage induced by exposure to environmental mutagens or from spontaneous errors in DNA replication or repair are involved in the development or progression of the cancer. Induced or spontaneous changes in the epigenome may also drive carcinogenesis. Advances in next-generation sequencing technology provide us opportunities to accurately, economically, and rapidly identify genetic variants, somatic mutations, gene expression profiles, and epigenetic alterations with single-base resolution. Whole genome sequencing, whole exome sequencing, and RNA sequencing of paired cancer and adjacent normal tissue present a comprehensive picture of the cancer genome. These new findings should benefit public health by providing insights in understanding cancer biology, and in improving cancer diagnosis and therapy. PMID:24875441

Inherited XX sex reversal originating from wild medaka populations.

PubMed

Shinomiya, A; Otake, H; Hamaguchi, S; Sakaizumi, M

2010-11-01

The teleost fish, medaka (Oryzias latipes), has an XX/XY sex-determining mechanism. A Y-linked DM domain gene, DMY, has been isolated by positional cloning as the sex-determining gene in this species. Previously, we conducted a field survey of genotypic sex and found that approximately 1% of wild medaka are sex-reversed (XX males and XY females). Here, we performed genetic analyses of nine spontaneous XX sex-reversed males to elucidate its genetic basis. In all cases, the F(1) progeny were all females, whereas XX males reappeared in the backcross (BC) progeny, suggesting that XX sex reversal is a recessive trait. Although the incidences of sex reversal in the BC progeny were mostly low, 40% were males derived from one XX male. We performed linkage analysis using 55 BC males and located a single major factor, sda-1 (sex-determining autosomal factor-1), controlling sex reversal in an autosomal linkage group. Thus, genes involved in the sex-determining pathway can be isolated from spontaneous mutants in wild populations.

An exploratory study of differences in views of factors affecting sexual orientation for a sample of lesbians and gay men.

PubMed

Otis, Melanie D; Skinner, William F

2004-06-01

An exploratory study of lesbians (70) and gay men (118) from a rural state in the mid-South was conducted using a self-administered, mail-out survey. The nonrandom sample was drawn from organizational mailing lists, snowball sampling, and a convenience sample at a community event. Respondents were asked to indicate the extent to which each of the following affected sexual orientation: genetics, relationship between parents, relationship with parents, birth order, peers, growing up in a dysfunctional family, growing up in a single-parent family, negative experiences with the opposite sex, and positive experiences with the same sex. Similar to studies of heterosexual men and women, these gay men were more likely to view sexual orientation as a result of genetics than the lesbian respondents. Further, the lesbian group were more likely to view positive relationships with the same sex to have a great influence on sexual orientation. These data indicate there are sex differences in views on factors that affect sexual orientation.

Variations in working memory capacity predict individual differences in general learning abilities among genetically diverse mice.

PubMed

Kolata, Stefan; Light, Kenneth; Townsend, David A; Hale, Gregory; Grossman, Henya C; Matzel, Louis D

2005-11-01

Up to 50% of an individuals' performance across a wide variety of distinct cognitive tests can be accounted for by a single factor (i.e., "general intelligence"). Despite its ubiquity, the processes or mechanisms regulating this factor are a matter of considerable debate. Although it has been hypothesized that working memory may impact cognitive performance across various domains, tests have been inconclusive due to the difficulty in isolating working memory from its overlapping operations, such as verbal ability. We address this problem using genetically diverse mice, which exhibit a trait analogous to general intelligence. The general cognitive abilities of CD-1 mice were found to covary with individuals' working memory capacity, but not with variations in long-term retention. These results provide evidence that independent of verbal abilities, variations in working memory are associated with general cognitive abilities, and further, suggest a conservation across species of mechanisms and/or processes that regulate cognitive abilities.

Mechanisms of mutations in myeloproliferative neoplasms.

PubMed

Levine, Ross L

2009-12-01

In recent years, a series of studies have provided genetic insight into the pathogenesis of myeloproliferative neoplasms (MPNs). It is now known that JAK2V617F mutations are present in 90% of patients with polycythaemia vera (PV), 60% of patients with essential thrombocytosis (ET) and 50% of patients with myelofibrosis (MF). Despite the high prevalence of JAK2V617F mutations in these three myeloid malignancies, several questions remain. For example, how does one mutation contribute to the pathogenesis of three clinically distinct diseases, and how do some patients develop these diseases in the absence of a JAK2V617F mutation? Single nucleotide polymorphisms at various loci and somatic mutations, such as those in MPLW515L/K, TET2 and in exon 12 of JAK2, may also contribute to the pathogenesis of these MPNs. There are likely additional germline and somatic genetic factors important to the MPN phenotype. Additional studies of large MPN and control cohorts with new techniques will help identify these factors.

Single stem cell gene therapy for genetic skin disease.

PubMed

Larsimont, Jean-Christophe; Blanpain, Cédric

2015-04-01

Stem cell gene therapy followed by transplantation into damaged regions of the skin has been successfully used to treat genetic skin blistering disorder. Usually, many stem cells are virally transduced to obtain a sufficient number of genetically corrected cells required for successful transplantation, as genetic insertion in every stem cell cannot be precisely defined. In this issue of EMBO Molecular Medicine, Droz-Georget Lathion et al developed a new strategy for ex vivo single cell gene therapy that allows extensive genomic and functional characterization of the genetically repaired individual cells before they can be used in clinical settings.

Association analyses of vitamin D-binding protein gene with compression strength index variation in Caucasian nuclear families.

PubMed

Xu, X-H; Xiong, D-H; Liu, X-G; Guo, Y; Chen, Y; Zhao, J; Recker, R R; Deng, H-W

2010-01-01

This study was conducted to test whether there exists an association between vitamin D-binding protein (DBP) gene and compression strength index (CSI) phenotype. Candidate gene association analyses were conducted in total sample, male subgroup, and female subgroup, respectively. Two single-nucleotide polymorphisms (SNPs) with significant association results were found in males, suggesting the importance of DBP gene polymorphisms on the variation in CSI especially in Caucasian males. CSI of the femoral neck (FN) is a newly developed phenotype integrating information about bone size, body size, and bone mineral density. It is considered to have the potential to improve the performance of risk assessment for hip fractures because it is based on a combination of phenotypic traits influencing hip fractures rather than a single trait. CSI is under moderate genetic determination (with a heritability of approximately 44% found in this study), but the relevant genetic study is still rather scarce. Based on the known physiological role of DBP in bone biology and the relatively high heritability of CSI, we tested 12 SNPs of the DBP gene for association with CSI variation in 405 Caucasian nuclear families comprising 1,873 subjects from the Midwestern US. Association analyses were performed in the total sample, male and female subgroups, respectively. Significant associations with CSI were found with two SNPs (rs222029, P = 0.0019; rs222020, P = 0.0042) for the male subgroup. Haplotype-based association tests corroborated the single-SNP results. Our findings suggest that the DBP gene might be one of the genetic factors influencing CSI phenotype in Caucasians, especially in males.

Single-Nucleotide Polymorphisms Associated with Skin Naphthyl–Keratin Adduct Levels in Workers Exposed to Naphthalene

PubMed Central

Jiang, Rong; French, John E.; Stober, Vandy P.; Kang-Sickel, Juei-Chuan C.; Zou, Fei

2012-01-01

Background: Individual genetic variation that results in differences in systemic response to xenobiotic exposure is not accounted for as a predictor of outcome in current exposure assessment models. Objective: We developed a strategy to investigate individual differences in single-nucleotide polymorphisms (SNPs) as genetic markers associated with naphthyl–keratin adduct (NKA) levels measured in the skin of workers exposed to naphthalene. Methods: The SNP-association analysis was conducted in PLINK using candidate-gene analysis and genome-wide analysis. We identified significant SNP–NKA associations and investigated the potential impact of these SNPs along with personal and workplace factors on NKA levels using a multiple linear regression model and the Pratt index. Results: In candidate-gene analysis, a SNP (rs4852279) located near the CYP26B1 gene contributed to the 2-naphthyl–keratin adduct (2NKA) level. In the multiple linear regression model, the SNP rs4852279, dermal exposure, exposure time, task replacing foam, age, and ethnicity all were significant predictors of 2NKA level. In genome-wide analysis, no single SNP reached genome-wide significance for NKA levels (all p ≥ 1.05 × 10–5). Pathway and network analyses of SNPs associated with NKA levels were predicted to be involved in the regulation of cellular processes and homeostasis. Conclusions: These results provide evidence that a quantitative biomarker can be used as an intermediate phenotype when investigating the association between genetic markers and exposure–dose relationship in a small, well-characterized exposed worker population. PMID:22391508

The Role of Host and Microbial Factors in the Pathogenesis of Pneumococcal Bacteraemia Arising from a Single Bacterial Cell Bottleneck

PubMed Central

Furi, Leonardo; Braccini, Tiziana; Manso, Ana Sousa; Pammolli, Andrea; Wang, Bo; Vivi, Antonio; Tassini, Maria; van Rooijen, Nico; Pozzi, Gianni; Ricci, Susanna; Andrew, Peter W.; Koedel, Uwe; Moxon, E. Richard; Oggioni, Marco R.

2014-01-01

The pathogenesis of bacteraemia after challenge with one million pneumococci of three isogenic variants was investigated. Sequential analyses of blood samples indicated that most episodes of bacteraemia were monoclonal events providing compelling evidence for a single bacterial cell bottleneck at the origin of invasive disease. With respect to host determinants, results identified novel properties of splenic macrophages and a role for neutrophils in early clearance of pneumococci. Concerning microbial factors, whole genome sequencing provided genetic evidence for the clonal origin of the bacteraemia and identified SNPs in distinct sub-units of F0/F1 ATPase in the majority of the ex vivo isolates. When compared to parental organisms of the inoculum, ex-vivo pneumococci with mutant alleles of the F0/F1 ATPase had acquired the capacity to grow at low pH at the cost of the capacity to grow at high pH. Although founded by a single cell, the genotypes of pneumococci in septicaemic mice indicate strong selective pressure for fitness, emphasising the within-host complexity of the pathogenesis of invasive disease. PMID:24651834

Comparative phylogeography of co-distributed Phrygilus species (Aves, Thraupidae) from the Central Andes.

PubMed

Álvarez-Varas, R; González-Acuña, D; Vianna, J A

2015-09-01

The Neotropical ecoregion has been an important place of avian diversification where dispersal and allopatric events coupled with periods of active orogeny and climate change (Late Pliocene-Pleistocene) have shaped the biogeography of the region. In the Neotropics, avian population structure has been sculpted not only by geographical barriers, but also by non-allopatric factors such as natural selection and local adaptation. We analyzed the genetic variation of six co-distributed Phrygilus species from the Central Andes, based on mitochondrial and nuclear markers in conjunction with morphological differentiation. We examined if Phrygilus species share patterns of population structure and historical demography, and reviewed the intraspecific taxonomy in part of their geographic range. Our results showed different phylogeographic patterns between species, even among those belonging to the same phylogenetic clade. P. alaudinus, P. atriceps, and P. unicolor showed genetic differentiation mediated by allopatric mechanisms in response to specific geographic barriers; P. gayi showed sympatric lineages in northern Chile, while P. plebejus and P. fruticeti showed a single genetic group. We found no relationship between geographic range size and genetic structure. Additionally, a signature of expansion was found in three species related to the expansion of paleolakes in the Altiplano region and the drying phase of the Atacama Desert. Morphological analysis showed congruence with molecular data and intraspecific taxonomy in most species. While we detected genetic and phenotypic patterns that could be related to natural selection and local adaptation, our results indicate that allopatric events acted as a major factor in the population differentiation of Phrygilus species. Copyright © 2015 Elsevier Inc. All rights reserved.

Landscape genomics in Atlantic salmon (Salmo salar): searching for gene-environment interactions driving local adaptation.

PubMed

Vincent, Bourret; Dionne, Mélanie; Kent, Matthew P; Lien, Sigbjørn; Bernatchez, Louis

2013-12-01

A growing number of studies are examining the factors driving historical and contemporary evolution in wild populations. By combining surveys of genomic variation with a comprehensive assessment of environmental parameters, such studies can increase our understanding of the genomic and geographical extent of local adaptation in wild populations. We used a large-scale landscape genomics approach to examine adaptive and neutral differentiation across 54 North American populations of Atlantic salmon representing seven previously defined genetically distinct regional groups. Over 5500 genome-wide single nucleotide polymorphisms were genotyped in 641 individuals and 28 bulk assays of 25 pooled individuals each. Genome scans, linkage map, and 49 environmental variables were combined to conduct an innovative landscape genomic analysis. Our results provide valuable insight into the links between environmental variation and both neutral and potentially adaptive genetic divergence. In particular, we identified markers potentially under divergent selection, as well as associated selective environmental factors and biological functions with the observed adaptive divergence. Multivariate landscape genetic analysis revealed strong associations of both genetic and environmental structures. We found an enrichment of growth-related functions among outlier markers. Climate (temperature-precipitation) and geological characteristics were significantly associated with both potentially adaptive and neutral genetic divergence and should be considered as candidate loci involved in adaptation at the regional scale in Atlantic salmon. Hence, this study significantly contributes to the improvement of tools used in modern conservation and management schemes of Atlantic salmon wild populations. © 2013 The Author(s). Evolution © 2013 The Society for the Study of Evolution.

Recent developments in the genetics of schizophrenia.

PubMed

Shastry, B S

1999-09-01

Schizophrenia, which is also called "split personality," is a complex and multifactorial mental disorder with variable clinical manifestations. It perhaps represents several diseases and occurs throughout the world. It is a more-prevalent disorder among homeless people and is clinically characterized by hallucinations and delusions. The pathophysiology of schizophrenia is not localized to a single region of the brain and the etiology of this illness is not understood. Because of its complex pattern of inheritance, genetic techniques are not readily applicable in identifying the genes responsible for this disorder. Family, twin, and adoption studies, however, provide strong but indirect support for genetic components in the etiology of schizophrenia. Extensive linkage analyses now suggest that susceptibility genes may be present on chromosomes 5q, 6p, 8p, 13q, 18p, and 22q. Identification and characterization of these and other genes, as well as non-genetic factors, is one of the greatest challenges in biomedicine. This may ultimately lead to the development of a new line of effective and safe drugs or treatments for its prevention or cure.

Complementary sex determination substantially increases extinction proneness of haplodiploid populations.

PubMed

Zayed, Amro; Packer, Laurence

2005-07-26

The role of genetic factors in extinction is firmly established for diploid organisms, but haplodiploids have been considered immune to genetic load impacts because deleterious alleles are readily purged in haploid males. However, we show that single-locus complementary sex determination ancestral to the haplodiploid Hymenoptera (ants, bees, and wasps) imposes a substantial genetic load through homozygosity at the sex locus that results in the production of inviable or sterile diploid males. Using stochastic modeling, we have discovered that diploid male production (DMP) can initiate a rapid and previously uncharacterized extinction vortex. The extinction rate in haplodiploid populations with DMP is an order of magnitude greater than in its absence under realistic but conservative demographic parameter values. Furthermore, DMP alone can elevate the base extinction risk in haplodiploids by over an order of magnitude higher than that caused by inbreeding depression in threatened diploids. Thus, contrary to previous expectations, haplodiploids are more, rather than less, prone to extinction for genetic reasons. Our findings necessitate a fundamental shift in approaches to the conservation and population biology of these ecologically and economically crucial insects.

The effect of increased genetic risk for Alzheimer’s disease on hippocampal and amygdala volume

PubMed Central

Lupton, Michelle K.; Strike, Lachlan; Hansell, Narelle K.; Wen, Wei; Mather, Karen A.; Armstrong, Nicola J.; Thalamuthu, Anbupalam; McMahon, Katie L.; de Zubicaray, Greig I.; Assareh, Amelia A.; Simmons, Andrew; Proitsi, Petroula; Powell, John F.; Montgomery, Grant W.; Hibar, Derrek P.; Westman, Eric; Tsolaki, Magda; Kloszewska, Iwona; Soininen, Hilkka; Mecocci, Patrizia; Velas, Bruno; Lovestone, Simon; Brodaty, Henry; Ames, David; Trollor, Julian N.; Martin, Nicholas G.; Thompson, Paul M.; Sachdev, Perminder S.; Wright, Margaret J.

2016-01-01

Reduction in hippocampal and amygdala volume measured via structural magnetic resonance imaging is an early marker of Alzheimer’s disease (AD). Whether genetic risk factors for AD exert an effect on these subcortical structures independent of clinical status has not been fully investigated. We examine whether increased genetic risk for AD influences hippocampal and amygdala volumes in case-control and population cohorts at different ages, in 1674 older (aged >53 years; 17% AD, 39% mild cognitive impairment [MCI]) and 467 young (16–30 years) adults. An AD polygenic risk score combining common risk variants excluding apolipoprotein E (APOE), and a single nucleotide polymorphism in TREM2, were both associated with reduced hippocampal volume in healthy older adults and those with MCI. APOE ɛ4 was associated with hippocampal and amygdala volume in those with AD and MCI but was not associated in healthy older adults. No associations were found in young adults. Genetic risk for AD affects the hippocampus before the clinical symptoms of AD, reflecting a neurodegenerative effect before clinical manifestations in older adults. PMID:26973105

The legacy of domestication: accumulation of deleterious mutations in the dog genome.

PubMed

Cruz, Fernando; Vilà, Carles; Webster, Matthew T

2008-11-01

Dogs exhibit more phenotypic variation than any other mammal and are affected by a wide variety of genetic diseases. However, the origin and genetic basis of this variation is still poorly understood. We examined the effect of domestication on the dog genome by comparison with its wild ancestor, the gray wolf. We compared variation in dog and wolf genes using whole-genome single nucleotide polymorphism (SNP) data. The d(N)/d(S) ratio (omega) was around 50% greater for SNPs found in dogs than in wolves, indicating that a higher proportion of nonsynonymous alleles segregate in dogs compared with nonfunctional genetic variation. We suggest that the majority of these alleles are slightly deleterious and that two main factors may have contributed to their increase. The first is a relaxation of selective constraint due to a population bottleneck and altered breeding patterns accompanying domestication. The second is a reduction of effective population size at loci linked to those under positive selection due to Hill-Robertson interference. An increase in slightly deleterious genetic variation could contribute to the prevalence of disease in modern dog breeds.

Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease

PubMed Central

Small, Gary W.; Ercoli, Linda M.; Silverman, Daniel H. S.; Huang, S.-C.; Komo, Scott; Bookheimer, Susan Y.; Lavretsky, Helen; Miller, Karen; Siddarth, Prabha; Rasgon, Natalie L.; Mazziotta, John C.; Saxena, Sanjaya; Wu, H. M.; Mega, Michael S.; Cummings, Jeffrey L.; Saunders, Ann M.; Pericak-Vance, Margaret A.; Roses, Allen D.; Barrio, Jorge R.; Phelps, Michael E.

2000-01-01

The major known genetic risk for Alzheimer's disease (AD), apolipoprotein E-4 (APOE-4), is associated with lowered parietal, temporal, and posterior cingulate cerebral glucose metabolism in patients with a clinical diagnosis of AD. To determine cognitive and metabolic decline patterns according to genetic risk, we investigated cerebral metabolic rates by using positron emission tomography in middle-aged and older nondemented persons with normal memory performance. A single copy of the APOE-4 allele was associated with lowered inferior parietal, lateral temporal, and posterior cingulate metabolism, which predicted cognitive decline after 2 years of longitudinal follow-up. For the 20 nondemented subjects followed longitudinally, memory performance scores did not decline significantly, but cortical metabolic rates did. In APOE-4 carriers, a 4% left posterior cingulate metabolic decline was observed, and inferior parietal and lateral temporal regions demonstrated the greatest magnitude (5%) of metabolic decline after 2 years. These results indicate that the combination of cerebral metabolic rates and genetic risk factors provides a means for preclinical AD detection that will assist in response monitoring during experimental treatments. PMID:10811879

Meiotic recombination hotspots - a comparative view.

PubMed

Choi, Kyuha; Henderson, Ian R

2015-07-01

During meiosis homologous chromosomes pair and undergo reciprocal genetic exchange, termed crossover. Meiotic recombination has a profound effect on patterns of genetic variation and is an important tool during crop breeding. Crossovers initiate from programmed DNA double-stranded breaks that are processed to form single-stranded DNA, which can invade a homologous chromosome. Strand invasion events mature into double Holliday junctions that can be resolved as crossovers. Extensive variation in the frequency of meiotic recombination occurs along chromosomes and is typically focused in narrow hotspots, observed both at the level of DNA breaks and final crossovers. We review methodologies to profile hotspots at different steps of the meiotic recombination pathway that have been used in different eukaryote species. We then discuss what these studies have revealed concerning specification of hotspot locations and activity and the contributions of both genetic and epigenetic factors. Understanding hotspots is important for interpreting patterns of genetic variation in populations and how eukaryotic genomes evolve. In addition, manipulation of hotspots will allow us to accelerate crop breeding, where meiotic recombination distributions can be limiting. © 2015 The Authors The Plant Journal © 2015 John Wiley & Sons Ltd.

A cognitive characterization of dyscalculia in Turner syndrome.

PubMed

Bruandet, Marie; Molko, Nicolas; Cohen, Laurent; Dehaene, Stanislas

2004-01-01

Current theories of number processing postulate that the human abilities for arithmetic are based on cerebral circuits that are partially laid down under genetic control and later modified by schooling and education. This view predicts the existence of genetic diseases that interfere specifically with components of the number system. Here, we investigate whether Turner syndrome (TS) corresponds to this definition. TS is a genetic disorder which affects one woman in 2500 and is characterized by partial or complete absence of one X chromosome. In addition to well-characterized physical and hormonal dysfunction, TS patients exhibit cognitive deficits including dyscalculia. We tested 12 women with Turner syndrome and 13 control subjects on a cognitive battery including arithmetical tests (addition, subtraction, multiplication, division) as well as tests of the understanding of numerosity and quantity (cognitive estimation, estimation, comparison, bisection, subitizing/counting). Impairments were observed in cognitive estimation, subitizing, and calculation. We examine whether these deficits can be attributed to a single source, and discuss the possible implications of hormonal and genetic factors in the neuropsychological profile of TS patients.

Experience with multiple control groups in a large population-based case-control study on genetic and environmental risk factors.

PubMed

Pomp, E R; Van Stralen, K J; Le Cessie, S; Vandenbroucke, J P; Rosendaal, F R; Doggen, C J M

2010-07-01

We discuss the analytic and practical considerations in a large case-control study that had two control groups; the first control group consisting of partners of patients and the second obtained by random digit dialling (RDD). As an example of the evaluation of a general lifestyle factor, we present body mass index (BMI). Both control groups had lower BMIs than the patients. The distribution in the partner controls was closer to that of the patients, likely due to similar lifestyles. A statistical approach was used to pool the results of both analyses, wherein partners were analyzed with a matched analysis, while RDDs were analyzed without matching. Even with a matched analysis, the odds ratio with partner controls remained closer to unity than with RDD controls, which is probably due to unmeasured confounders in the comparison with the random controls as well as intermediary factors. However, when studying injuries as a risk factor, the odds ratio remained higher with partner control subjects than with RRD control subjects, even after taking the matching into account. Finally we used factor V Leiden as an example of a genetic risk factor. The frequencies of factor V Leiden were identical in both control groups, indicating that for the analyses of this genetic risk factor the two control groups could be combined in a single unmatched analysis. In conclusion, the effect measures with the two control groups were in the same direction, and of the same order of magnitude. Moreover, it was not always the same control group that produced the higher or lower estimates, and a matched analysis did not remedy the differences. Our experience with the intricacies of dealing with two control groups may be useful to others when thinking about an optimal research design or the best statistical approach.

p16 gene silencing along with p53 single-nucleotide polymorphism and risk of esophageal cancer in Northeast India.

PubMed

Das, Mandakini; Sharma, Santanu Kumar; Sekhon, Gaganpreet Singh; Mahanta, Jagadish; Phukan, Rup Kumar; Jalan, Bimal Kumar

2017-05-01

The high incidence of esophageal cancer in Northeast India and the unique ethnic background and dietary habits provide a great opportunity to study the molecular genetics behind esophageal squamous cell carcinoma in this part of the region. We hypothesized that in addition to currently known environmental risk factors for esophageal cancer, genetic and epigenetic factors are also involved in esophageal carcinogenesis in Northeast India. Therefore, in this study, we explored the possible association between the two important G1 cell cycle regulatory genes p16 and p53 and environmental risk factors and risk of esophageal carcinogenesis. A total of 100 newly diagnosed esophageal cancer cases along with equal number of age-, sex-, and ethnicity-matched controls were included in this study. Methylation-specific polymerase chain reaction was used to determine the p16 promoter methylation status. Single-nucleotide polymorphism at codon 72 of p53 gene was assessed by the polymerase chain reaction-restriction fragment length polymorphism method. Aberrant methylation of p16 gene was seen in 81% of esophageal cancer cases. Hypermethylation of p16 gene was not found in healthy controls. p53 Pro/Pro genotype was found to be a risk genotype in Northeast India compared with Arg/Pro and Arg/Arg. p53 variant/polymorphism was significantly associated with esophageal cancer risk in the study population under all three genetic models, namely, dominant model (Arg/Pro + Pro/Pro vs Arg/Arg odds ratio = 2.25, confidence interval = 1.19-4.26; p = 0.012), recessive model (Arg/Arg + Arg/Pro vs Pro/Pro odds ratio = 2.35, confidence interval = 1.24-4.44; p = 0.008), and homozygous model (Pro/Pro vs Arg/Arg odds ratio = 3.33, confidence interval = 1.54-7.20; p = 0.002). However, p53 variant/polymorphism was not statistically associated with esophageal cancer risk under the heterozygous model (Pro/Pro vs Arg/Pro). In the case-only analysis based on p16 methylation, the p53 variant/polymorphism (Pro/Pro or Arg/Pro) showed significant association for esophageal cancer risk (odds ratio = 3.33, confidence interval = 1.54-7.20; p = 0.002). Gene-gene and gene-environment interaction using the case-only approach revealed a strong association between p16 methylation, p53 single-nucleotide polymorphism, and environmental factors and esophageal cancer risk. Cases with p16 methylation and p53 variant/polymorphism (Pro/Pro or Arg/Pro) along with both betel quid and tobacco chewing habit (odds ratio = 8.29, confidence interval = 1.14-60.23; p = 0.037) conferred eightfold increased risk toward esophageal cancer development. This study reveals a synergistic interaction between epigenetic, genetic, and environmental factors and risk of esophageal cancer in this high-incidence region of Northeast India. The inactivation of either p16 or p53 in a majority of esophageal cancer cases in this study suggests the possible crosstalk between the important cell cycle genes.

Humanized Androgen Receptor Mice: A Genetic Model for Differential Response to Prostate Cancer Therapy

DTIC Science & Technology

2009-07-01

transfected with 4 ng of receptor (12Q, 21Q or 48Q), 400 ng of reporter and 100 ng of promoterless renilla luciferase as an internal control. 24 hrs...The histograms represent average values normalized to renilla from either three (A and B) or two (C) independent trials. Fold activation was...luciferase activities normalized to renilla from three independent trials. * p≤0.02, significant differences based on Anova single factor analysis

The maternally expressed WRKY transcription factor TTG2 controls lethality in interploidy crosses of Arabidopsis.

PubMed

Dilkes, Brian P; Spielman, Melissa; Weizbauer, Renate; Watson, Brian; Burkart-Waco, Diana; Scott, Rod J; Comai, Luca

2008-12-09

The molecular mechanisms underlying lethality of F1 hybrids between diverged parents are one target of speciation research. Crosses between diploid and tetraploid individuals of the same genotype can result in F1 lethality, and this dosage-sensitive incompatibility plays a role in polyploid speciation. We have identified variation in F1 lethality in interploidy crosses of Arabidopsis thaliana and determined the genetic architecture of the maternally expressed variation via QTL mapping. A single large-effect QTL, DR. STRANGELOVE 1 (DSL1), was identified as well as two QTL with epistatic relationships to DSL1. DSL1 affects the rate of postzygotic lethality via expression in the maternal sporophyte. Fine mapping placed DSL1 in an interval encoding the maternal effect transcription factor TTG2. Maternal parents carrying loss-of-function mutations in TTG2 suppressed the F1 lethality caused by paternal excess interploidy crosses. The frequency of cellularization in the endosperm was similarly affected by both natural variation and ttg2 loss-of-function mutants. The simple genetic basis of the natural variation and effects of single-gene mutations suggests that F1 lethality in polyploids could evolve rapidly. Furthermore, the role of the sporophytically active TTG2 gene in interploidy crosses indicates that the developmental programming of the mother regulates the viability of interploidy hybrid offspring.

Estimation of genetic parameters and detection of quantitative trait loci for metabolites in Danish Holstein milk.

PubMed

Buitenhuis, A J; Sundekilde, U K; Poulsen, N A; Bertram, H C; Larsen, L B; Sørensen, P

2013-05-01

Small components and metabolites in milk are significant for the utilization of milk, not only in dairy food production but also as disease predictors in dairy cattle. This study focused on estimation of genetic parameters and detection of quantitative trait loci for metabolites in bovine milk. For this purpose, milk samples were collected in mid lactation from 371 Danish Holstein cows in first to third parity. A total of 31 metabolites were detected and identified in bovine milk by using (1)H nuclear magnetic resonance (NMR) spectroscopy. Cows were genotyped using a bovine high-density single nucleotide polymorphism (SNP) chip. Based on the SNP data, a genomic relationship matrix was calculated and used as a random factor in a model together with 2 fixed factors (herd and lactation stage) to estimate the heritability and breeding value for individual metabolites in the milk. Heritability was in the range of 0 for lactic acid to >0.8 for orotic acid and β-hydroxybutyrate. A single SNP association analysis revealed 7 genome-wide significant quantitative trait loci [malonate: Bos taurus autosome (BTA)2 and BTA7; galactose-1-phosphate: BTA2; cis-aconitate: BTA11; urea: BTA12; carnitine: BTA25; and glycerophosphocholine: BTA25]. These results demonstrate that selection for metabolites in bovine milk may be possible. Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

EINVis: a visualization tool for analyzing and exploring genetic interactions in large-scale association studies.

PubMed

Wu, Yubao; Zhu, Xiaofeng; Chen, Jian; Zhang, Xiang

2013-11-01

Epistasis (gene-gene interaction) detection in large-scale genetic association studies has recently drawn extensive research interests as many complex traits are likely caused by the joint effect of multiple genetic factors. The large number of possible interactions poses both statistical and computational challenges. A variety of approaches have been developed to address the analytical challenges in epistatic interaction detection. These methods usually output the identified genetic interactions and store them in flat file formats. It is highly desirable to develop an effective visualization tool to further investigate the detected interactions and unravel hidden interaction patterns. We have developed EINVis, a novel visualization tool that is specifically designed to analyze and explore genetic interactions. EINVis displays interactions among genetic markers as a network. It utilizes a circular layout (specially, a tree ring view) to simultaneously visualize the hierarchical interactions between single nucleotide polymorphisms (SNPs), genes, and chromosomes, and the network structure formed by these interactions. Using EINVis, the user can distinguish marginal effects from interactions, track interactions involving more than two markers, visualize interactions at different levels, and detect proxy SNPs based on linkage disequilibrium. EINVis is an effective and user-friendly free visualization tool for analyzing and exploring genetic interactions. It is publicly available with detailed documentation and online tutorial on the web at http://filer.case.edu/yxw407/einvis/. © 2013 WILEY PERIODICALS, INC.

HBEGF, SRA1, and IK: Three cosegregating genes as determinants of cardiomyopathy.

PubMed

Friedrichs, Frauke; Zugck, Christian; Rauch, Gerd-Jörg; Ivandic, Boris; Weichenhan, Dieter; Müller-Bardorff, Margit; Meder, Benjamin; El Mokhtari, Nour Eddine; Regitz-Zagrosek, Vera; Hetzer, Roland; Schäfer, Arne; Schreiber, Stefan; Chen, Jian; Neuhaus, Isaac; Ji, Ruiru; Siemers, Nathan O; Frey, Norbert; Rottbauer, Wolfgang; Katus, Hugo A; Stoll, Monika

2009-03-01

Human dilated cardiomyopathy (DCM), a disorder of the cardiac muscle, causes considerable morbidity and mortality and is one of the major causes of sudden cardiac death. Genetic factors play a role in the etiology and pathogenesis of DCM. Disease-associated genetic variations identified to date have been identified in single families or single sporadic patients and explain a minority of the etiology of DCM. We show that a 600-kb region of linkage disequilibrium (LD) on 5q31.2-3, harboring multiple genes, is associated with cardiomyopathy in three independent Caucasian populations (combined P-value = 0.00087). Functional assessment in zebrafish demonstrates that at least three genes, orthologous to loci in this LD block, HBEGF, IK, and SRA1, result independently in a phenotype of myocardial contractile dysfunction when their expression is reduced with morpholino antisense reagents. Evolutionary analysis across multiple vertebrate genomes suggests that this heart failure-associated LD block emerged by a series of genomic rearrangements across amphibian, avian, and mammalian genomes and is maintained as a cluster in mammals. Taken together, these observations challenge the simple notion that disease phenotypes can be traced to altered function of a single locus within a haplotype and suggest that a more detailed assessment of causality can be necessary.

HBEGF, SRA1, and IK: Three cosegregating genes as determinants of cardiomyopathy

PubMed Central

Friedrichs, Frauke; Zugck, Christian; Rauch, Gerd-Jörg; Ivandic, Boris; Weichenhan, Dieter; Müller-Bardorff, Margit; Meder, Benjamin; El Mokhtari, Nour Eddine; Regitz-Zagrosek, Vera; Hetzer, Roland; Schäfer, Arne; Schreiber, Stefan; Chen, Jian; Neuhaus, Isaac; Ji, Ruiru; Siemers, Nathan O.; Frey, Norbert; Rottbauer, Wolfgang; Katus, Hugo A.; Stoll, Monika

2009-01-01

Human dilated cardiomyopathy (DCM), a disorder of the cardiac muscle, causes considerable morbidity and mortality and is one of the major causes of sudden cardiac death. Genetic factors play a role in the etiology and pathogenesis of DCM. Disease-associated genetic variations identified to date have been identified in single families or single sporadic patients and explain a minority of the etiology of DCM. We show that a 600-kb region of linkage disequilibrium (LD) on 5q31.2-3, harboring multiple genes, is associated with cardiomyopathy in three independent Caucasian populations (combined P-value = 0.00087). Functional assessment in zebrafish demonstrates that at least three genes, orthologous to loci in this LD block, HBEGF, IK, and SRA1, result independently in a phenotype of myocardial contractile dysfunction when their expression is reduced with morpholino antisense reagents. Evolutionary analysis across multiple vertebrate genomes suggests that this heart failure-associated LD block emerged by a series of genomic rearrangements across amphibian, avian, and mammalian genomes and is maintained as a cluster in mammals. Taken together, these observations challenge the simple notion that disease phenotypes can be traced to altered function of a single locus within a haplotype and suggest that a more detailed assessment of causality can be necessary. PMID:19064678

The importance of detailed epigenomic profiling of different cell types within organs.

PubMed

Stueve, Theresa Ryan; Marconett, Crystal N; Zhou, Beiyun; Borok, Zea; Laird-Offringa, Ite A

2016-06-01

The human body consists of hundreds of kinds of cells specified from a single genome overlaid with cell type-specific epigenetic information. Comprehensively profiling the body's distinct epigenetic landscapes will allow researchers to verify cell types used in regenerative medicine and to determine the epigenetic effects of disease, environmental exposures and genetic variation. Key marks/factors that should be investigated include regions of nucleosome-free DNA accessible to regulatory factors, histone marks defining active enhancers and promoters, DNA methylation levels, regulatory RNAs, and factors controlling the three-dimensional conformation of the genome. Here we use the lung to illustrate the importance of investigating an organ's purified cell epigenomes, and outline the challenges and promise of realizing a comprehensive catalog of primary cell epigenomes.

Crystal Genetics, Inc.

PubMed

Kermani, Bahram G

2016-07-01

Crystal Genetics, Inc. is an early-stage genetic test company, focused on achieving the highest possible clinical-grade accuracy and comprehensiveness for detecting germline (e.g., in hereditary cancer) and somatic (e.g., in early cancer detection) mutations. Crystal's mission is to significantly improve the health status of the population, by providing high accuracy, comprehensive, flexible and affordable genetic tests, primarily in cancer. Crystal's philosophy is that when it comes to detecting mutations that are strongly correlated with life-threatening diseases, the detection accuracy of every single mutation counts: a single false-positive error could cause severe anxiety for the patient. And, more importantly, a single false-negative error could potentially cost the patient's life. Crystal's objective is to eliminate both of these error types.

Convergent synaptic and circuit substrates underlying autism genetic risks.

PubMed

McGee, Aaron; Li, Guohui; Lu, Zhongming; Qiu, Shenfeng

2014-02-01

There has been a surge of diagnosis of autism spectrum disorders (ASD) over the past decade. While large, high powered genome screening studies of children with ASD have identified numerous genetic risk factors, research efforts to understanding how each of these risk factors contributes to the development autism has met with limited success. Revealing the mechanisms by which these genetic risk factors affect brain development and predispose a child to autism requires mechanistic understanding of the neurobiological changes underlying this devastating group of developmental disorders at multifaceted molecular, cellular and system levels. It has been increasingly clear that the normal trajectory of neurodevelopment is compromised in autism, in multiple domains as much as aberrant neuronal production, growth, functional maturation, patterned connectivity, and balanced excitation and inhibition of brain networks. Many autism risk factors identified in humans have been now reconstituted in experimental mouse models to allow mechanistic interrogation of the biological role of the risk gene. Studies utilizing these mouse models have revealed that underlying the enormous heterogeneity of perturbed cellular events, mechanisms directing synaptic and circuit assembly may provide a unifying explanation for the pathophysiological changes and behavioral endophenotypes seen in autism, although synaptic perturbations are far from being the only alterations relevant for ASD. In this review, we discuss synaptic and circuit abnormalities obtained from several prevalent mouse models, particularly those reflecting syndromic forms of ASD that are caused by single gene perturbations. These compiled results reveal that ASD risk genes contribute to proper signaling of the developing gene networks that maintain synaptic and circuit homeostasis, which is fundamental to normal brain development.

Genetic effects of landscape, habitat preference and demography on three co-occurring turtle species.

PubMed

Reid, Brendan N; Mladenoff, David J; Peery, M Zachariah

2017-02-01

Expanding the scope of landscape genetics beyond the level of single species can help to reveal how species traits influence responses to environmental change. Multispecies studies are particularly valuable in highly threatened taxa, such as turtles, in which the impacts of anthropogenic change are strongly influenced by interspecific differences in life history strategies, habitat preferences and mobility. We sampled approximately 1500 individuals of three co-occurring turtle species across a gradient of habitat change (including varying loss of wetlands and agricultural conversion of upland habitats) in the Midwestern USA. We used genetic clustering and multiple regression methods to identify associations between genetic structure and permanent landscape features, past landscape composition and landscape change in each species. Two aquatic generalists (the painted turtle, Chrysemys picta, and the snapping turtle Chelydra serpentina) both exhibited population genetic structure consistent with isolation by distance, modulated by aquatic landscape features. Genetic divergence for the more terrestrial Blanding's turtle (Emydoidea blandingii), on the other hand, was not strongly associated with geographic distance or aquatic features, and Bayesian clustering analysis indicated that many Emydoidea populations were genetically isolated. Despite long generation times, all three species exhibited associations between genetic structure and postsettlement habitat change, indicating that long generation times may not be sufficient to delay genetic drift resulting from recent habitat fragmentation. The concordances in genetic structure observed between aquatic species, as well as isolation in the endangered, long-lived Emydoidea, reinforce the need to consider both landscape composition and demographic factors in assessing differential responses to habitat change in co-occurring species. © 2016 John Wiley & Sons Ltd.

Genetic analysis of an elite super-hybrid rice parent using high-density SNP markers.

PubMed

Duan, Meijuan; Sun, Zhizhong; Shu, Liping; Tan, Yanning; Yu, Dong; Sun, Xuewu; Liu, Ruifen; Li, Yujie; Gong, Siyu; Yuan, Dingyang

2013-08-15

With an increasing world population and a gradual decline in the amount of arable land, food security remains a global challenge. Continued increases in rice yield will be required to break through the barriers to grain output. In order to transition from hybrid rice to super-hybrid rice, breeding demands cannot be addressed through traditional heterosis. Therefore, it is necessary to incorporate high yield loci from other rice genetic groups and to scientifically utilize intersubspecific heterosis in breeding lines. In this study, 781 lines from a segregating F2 population constructed by crossing the indica variety, "Giant Spike Rice" R1128 as trait donor with the japonica cultivar 'Nipponbare', were re-sequenced using high-throughout multiplexed shotgun genotyping (MSG) technology. In combination with high-density single nucleotide polymorphisms, quantitative trait locus (QTL) mapping and genetic effect analysis were performed for five yield factors (spikelet number per panicle, primary branches per panicle, secondary branches per panicle, plant height, and panicle length) to explore the genetic mechanisms underlying the formation of the giant panicle of R1128. Also, they were preformed to locate new high-yielding rice genetic intervals, providing data for super-high-yielding rice breeding. QTL mapping and genetic effect analysis for five yield factors in the population gave the following results: 49 QTLs for the five yield factors were distributed on 11 of 12 chromosomes. The super-hybrid line R1128 carries multiple major genes for good traits, including Sd1 for plant height, Hd1 and Ehd1 for heading date, Gn1a for spikelet number and IPA1 for ideal plant shape. These genes accounted for 44.3%, 21.9%, 6.2%, 12.9% and 10.6% of the phenotypic variation in the individual traits. Six novel QTLs, qph1-2, qph9-1, qpl12-1, qgn3-1, qgn11-1and qsbn11-1 are reported here for the first time. High-throughout sequencing technology makes it convenient to study rice genomics and makes the QTL/gene mapping direct, efficient, and more reliable. The genetic regions discovered in this study will be valuable for breeding in rice varieties because of the diverse genetic backgrounds of the rice.

MAX mutations status in Swedish patients with pheochromocytoma and paraganglioma tumours.

PubMed

Crona, Joakim; Maharjan, Rajani; Delgado Verdugo, Alberto; Stålberg, Peter; Granberg, Dan; Hellman, Per; Björklund, Peyman

2014-03-01

Pheochromocytoma (PCC) and Paraganglioma are rare tumours originating from neuroendocrine cells. Up to 60% of cases have either germline or somatic mutation in one of eleven described susceptibility loci, SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, RET, NF1, TMEM127 and MYC associated factor-X (MAX). Recently, germline mutations in MAX were found to confer susceptibility to PCC and paraganglioma (PGL). A subsequent multicentre study found about 1% of PCCs and PGLs to have germline or somatic mutations in MAX. However, there has been no study investigating the frequency of MAX mutations in a Scandinavian cohort. We analysed tumour specimens from 63 patients with PCC and PGL treated at Uppsala University hospital, Sweden, for re-sequencing of MAX using automated Sanger sequencing. Our results show that 0% (0/63) of tumours had mutations in MAX. Allele frequencies of known single nucleotide polymorphisms rs4902359, rs45440292, rs1957948 and rs1957949 corresponded to those available in the Single Nucleotide Polymorphism Database. We conclude that MAX mutations remain unusual events and targeted genetic screening should be considered after more common genetic events have been excluded.

The Role of Constitutional Copy Number Variants in Breast Cancer

PubMed Central

Walker, Logan C.; Wiggins, George A.R.; Pearson, John F.

2015-01-01

Constitutional copy number variants (CNVs) include inherited and de novo deviations from a diploid state at a defined genomic region. These variants contribute significantly to genetic variation and disease in humans, including breast cancer susceptibility. Identification of genetic risk factors for breast cancer in recent years has been dominated by the use of genome-wide technologies, such as single nucleotide polymorphism (SNP)-arrays, with a significant focus on single nucleotide variants. To date, these large datasets have been underutilised for generating genome-wide CNV profiles despite offering a massive resource for assessing the contribution of these structural variants to breast cancer risk. Technical challenges remain in determining the location and distribution of CNVs across the human genome due to the accuracy of computational prediction algorithms and resolution of the array data. Moreover, better methods are required for interpreting the functional effect of newly discovered CNVs. In this review, we explore current and future application of SNP array technology to assess rare and common CNVs in association with breast cancer risk in humans. PMID:27600231

In Vivo Characterization of Human APOA5 Haplotypes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ahituv, Nadav; Akiyama, Jennifer; Chapman-Helleboid, Audrey

2006-10-01

Increased plasma triglycerides concentrations are an independent risk factor for cardiovascular disease. Numerous studies support a reproducible genetic association between two minor haplotypes in the human apolipoprotein A5 gene (APOA5) and increased plasma triglyceride concentrations. We thus sought to investigate the effect of these minor haplotypes (APOA5*2 and APOA5*3) on ApoAV plasma levels through the precise insertion of single-copy intact APOA5 haplotypes at a targeted location in the mouse genome. While we found no difference in the amount of human plasma ApoAV in mice containing the common APOA5*1 and minor APOA5*2 haplotype, the introduction of the single APOA5*3 defining allelemore » (19W) resulted in 3-fold lower ApoAV plasma levels consistent with existing genetic association studies. These results indicate that S19W polymorphism is likely to be functional and explain the strong association of this variant with plasma triglycerides supporting the value of sensitive in vivo assays to define the functional nature of human haplotypes.« less

Associations of Smoking and Age With Inflammatory Joint Signs Among Unaffected First-Degree Relatives of Rheumatoid Arthritis Patients: Results From Studies of the Etiology of Rheumatoid Arthritis.

PubMed

Sparks, Jeffrey A; Chang, Shun-Chiao; Deane, Kevin D; Gan, Ryan W; Kristen Demoruelle, M; Feser, Marie L; Moss, LauraKay; Buckner, Jane H; Keating, Richard M; Costenbader, Karen H; Gregersen, Peter K; Weisman, Michael H; Mikuls, Ted R; O'Dell, James R; Michael Holers, V; Norris, Jill M; Karlson, Elizabeth W

2016-08-01

To examine whether genetic, environmental, and serologic rheumatoid arthritis (RA) risk factors are associated with inflammatory joint signs in a cohort of first-degree relatives (FDRs) of RA patients. We evaluated RA risk factors and inflammatory joint signs in a prospective cohort of FDRs without RA in the Studies of the Etiology of RA. Genetic factors included 5 HLA-DRB1 shared epitope alleles and 45 RA-associated single-nucleotide polymorphisms; loci were combined using genetic risk scores weighted by RA risk. Environmental factors (smoking, body mass index, education, and parity) and RA-related autoantibodies were assessed at baseline. Physical examination was performed at baseline and 2-year follow-up, by observers who were blinded with regard to autoantibody status, to assess inflammatory joint signs as tender or swollen joints at sites typical for RA. Logistic regression was performed to evaluate associations of genetic, environmental, and serologic factors with inflammatory joint signs. We analyzed 966 non-Hispanic white FDRs at baseline and 262 at 2-year follow-up after excluding those with inflammatory joint signs at baseline. The mean ± SD age was 47.2 ± 15.5 years, 71% were female, and 55% were shared epitope positive. Smoking >10 pack-years was associated with inflammatory joint signs at baseline (odds ratio [OR] 1.89 [95% confidence interval (95% CI) 1.26-2.82]) and at 2 years (OR 2.66 [95% CI 1.01-7.03]), compared to never smokers. There was a significant interaction between smoking and age with regard to risk of inflammatory joint signs (P = 0.02). FDRs younger than 50 years with >10 pack-years had the highest risk of inflammatory joint signs (OR 4.39 [95% CI 2.22-8.66], compared to never smokers younger than 50 years). In a high-risk cohort of FDRs, smoking and age were associated with both prevalent and incident inflammatory joint signs at sites typical for RA. Further prospective investigations of the factors affecting the transitions between preclinical RA phases are warranted. © 2016, American College of Rheumatology.

The KCNQ1 gene polymorphism as a shared genetic risk for rheumatoid arthritis and chronic periodontitis in Japanese adults: A pilot case-control study.

PubMed

Kobayashi, Tetsuo; Kido, Jun-Ichi; Ishihara, Yuichi; Omori, Kazuhiro; Ito, Satoshi; Matsuura, Takato; Bando, Takashi; Wada, Jun; Murasawa, Akira; Nakazono, Kiyoshi; Mitani, Akio; Takashiba, Shogo; Nagata, Toshihiko; Yoshie, Hiromasa

2018-03-01

A number of studies have suggested a bidirectional relationship of periodontitis with rheumatoid arthritis (RA) and type 2 diabetes mellitus (T2DM). However, the genetic factors that underlie these relationships have not been elucidated. We conducted a multicenter case-control study that included 185 patients with RA and chronic periodontitis (CP), 149 patients with T2DM and CP, 251 patients with CP, and 130 systemically and periodontally healthy controls from a cohort of Japanese adults to assess the shared genetic risk factors for RA and CP as well as for T2DM and CP. A total of 17 candidate single nucleotide polymorphisms (SNPs) associated with RA, T2DM, and CP were genotyped. Multiple logistic regression analyses revealed that the KCNQ1 rs2237892 was significantly associated with comorbidity of RA and CP (P = 0.005) after adjustment for age, sex, and smoking status. The carriers of the T allele among patients with RA and CP showed significantly higher disease activity scores including 28 joints using C-reactive protein values than the non-carriers (P = 0.02), although the age, female percentage, and smoking status were comparable. Other SNPs were not associated with comorbidity of RA and CP, T2DM and CP, or susceptibility to CP. The results of the present pilot study suggest for the first time that the KCNQ1 rs2237892 may constitute a shared genetic risk factor for RA and CP, but not for T2DM and CP in Japanese adults. © 2018 American Academy of Periodontology.

Novel genetic association of TNF-α-238 and PDCD1-7209 polymorphisms with long-term non-progressive HIV-1 infection.

PubMed

Nasi, Milena; Riva, Agostino; Borghi, Vanni; D'Amico, Roberto; Del Giovane, Cinzia; Casoli, Claudio; Galli, Massimo; Vicenzi, Elisa; Gibellini, Lara; De Biasi, Sara; Clerici, Mario; Mussini, Cristina; Cossarizza, Andrea; Pinti, Marcello

2013-10-01

About 2-5% of HIV-1-infected subjects, defined as long-term non-progressors (LTNPs), remain immunologically stable for a long time without treatment. The factors governing this condition are known only in part, and include genetic factors. Thus, we studied 20 polymorphisms of 15 genes encoding proinflammatory and immunoregulatory cytokines, chemokines and their receptors, genes involved in apoptosis, and the gene HCP5. We analyzed 47 Caucasian LTNPs infected for >9 years, compared with 131 HIV-1-infected Caucasian patients defined as 'usual progressors'. The genotypes were determined by methods based upon PCR, and the statistical analysis was performed by univariate logistic regression. The well-known CCR5Δ32 del32 allele, the cell death-related TNF-α-238 A and PDCD1-7209 T alleles, and HCP5 rs2395029 G, a non-coding protein associated with the HLA-B*5701, were found positively associated with the LTNP condition. No association was observed for other single nucleotide polymorphisms (SDF-1-801, IL-10-592, MCP-1-2518, CX3CR1 V249I, CCR2V64I, RANTES-403, IL-2-330, IL-1β-511, IL-4-590, FASL IVS3nt-169, FAS-670, FAS-1377, FASL IVS2nt-124, PDCD1-7146, MMP-7-181, and MMP7-153). The novel genetic associations between allelic variants of genes TNF-α-238 and PDCD1-7209 with the LTNP condition underline the importance of host genetic factors in the progression of HIV-1 infection and in immunological preservation. Copyright © 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Polygenic scores predict alcohol problems in an independent sample and show moderation by the environment.

PubMed

Salvatore, Jessica E; Aliev, Fazil; Edwards, Alexis C; Evans, David M; Macleod, John; Hickman, Matthew; Lewis, Glyn; Kendler, Kenneth S; Loukola, Anu; Korhonen, Tellervo; Latvala, Antti; Rose, Richard J; Kaprio, Jaakko; Dick, Danielle M

2014-04-10

Alcohol problems represent a classic example of a complex behavioral outcome that is likely influenced by many genes of small effect. A polygenic approach, which examines aggregate measured genetic effects, can have predictive power in cases where individual genes or genetic variants do not. In the current study, we first tested whether polygenic risk for alcohol problems-derived from genome-wide association estimates of an alcohol problems factor score from the age 18 assessment of the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 4304 individuals of European descent; 57% female)-predicted alcohol problems earlier in development (age 14) in an independent sample (FinnTwin12; n = 1162; 53% female). We then tested whether environmental factors (parental knowledge and peer deviance) moderated polygenic risk to predict alcohol problems in the FinnTwin12 sample. We found evidence for both polygenic association and for additive polygene-environment interaction. Higher polygenic scores predicted a greater number of alcohol problems (range of Pearson partial correlations 0.07-0.08, all p-values ≤ 0.01). Moreover, genetic influences were significantly more pronounced under conditions of low parental knowledge or high peer deviance (unstandardized regression coefficients (b), p-values (p), and percent of variance (R2) accounted for by interaction terms: b = 1.54, p = 0.02, R2 = 0.33%; b = 0.94, p = 0.04, R2 = 0.30%, respectively). Supplementary set-based analyses indicated that the individual top single nucleotide polymorphisms (SNPs) contributing to the polygenic scores were not individually enriched for gene-environment interaction. Although the magnitude of the observed effects are small, this study illustrates the usefulness of polygenic approaches for understanding the pathways by which measured genetic predispositions come together with environmental factors to predict complex behavioral outcomes.

Genetic variant rs17225178 in the ARNT2 gene is associated with Asperger Syndrome.

PubMed

Di Napoli, Agnese; Warrier, Varun; Baron-Cohen, Simon; Chakrabarti, Bhismadev

2015-01-01

Autism Spectrum Conditions (ASC) are neurodevelopmental conditions characterized by difficulties in communication and social interaction, alongside unusually repetitive behaviours and narrow interests. Asperger Syndrome (AS) is one subgroup of ASC and differs from classic autism in that in AS there is no language or general cognitive delay. Genetic, epigenetic and environmental factors are implicated in ASC and genes involved in neural connectivity and neurodevelopment are good candidates for studying the susceptibility to ASC. The aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) gene encodes a transcription factor involved in neurodevelopmental processes, neuronal connectivity and cellular responses to hypoxia. A mutation in this gene has been identified in individuals with ASC and single nucleotide polymorphisms (SNPs) have been nominally associated with AS and autistic traits in previous studies. In this study, we tested 34 SNPs in ARNT2 for association with AS in 118 cases and 412 controls of Caucasian origin. P values were adjusted for multiple comparisons, and linkage disequilibrium (LD) among the SNPs analysed was calculated in our sample. Finally, SNP annotation allowed functional and structural analyses of the genetic variants in ARNT2. We tested the replicability of our result using the genome-wide association studies (GWAS) database of the Psychiatric Genomics Consortium (PGC). We report statistically significant association of rs17225178 with AS. This SNP modifies transcription factor binding sites and regions that regulate the chromatin state in neural cell lines. It is also included in a LD block in our sample, alongside other genetic variants that alter chromatin regulatory regions in neural cells. These findings demonstrate that rs17225178 in the ARNT2 gene is associated with AS and support previous studies that pointed out an involvement of this gene in the predisposition to ASC.

Exploration of 19 serotoninergic candidate genes in adults and children with attention-deficit/hyperactivity disorder identifies association for 5HT2A, DDC and MAOB.

PubMed

Ribasés, M; Ramos-Quiroga, J A; Hervás, A; Bosch, R; Bielsa, A; Gastaminza, X; Artigas, J; Rodriguez-Ben, S; Estivill, X; Casas, M; Cormand, B; Bayés, M

2009-01-01

Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder in which different genetic and environmental susceptibility factors are involved. Several lines of evidence support the view that at least 30% of ADHD patients diagnosed in childhood continue to suffer the disorder during adulthood and that genetic risk factors may play an essential role in the persistence of the disorder throughout lifespan. Genetic, biochemical and pharmacological studies support the idea that the serotonin system participates in the etiology of ADHD. Based on these data, we aimed to analyze single nucleotide polymorphisms across 19 genes involved in the serotoninergic neurotransmission in a clinical sample of 451 ADHD patients (188 adults and 263 children) and 400 controls using a population-based association study. Several significant associations were found after correcting for multiple testing: (1) the DDC gene was strongly associated with both adulthood (P=0.00053; odds ratio (OR)=2.17) and childhood ADHD (P=0.0017; OR=1.90); (2) the MAOB gene was found specifically associated in the adult ADHD sample (P=0.0029; OR=1.90) and (3) the 5HT2A gene showed evidence of association only with the combined ADHD subtype both in adults (P=0.0036; OR=1.63) and children (P=0.0084; OR=1.49). Our data support the contribution of the serotoninergic system in the genetic predisposition to ADHD, identifying common childhood and adulthood ADHD susceptibility factors, associations that are specific to ADHD subtypes and one variant potentially involved in the continuity of the disorder throughout lifespan.

Modifiable risk factors for schizophrenia and autism--shared risk factors impacting on brain development.

PubMed

Hamlyn, Jess; Duhig, Michael; McGrath, John; Scott, James

2013-05-01

Schizophrenia and autism are two poorly understood clinical syndromes that differ in age of onset and clinical profile. However, recent genetic and epidemiological research suggests that these two neurodevelopmental disorders share certain risk factors. The aims of this review are to describe modifiable risk factors that have been identified in both disorders, and, where available, collate salient systematic reviews and meta-analyses that have examined shared risk factors. Based on searches of Medline, Embase and PsycINFO, inspection of review articles and expert opinion, we first compiled a set of candidate modifiable risk factors associated with autism. Where available, we next collated systematic-reviews (with or without meta-analyses) related to modifiable risk factors associated with both autism and schizophrenia. We identified three modifiable risk factors that have been examined in systematic reviews for both autism and schizophrenia. Advanced paternal age was reported as a risk factor for schizophrenia in a single meta-analysis and as a risk factor in two meta-analyses for autism. With respect to pregnancy and birth complications, for autism one meta-analysis identified maternal diabetes and bleeding during pregnancy as risks factors for autism whilst a meta-analysis of eight studies identified obstetric complications as a risk factor for schizophrenia. Migrant status was identified as a risk factor for both autism and schizophrenia. Two separate meta-analyses were identified for each disorder. Despite distinct clinical phenotypes, the evidence suggests that at least some non-genetic risk factors are shared between these two syndromes. In particular, exposure to drugs, nutritional excesses or deficiencies and infectious agents lend themselves to public health interventions. Studies are now needed to quantify any increase in risk of either autism or schizophrenia that is associated with these modifiable environmental factors. Copyright © 2012 Elsevier Inc. All rights reserved.

Antibody-ribosome-mRNA (ARM) complexes as efficient selection particles for in vitro display and evolution of antibody combining sites.

PubMed Central

He, M; Taussig, M J

1997-01-01

We describe a rapid, eukaryotic, in vitro method for selection and evolution of antibody combining sites using antibody-ribosome-mRNA (ARM) complexes as selection particles. ARMs carrying single-chain (VH/K) binding fragments specific for progesterone were selected using antigen-coupled magnetic beads; selection simultaneously captured the genetic information as mRNA, making it possible to generate and amplify cDNA by single-step RT-PCR on the ribosome-bound mRNA for further manipulation. Using mutant libraries, antigen-binding ARMs were enriched by a factor of 10(4)-10(5)-fold in a single cycle, with further enrichment in repeated cycles. While demonstrated here for antibodies, the method has the potential to be applied equally for selection of receptors or peptides from libraries. PMID:9396828

Antibody-ribosome-mRNA (ARM) complexes as efficient selection particles for in vitro display and evolution of antibody combining sites.

PubMed

He, M; Taussig, M J

1997-12-15

We describe a rapid, eukaryotic, in vitro method for selection and evolution of antibody combining sites using antibody-ribosome-mRNA (ARM) complexes as selection particles. ARMs carrying single-chain (VH/K) binding fragments specific for progesterone were selected using antigen-coupled magnetic beads; selection simultaneously captured the genetic information as mRNA, making it possible to generate and amplify cDNA by single-step RT-PCR on the ribosome-bound mRNA for further manipulation. Using mutant libraries, antigen-binding ARMs were enriched by a factor of 10(4)-10(5)-fold in a single cycle, with further enrichment in repeated cycles. While demonstrated here for antibodies, the method has the potential to be applied equally for selection of receptors or peptides from libraries.

Methods for meta-analysis of multiple traits using GWAS summary statistics.

PubMed

Ray, Debashree; Boehnke, Michael

2018-03-01

Genome-wide association studies (GWAS) for complex diseases have focused primarily on single-trait analyses for disease status and disease-related quantitative traits. For example, GWAS on risk factors for coronary artery disease analyze genetic associations of plasma lipids such as total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides (TGs) separately. However, traits are often correlated and a joint analysis may yield increased statistical power for association over multiple univariate analyses. Recently several multivariate methods have been proposed that require individual-level data. Here, we develop metaUSAT (where USAT is unified score-based association test), a novel unified association test of a single genetic variant with multiple traits that uses only summary statistics from existing GWAS. Although the existing methods either perform well when most correlated traits are affected by the genetic variant in the same direction or are powerful when only a few of the correlated traits are associated, metaUSAT is designed to be robust to the association structure of correlated traits. metaUSAT does not require individual-level data and can test genetic associations of categorical and/or continuous traits. One can also use metaUSAT to analyze a single trait over multiple studies, appropriately accounting for overlapping samples, if any. metaUSAT provides an approximate asymptotic P-value for association and is computationally efficient for implementation at a genome-wide level. Simulation experiments show that metaUSAT maintains proper type-I error at low error levels. It has similar and sometimes greater power to detect association across a wide array of scenarios compared to existing methods, which are usually powerful for some specific association scenarios only. When applied to plasma lipids summary data from the METSIM and the T2D-GENES studies, metaUSAT detected genome-wide significant loci beyond the ones identified by univariate analyses. Evidence from larger studies suggest that the variants additionally detected by our test are, indeed, associated with lipid levels in humans. In summary, metaUSAT can provide novel insights into the genetic architecture of a common disease or traits. © 2017 WILEY PERIODICALS, INC.

Dog-Owner Attachment Is Associated With Oxytocin Receptor Gene Polymorphisms in Both Parties. A Comparative Study on Austrian and Hungarian Border Collies.

PubMed

Kovács, Krisztina; Virányi, Zsófia; Kis, Anna; Turcsán, Borbála; Hudecz, Ágnes; Marmota, Maria T; Koller, Dóra; Rónai, Zsolt; Gácsi, Márta; Topál, József

2018-01-01

Variations in human infants' attachment behavior are associated with single nucleotide polymorphisms (SNPs) in the oxytocin receptor (OXTR) gene, suggesting a genetic component to infant-mother attachment. However, due to the genetic relatedness of infants and their mothers, it is difficult to separate the genetic effects of infants' OXTR genotype from the environmental effects of mothers' genotype possibly affecting their parental behavior. The apparent functional analogy between child-parent and dog-owner relationship, however, offers a way to disentangle the effects of these factors because pet dogs are not genetically related to their caregivers. In the present study we investigated whether single nucleotide polymorphisms of pet dogs' OXTR gene (-213AG,-94TC,-74CG) and their owners' OXTR gene (rs53576, rs1042778, rs2254298) are associated with components of dog-owner attachment. In order to investigate whether social-environmental effects modulate the potential genetic influence on attachment, dogs and their owners from two different countries (Austria and Hungary, N = 135 in total) were tested in a modified version of the Ainsworth Strange Situation Test (SST) and questionnaires were also used to collect information about owner personality and attachment style. We coded variables related to three components of attachment behavior in dogs: their sensitivity to the separation from and interaction with the owner (Attachment), stress caused by the unfamiliar environment (Anxiety), and their responsiveness to the stranger (Acceptance). We found that (1) dogs' behavior was significantly associated with polymorphisms in both dogs' and owners' OXTR gene, (2) SNPs in dogs' and owners' OXTR gene interactively influenced dog-human relationship, (3) dogs' attachment behavior was affected by the country of origin, and (4) it was related to their owners' personality as well as attachment style. Thus, the present study provides evidence, for the first time, that both genetic variation in the OXTR gene and various aspects of pet dogs' environmental background are associated with their attachment to their human caregivers.

The impact of non-genetic and genetic factors on a stable warfarin dose in Thai patients.

PubMed

Wattanachai, Nitsupa; Kaewmoongkun, Sutthida; Pussadhamma, Burabha; Makarawate, Pattarapong; Wongvipaporn, Chaiyasith; Kiatchoosakun, Songsak; Vannaprasaht, Suda; Tassaneeyakul, Wichittra

2017-08-01

The aim of this study was to investigate the contributions of non-genetic and genetic factors on the variability of stable warfarin doses in Thai patients. A total of 250 Thai patients with stable warfarin doses were enrolled in the study. Demographics and clinical data, e.g., age, body mass index, indications for warfarin and concomitant medications, were documented. Four single nucleotide polymorphisms in the VKORC1 - 1639G > A, CYP2C9*3, CYP4F2 rs2108622, and UGT1A1 rs887829 genes were detected from gDNA using TaqMan allelic discrimination assays. The patients with variant genotypes of VKORC1 - 1639G > A required significantly lower warfarin stable weekly doses (SWDs) than those with wild-type genotype (p < 0.001). Similarly, the patients with CYP2C9*3 variant allele required significantly lower warfarin SWDs than those with homozygous wild-type (p = 0.006). In contrast, there were no significant differences in the SWDs between the patients who carried variant alleles of CYP4F2 rs2108622 and UGT1A1 rs887829 as compared to wild-type allele carriers. Multivariate analysis, however, showed that CYP4F2 rs2108622 TT genotype accounted for a modest part of warfarin dose variability (1.2%). In contrast, VKORC1 - 1639G > A, CYP2C9*3, CYP4F2 rs2108622 genotypes and non-genetic factors accounted for 51.3% of dose variability. VKORC1 - 1639G > A, CYP2C9*3, and CYP4F2 rs2108622 polymorphisms together with age, body mass index, antiplatelet drug use, amiodarone use, and current smoker status explained 51.3% of individual variability in stable warfarin doses. In contrast, the UGT1A1 rs887829 polymorphism did not contribute to dose variability.