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Sample records for candidate gene-environment interactions

  1. Candidate Gene-Environment Interaction Research: Reflections and Recommendations

    PubMed Central

    Dick, Danielle M.; Agrawal, Arpana; Keller, Matthew C.; Adkins, Amy; Aliev, Fazil; Monroe, Scott; Hewitt, John K.; Kendler, Kenneth S.; Sher, Kenneth J.

    2014-01-01

    Studying how genetic predispositions come together with environmental factors to contribute to complex behavioral outcomes has great potential for advancing our understanding of the development of psychopathology. It represents a clear theoretical advance over studying these factors in isolation. However, research at the intersection of multiple fields creates many challenges. We review several reasons why the rapidly expanding candidate gene-environment interaction (cGxE) literature should be considered with a degree of caution. We discuss lessons learned about candidate gene main effects from the evolving genetics literature and how these inform the study of cGxE. We review the importance of the measurement of the gene and environment of interest in cGxE studies. We discuss statistical concerns with modeling cGxE that are frequently overlooked. And we review other challenges that have likely contributed to the cGxE literature being difficult to interpret, including low power and publication bias. Many of these issues are similar to other concerns about research integrity (e.g., high false positive rates) that have received increasing attention in the social sciences. We provide recommendations for rigorous research practices for cGxE studies that we believe will advance its potential to contribute more robustly to the understanding of complex behavioral phenotypes. PMID:25620996

  2. Methods for Investigating Gene-Environment Interactions in Candidate Pathway and Genome-Wide Association Studies

    PubMed Central

    Thomas, Duncan

    2010-01-01

    Despite the considerable enthusiasm about the yield of novel and replicated discoveries of genetic associations from the new generation of genome-wide association studies (GWAS), the proportion of the heritability of most complex diseases that have been studied to date remains small. Some of this “dark matter” could be due to gene-environment (G×E) interactions or more complex pathways involving multiple genes and exposures. We review the basic epidemiologic study design and statistical analysis approaches to studying G×E interactions individually and then consider more comprehensive approaches to studying entire pathways or GWAS data. In addition to the usual issues in genetic association studies, particular care is needed in exposure assessment and very large sample sizes are required. Although hypothesis-driven pathway-based and “agnostic” GWAS approaches are generally viewed as opposite poles, we suggest that the two can be usefully married using hierarchical modeling strategies that exploit external pathway knowledge in mining genome-wide data. PMID:20070199

  3. Refining the Candidate Environment: Interpersonal Stress, the Serotonin Transporter Polymorphism, and Gene-Environment Interactions in Major Depression

    PubMed Central

    Vrshek-Schallhorn, Suzanne; Mineka, Susan; Zinbarg, Richard E.; Craske, Michelle G.; Griffith, James W.; Sutton, Jonathan; Redei, Eva E.; Wolitzky-Taylor, Kate; Hammen, Constance; Adam, Emma K.

    2014-01-01

    Meta-analytic evidence supports a gene-environment (G×E) interaction between life stress and the serotonin transporter polymorphism (5-HTTLPR) on depression, but few studies have examined factors that influence detection of this effect, despite years of inconsistent results. We propose that the “candidate environment” (akin to a candidate gene) is key. Theory and evidence implicate major stressful life events (SLEs)—particularly major interpersonal SLEs—as well as chronic family stress. Participants (N = 400) from the Youth Emotion Project (which began with 627 high school juniors oversampled for high neuroticism) completed up to five annual diagnostic and life stress interviews and provided DNA samples. A significant G×E effect for major SLEs and S-carrier genotype was accounted for significantly by major interpersonal SLEs but not significantly by major non-interpersonal SLEs. S-carrier genotype and chronic family stress also significantly interacted. Identifying such candidate environments may facilitate future G×E research in depression and psychopathology more broadly.

  4. Neuregulin 1: a prime candidate for research into gene-environment interactions in schizophrenia? Insights from genetic rodent models

    PubMed Central

    Karl, Tim

    2013-01-01

    Schizophrenia is a multi-factorial disease characterized by a high heritability and environmental risk factors. In recent years, an increasing number of researchers worldwide have started investigating the “two-hit hypothesis” of schizophrenia predicting that genetic and environmental risk factors (GxE) interactively cause the development of the disorder. This work is starting to produce valuable new animal models and reveal novel insights into the pathophysiology of schizophrenia. This mini review will focus on recent advancements in the field made by challenging mutant and transgenic rodent models for the schizophrenia candidate gene neuregulin 1 (NRG1) with particular environmental factors. It will outline results obtained from mouse and rat models for various Nrg1 isoforms/isoform types (e.g., transmembrane domain Nrg1, Type II Nrg1), which have been exposed to different forms of stress (acute versus chronic, restraint versus social) and housing conditions (standard laboratory versus minimally enriched housing). These studies suggest Nrg1 as a prime candidate for GxE interactions in schizophrenia rodent models and that the use of rodent models will enable a better understanding of GxE interactions and the underlying mechanisms. PMID:23966917

  5. Gene-Environment Interactions in Human Disease: Nuisance or Opportunity?

    PubMed Central

    Ober, Carole; Vercelli, Donata

    2010-01-01

    Many environmental risk factors for common, complex human diseases have been revealed by epidemiologic studies, but how genotypes at specific loci modulate individual responses to environmental risk factors is largely unknown. Gene-environment interactions will be missed in genome-wide association studies and may account for some of the ‘missing heritability’ for these diseases. In this review, we focus on asthma as a model disease for studying gene-environment interactions because of relatively large numbers of candidate gene-environment interactions with asthma risk in the literature. Identifying these interactions using genome-wide approaches poses formidable methodological problems and elucidating molecular mechanisms for these interactions has been challenging. We suggest that studying gene-environment interactions in animal models, while more tractable, is not likely to shed light on the genetic architecture of human diseases. Lastly, we propose avenues for future studies to find gene-environment interactions. PMID:21216485

  6. Why study gene-environment interactions?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    PURPOSE OF REVIEW: We examine the reasons for investigating gene-environment interactions and address recent reports evaluating interactions between genes and environmental modulators in relation to cardiovascular disease and its common risk factors. RECENT FINDINGS: Studies focusing on smoking, phy...

  7. Biological Implications of Gene-Environment Interaction

    ERIC Educational Resources Information Center

    Rutter, Michael

    2008-01-01

    Gene-environment interaction (G x E) has been treated as both a statistical phenomenon and a biological reality. It is argued that, although there are important statistical issues that need to be considered, the focus has to be on the biological implications of G x E. Four reports of G x E deriving from the Dunedin longitudinal study are used as…

  8. Gene-environment interactions on growth trajectories.

    PubMed

    Wang, Shuang; Xiong, Wei; Ma, Weiping; Chanock, Stephen; Jedrychowski, Wieslaw; Wu, Rongling; Perera, Frederica P

    2012-04-01

    It has been suggested that children with larger brains tend to perform better on IQ tests or cognitive function tests. Prenatal head growth and head growth in infancy are two crucial periods for subsequent intelligence. Studies have shown that environmental exposure to air pollutants during pregnancy is associated with fetal growth reduction, developmental delay, and reduced IQ. Meanwhile, genetic polymorphisms may modify the effect of environment on head growth. However, studies on gene-environment or gene-gene interactions on growth trajectories have been quite limited partly due to the difficulty to quantitatively measure interactions on growth trajectories. Moreover, it is known that assessing the significance of gene-environment or gene-gene interactions on cross-sectional outcomes empirically using the permutation procedures may bring substantial errors in the tests. We proposed a score that quantitatively measures interactions on growth trajectories and developed an algorithm with a parametric bootstrap procedure to empirically assess the significance of the interactions on growth trajectories under the likelihood framework. We also derived a Wald statistic to test for interactions on growth trajectories and compared it to the proposed parametric bootstrap procedure. Through extensive simulation studies, we demonstrated the feasibility and power of the proposed testing procedures. We applied our method to a real dataset with head circumference measures from birth to age 7 on a cohort currently being conducted by the Columbia Center for Children's Environmental Health (CCCEH) in Krakow, Poland, and identified several significant gene-environment interactions on head circumference growth trajectories. PMID:22311237

  9. Gene-environment interactions in sarcoidosis

    PubMed Central

    Culver, Daniel A.; Newman, Lee S.; Kavuru, Mani S.

    2007-01-01

    Susceptibility to most human diseases is polygenic, with complex interactions between functional polymorphisms of single genes governing disease incidence, phenotype, or both. In this context, the contribution of any discrete gene is generally modest for a single individual, but may confer substantial attributable risk on a population level. Environmental exposure can modify the effects of a polymorphism, either by providing a necessary substrate for development of human disease or because the effects of a given exposure modulate the effects of the gene. In several diseases, genetic polymorphisms have been shown to be context-dependent, i.e. the effects of a genetic variant are realized only in the setting of a relevant exposure. Since sarcoidosis susceptibility is dependent on both genetic and environmental modifiers, the study of gene-environment interactions may yield important pathogenetic information and will likely be crucial for uncovering the range of genetic susceptibility loci. However, the complexity of these relationships implies that investigations of gene-environment interactions will require the study of large cohorts with carefully-defined exposures and similar clinical phenotypes. A general principle is that the study of gene-environment interactions requires a sample size at least several-fold greater than for either factor alone. To date, the presence of environmental modifiers has been demonstrated for one sarcoidosis susceptibility locus, HLA-DQB1, in African-American families. This article reviews general considerations obtaining for the study of gene-environment interactions in sarcoidosis. It also describes the limited current understanding of the role of environmental influences on sarcoidosis susceptibility genes. PMID:17560304

  10. Gene-environment interactions in esophageal cancer.

    PubMed

    Matejcic, Marco; Iqbal Parker, M

    2015-01-01

    Esophageal cancer (EC) is one of the most common malignancies in low- and medium-income countries and represents a disease of public health importance because of its poor prognosis and high mortality rate in these regions. The striking variation in the prevalence of EC among different ethnic groups suggests a significant contribution of population-specific environmental and dietary factors to susceptibility to the disease. Although individuals within a demarcated geographical area are exposed to the same environment and share similar dietary habits, not all of them will develop the disease; thus genetic susceptibility to environmental risk factors may play a key role in the development of EC. A wide range of xenobiotic-metabolizing enzymes are responsible for the metabolism of carcinogens introduced via the diet or inhaled from the environment. Such dietary or environmental carcinogens can bind to DNA, resulting in mutations that may lead to carcinogenesis. Genes involved in the biosynthesis of these enzymes are all subject to genetic polymorphisms that can lead to altered expression or activity of the encoded proteins. Genetic polymorphisms may, therefore, act as molecular biomarkers that can provide important predictive information about carcinogenesis. The aim of this review is to discuss our current knowledge on the genetic risk factors associated with the development of EC in different populations; it addresses mainly the topics of genetic polymorphisms, gene-environment interactions, and carcinogenesis. We have reviewed the published data on genetic polymorphisms of enzymes involved in the metabolism of xenobiotics and discuss some of the potential gene-environment interactions underlying esophageal carcinogenesis. The main enzymes discussed in this review are the glutathione S-transferases (GSTs), N-acetyltransferases (NATs), cytochrome P450s (CYPs), sulfotransferases (SULTs), UDP-glucuronosyltransferases (UGTs), and epoxide hydrolases (EHs), all of which

  11. Gene-environment interactions in ocular diseases.

    PubMed

    Sacca, S C; Bolognesi, C; Battistella, A; Bagnis, A; Izzotti, A

    2009-07-10

    Degenerative ocular diseases are widespread in the population and represent a major cause of reversible and irreversible blindness. Scientific evidences have been accumulating supporting the role of genotoxic damage and gene environment interactions in the pathogenesis of these diseases mainly including glaucoma, age-related macular degeneration, and cataract. Glaucoma, in its degenerative form, is characterized by the degeneration of the trabecular meshwork, the tissue of the anterior chamber of the eye devoted to aqueous-humour outflow. Such a degenerative process results in intra-ocular pressure increase and progressive damage of optic nerve head. Oxidative stress and DNA damage play an important role in inducing the degeneration of these well differentiated target tissues in which DNA damage results in a progressive cell loss. Macular degeneration is a common age-related disease affecting the central regions of the retina inducing progressive accumulation of oxidized lipoproteins and neovascularization. Environmental genotoxic risk factors include diet, light, and cigarette smoke paralleled by individual susceptibility as determined by adverse genetic assets. Cataract is a progressive opacity of the crystalline lens resulting from molecular damages induced by various risk factors including UV-containing light. This disease has been related to a failure in antioxidant defences. Experimental study provides evidence that cataract patients possess higher basal level of DNA damage, as evaluated by Comet test, in lymphocytes than controls. This finding is paralleled by the higher susceptibility to oxidative stress observed in the same patients. These novel experimental data further support the role of DNA damage as a main factor contributing to cataract onset. In conclusion, the examined degenerative ocular diseases recognise environmental risk factors often displaying genotoxic attitudes. Whenever these factors target individuals who are susceptible due their

  12. Gene-environment interactions in geriatric depression

    PubMed Central

    Lotrich, Francis E.

    2011-01-01

    Risk for the development of major depressive disorder (MDD) is likely influenced by an interacting set of genes and environments. Many elderly are exposed to a variety of potential MDD precipitants. Medical co-morbidities, high inflammatory states, care-giver stress, and cerebrovascular changes are often observed proximal to the development of an episode. Additionally, some adults have histories of exposure to environmental stressors such as early life traumas that may result in a life-long predisposition to MDD. Despite these exposures, many people do not develop MDD; and genetic influences are hypothesized to be one influence on vulnerability and resilience. Over the last seven years, several studies have examined a variety of genes for this gene × environment (G×E) interaction. Most have examined a length polymorphism in the promoter region for the serotonin transporter gene, but some have examined brain derived neurotrophic factor, various genes encoding for key players in the hypothalamic-pituitary-adrenal axis, as well as other genes involved in the monoaminergic, neuroendocrine, and inflammatory systems. There is marked variation in the design of these studies, as well as in the measures of environment, MDD, and genotyping. Interpreting the sometimes inconsistent findings among studies is complicated by this heterogeneity. However, some tentative trends have emerged. An overview is provided of both the methodologies and results of these studies, noting consistent trends as well as confounds. The progress made to date will hopefully inform the next generation of studies. PMID:21536163

  13. Gene environment interaction from international cohorts

    PubMed Central

    Gaffney, Adam; Christiani, David C.

    2016-01-01

    Environmental and occupational pulmonary diseases impose a substantial burden of morbidity and mortality on the global population. However, it has been long observed that only some of those who are exposed to pulmonary toxicants go on to develop disease; increasingly, it is being recognized that genetic differences may underlie some of this person-to-person variability. Studies performed throughout the globe are demonstrating important gene-by-environment interactions for diseases as diverse as chronic beryllium disease, coal workers’ pneumoconiosis, silicosis, asbestosis, bysinnosis, occupational asthma, and pollution-associated asthma. These findings have, in many instances, elucidated the pathogenesis of these highly complex diseases. At the same time, however, translation of this research into clinical practice has, for good reasons, proceeded slowly. No genetic test has yet emerged with sufficiently robust operating characteristics to be clearly useful or practicable in an occupational or environmental setting. Additionally, occupational genetic testing raises serious ethical and policy concerns. Therefore, the primary objective must remain ensuring that the workplace and the environment are safe for all. PMID:26024343

  14. Gene-Environment Interactions in Genome-Wide Association Studies: Current Approaches and New Directions

    ERIC Educational Resources Information Center

    Winham, Stacey J.; Biernacka, Joanna M.

    2013-01-01

    Background: Complex psychiatric traits have long been thought to be the result of a combination of genetic and environmental factors, and gene-environment interactions are thought to play a crucial role in behavioral phenotypes and the susceptibility and progression of psychiatric disorders. Candidate gene studies to investigate hypothesized…

  15. Gene-environment interaction and risk of breast cancer.

    PubMed

    Rudolph, Anja; Chang-Claude, Jenny; Schmidt, Marjanka K

    2016-01-19

    Hereditary, genetic factors as well as lifestyle and environmental factors, for example, parity and body mass index, predict breast cancer development. Gene-environment interaction studies may help to identify subgroups of women at high-risk of breast cancer and can be leveraged to discover new genetic risk factors. A few interesting results in studies including over 30,000 breast cancer cases and healthy controls indicate that such interactions exist. Explorative gene-environment interaction studies aiming to identify new genetic or environmental factors are scarce and still underpowered. Gene-environment interactions might be stronger for rare genetic variants, but data are lacking. Ongoing initiatives to genotype larger sample sets in combination with comprehensive epidemiologic databases will provide further opportunities to study gene-environment interactions in breast cancer. However, based on the available evidence, we conclude that associations between the common genetic variants known today and breast cancer risk are only weakly modified by environmental factors, if at all. PMID:26757262

  16. Understanding risk for psychopathology through imaging gene-environment interactions

    PubMed Central

    Hyde, Luke W.; Bogdan, Ryan; Hariri, Ahmad R.

    2011-01-01

    Examining the interplay of genes, experience, and the brain is critical to understanding psychopathology. We review the recent gene-environment interaction (GxE) and imaging genetics literature with the goal of developing models to bridge these approaches within single imaging gene-environment interaction (IGxE) studies. We explore challenges inherent in both GxE and imaging genetics and highlight studies that address these limitations. In specifying IGxE models, we examine statistical methods for combining these approaches, and explore plausible biological mechanisms (e.g., epigenetics) through which these conditional mechanisms can be understood. Finally, we discuss the potential contribution that IGxE studies can make to understanding psychopathology and developing more personalized and effective prevention and treatment. PMID:21839667

  17. The importance of gene-environment interactions in human obesity.

    PubMed

    Reddon, Hudson; Guéant, Jean-Louis; Meyre, David

    2016-09-01

    The worldwide obesity epidemic has been mainly attributed to lifestyle changes. However, who becomes obese in an obesity-prone environment is largely determined by genetic factors. In the last 20 years, important progress has been made in the elucidation of the genetic architecture of obesity. In parallel with successful gene identifications, the number of gene-environment interaction (GEI) studies has grown rapidly. This paper reviews the growing body of evidence supporting gene-environment interactions in the field of obesity. Heritability, monogenic and polygenic obesity studies provide converging evidence that obesity-predisposing genes interact with a variety of environmental, lifestyle and treatment exposures. However, some skepticism remains regarding the validity of these studies based on several issues, which include statistical modelling, confounding, low replication rate, underpowered analyses, biological assumptions and measurement precision. What follows in this review includes (1) an introduction to the study of GEI, (2) the evidence of GEI in the field of obesity, (3) an outline of the biological mechanisms that may explain these interaction effects, (4) methodological challenges associated with GEI studies and potential solutions, and (5) future directions of GEI research. Thus far, this growing body of evidence has provided a deeper understanding of GEI influencing obesity and may have tremendous applications in the emerging field of personalized medicine and individualized lifestyle recommendations. PMID:27503943

  18. HTR1B, ADIPOR1, PPARGC1A, and CYP19A1 and Obesity in a Cohort of Caucasians and African Americans: An Evaluation of Gene-Environment Interactions and Candidate Genes

    PubMed Central

    Edwards, Todd L.; Velez Edwards, Digna R.; Villegas, Raquel; Cohen, Sarah S.; Buchowski, Maciej S.; Fowke, Jay H.; Schlundt, David; Long, Ji Rong; Cai, Qiuyin; Zheng, Wei; Shu, Xiao-Ou; Hargreaves, Margaret K.; Jeffrey, Smith; Williams, Scott M.; Signorello, Lisa B.; Blot, William J.; Matthews, Charles E.

    2012-01-01

    The World Health Organization estimates that the number of obese and overweight adults has increased to 1.6 billion, with concomitant increases in comorbidity. While genetic factors for obesity have been extensively studied in Caucasians, fewer studies have investigated genetic determinants of body mass index (BMI; weight (kg)/height (m)2) in African Americans. A total of 38 genes and 1,086 single nucleotide polymorphisms (SNPs) in African Americans (n = 1,173) and 897 SNPs in Caucasians (n = 1,165) were examined in the Southern Community Cohort Study (2002–2009) for associations with BMI and gene × environment interactions. A statistically significant association with BMI survived correction for multiple testing at rs4140535 (β = −0.04, 95% confidence interval: −0.06, −0.02; P = 5.76 × 10−5) in African Americans but not in Caucasians. Gene-environment interactions were observed with cigarette smoking and a SNP in ADIPOR1 in African Americans, as well as between a different SNP in ADIPOR1 and physical activity in Caucasians. A SNP in PPARGC1A interacted with alcohol consumption in African Americans, and a different SNP in PPARGC1A was nominally associated in Caucasians. A SNP in CYP19A1 interacted with dietary energy intake in African Americans, and another SNP in CYP191A had an independent association with BMI in Caucasians. PMID:22106445

  19. A penalized robust semiparametric approach for gene-environment interactions.

    PubMed

    Wu, Cen; Shi, Xingjie; Cui, Yuehua; Ma, Shuangge

    2015-12-30

    In genetic and genomic studies, gene-environment (G×E) interactions have important implications. Some of the existing G×E interaction methods are limited by analyzing a small number of G factors at a time, by assuming linear effects of E factors, by assuming no data contamination, and by adopting ineffective selection techniques. In this study, we propose a new approach for identifying important G×E interactions. It jointly models the effects of all E and G factors and their interactions. A partially linear varying coefficient model is adopted to accommodate possible nonlinear effects of E factors. A rank-based loss function is used to accommodate possible data contamination. Penalization, which has been extensively used with high-dimensional data, is adopted for selection. The proposed penalized estimation approach can automatically determine if a G factor has an interaction with an E factor, main effect but not interaction, or no effect at all. The proposed approach can be effectively realized using a coordinate descent algorithm. Simulation shows that it has satisfactory performance and outperforms several competing alternatives. The proposed approach is used to analyze a lung cancer study with gene expression measurements and clinical variables. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26239060

  20. Music training and speech perception: a gene-environment interaction.

    PubMed

    Schellenberg, E Glenn

    2015-03-01

    Claims of beneficial side effects of music training are made for many different abilities, including verbal and visuospatial abilities, executive functions, working memory, IQ, and speech perception in particular. Such claims assume that music training causes the associations even though children who take music lessons are likely to differ from other children in music aptitude, which is associated with many aspects of speech perception. Music training in childhood is also associated with cognitive, personality, and demographic variables, and it is well established that IQ and personality are determined largely by genetics. Recent evidence also indicates that the role of genetics in music aptitude and music achievement is much larger than previously thought. In short, music training is an ideal model for the study of gene-environment interactions but far less appropriate as a model for the study of plasticity. Children seek out environments, including those with music lessons, that are consistent with their predispositions; such environments exaggerate preexisting individual differences. PMID:25773632

  1. Childhood Temperament: Passive Gene-Environment Correlation, Gene-Environment Interaction, and the Hidden Importance of the Family Environment

    PubMed Central

    Lemery-Chalfant, Kathryn; Kao, Karen; Swann, Gregory; Goldsmith, H. Hill

    2013-01-01

    Biological parents pass on genotypes to their children, as well as provide home environments that correlate with their genotypes; thus, the association between the home environment and children's temperament can be genetically (i.e. passive gene-environment correlation) or environmentally mediated. Furthermore, family environments may suppress or facilitate the heritability of children's temperament (i.e. gene-environment interaction). The sample comprised 807 twin pairs (M age = 7.93 years) from the longitudinal Wisconsin Twin Project. Important passive gene-environment correlations emerged, such that home environments were less chaotic for children with high Effortful Control, and this association was genetically mediated. Children with high Extraversion/Surgency experienced more chaotic home environments, and this correlation was also genetically mediated. In addition, heritability of children's temperament was moderated by home environments, such that Effortful Control and Extraversion/Surgency were more heritable in chaotic homes, and Negative Affectivity was more heritable under crowded or unsafe home conditions. Modeling multiple types of gene-environment interplay uncovered the complex role of genetic factors and the hidden importance of the family environment for children's temperament and development more generally. PMID:23398752

  2. Study of oral clefts: Indication of gene-environment interaction

    SciTech Connect

    Hwang, S.J.; Beaty, T.H.; Panny, S.

    1994-09-01

    In this study of infants with isolated birth defects, 69 cleft palate-only (CPO) cases, 114 cleft lip with or without palate (CL/P), and 284 controls with non-cleft birth defects (all born in Maryland during 1984-1992) were examined to test for associations among genetic markers and different oral clefts. Modest associations were found between transforming growth factor {alpha} (TGF{alpha}) marker and CPO, as well as that between D17S579 (Mfd188) and CL/P in this study. The association between TGF{alpha} marker and CPO reflects a statistical interaction between mother`s smoking and child`s TGF{alpha} genotype. A significantly higher risk of CPO was found among those reporting maternal smoking during pregnancy and carrying less common TGF{alpha} TaqI allele (odds ratio=7.02 with 95% confidence interval 1.8-27.6). This gene-environment interaction was also found among those who reported no family history of any type of birth defect (odds ratio=5.60 with 95% confidence interval 1.4-22.9). Similar associations were seen for CL/P, but these were not statistically significant.

  3. Sleep Duration and Depressive Symptoms: A Gene-Environment Interaction

    PubMed Central

    Watson, Nathaniel F.; Harden, Kathryn Paige; Buchwald, Dedra; Vitiello, Michael V.; Pack, Allan I.; Strachan, Eric; Goldberg, Jack

    2014-01-01

    Objective: We used quantitative genetic models to assess whether sleep duration modifies genetic and environmental influences on depressive symptoms. Method: Participants were 1,788 adult twins from 894 same-sex twin pairs (192 male and 412 female monozygotic [MZ] pairs, and 81 male and 209 female dizygotic [DZ] pairs] from the University of Washington Twin Registry. Participants self-reported habitual sleep duration and depressive symptoms. Data were analyzed using quantitative genetic interaction models, which allowed the magnitude of additive genetic, shared environmental, and non-shared environmental influences on depressive symptoms to vary with sleep duration. Results: Within MZ twin pairs, the twin who reported longer sleep duration reported fewer depressive symptoms (ec = -0.17, SE = 0.06, P < 0.05). There was a significant gene × sleep duration interaction effect on depressive symptoms (a'c = 0.23, SE = 0.08, P < 0.05), with the interaction occurring on genetic influences that are common to both sleep duration and depressive symptoms. Among individuals with sleep duration within the normal range (7-8.9 h/night), the total heritability (h2) of depressive symptoms was approximately 27%. However, among individuals with sleep duration within the low (< 7 h/night) or high (≥ 9 h/night) range, increased genetic influence on depressive symptoms was observed, particularly at sleep duration extremes (5 h/night: h2 = 53%; 10 h/night: h2 = 49%). Conclusion: Genetic contributions to depressive symptoms increase at both short and long sleep durations. Citation: Watson NF; Harden KP; Buchwald D; Vitiello MV; Pack AI; Stachan E; Goldberg J. Sleep duration and depressive symptoms: a gene-environment interaction. SLEEP 2014;37(2):351-358. PMID:24497663

  4. Gene-environment Interactions in the Etiology of Dental Caries.

    PubMed

    Yildiz, G; Ermis, R B; Calapoglu, N S; Celik, E U; Türel, G Y

    2016-01-01

    Dental caries is a multifactorial disease that can be conceptualized as an interaction between genetic and environmental risk factors. The aim of this study is to examine the effects of AMELX, CA6, DEFB1, and TAS2R38 gene polymorphism and gene-environment interactions on caries etiology and susceptibility in adults. Genomic DNA was extracted from the buccal mucosa, and adults aged 20 to 60 y were placed into 1 of 2 groups: low caries risk (DMFT ≤ 5; n = 77) and high caries risk (DMFT ≥ 14; n = 77). The frequency of AMELX (+522), CA6 (T55M), DEFB1 (G-20A), and TAS2R38 (A49P) single-nucleotide polymorphisms was genotyped with the polymerase chain reaction-restriction fragment length polymorphism method. Environmental risk factors examined in the study included plaque amount, toothbrushing frequency, dietary intake between meals, saliva secretion rate, saliva buffer capacity, mutans streptococci counts, and lactobacilli counts. There was no difference between the caries risk groups in relation to AMELX (+522) polymorphism (χ(2) test, P > 0.05). The distribution of CA6 genotype and allele frequencies in the low caries risk group did not differ from the high caries risk group (χ(2) test, P > 0.05). Polymorphism of DEFB1 (G-20A) was positively associated, and TAS2R38 (A49P) negatively associated, with caries risk (χ(2) test, P = 0.000). There were significant differences between caries susceptibility and each environmental risk factor, except for the saliva secretion rate (Mann-Whitney U test, P = 0.000). Based on stepwise multiple linear regression analyses, dental plaque amount, lactobacilli count, age, and saliva buffer capacity, as well as DEFB1 (G-20A), TAS2R38 (A49P), and CA6 (T55M) gene polymorphism, explained a total of 87.8% of the variations in DMFT scores. It can be concluded that variation in CA6 (T55M), DEFB1 (G-20A), and TAS2R38 (A49P) may be associated with caries experience in Turkish adults with a high level of dental plaque, lactobacilli count

  5. Disentangling Gene-Environment Correlations and Interactions on Adolescent Depressive Symptoms

    ERIC Educational Resources Information Center

    Lau, Jennifer Y. F.; Eley, Thalia C.

    2008-01-01

    Background: Genetic risks for depression may be expressed through greater exposure towards environmental stressors (gene-environment correlation, rGE) and increased susceptibility to these stressors (gene-environment interaction, G x E). While these effects are often studied independently, evidence supports their co-occurrence on depression.…

  6. Gene-environment interactions in asthma and allergic diseases: challenges and perspectives.

    PubMed

    Kauffmann, Francine; Demenais, Florence

    2012-12-01

    The concept of gene-environment (GxE) interactions has dramatically evolved in the last century and has now become a central theme in studies that assess the causes of human disease. Despite the numerous efforts to discover genes associated in asthma and allergy through various approaches, including the recent genome-wide association studies, investigation of GxE interactions has been mainly limited to candidate genes, candidate environmental exposures, or both. This review discusses the various strategies from hypothesis-driven strategies to the full agnostic search of GxE interactions with an illustration from recently published articles. Challenges raised by each piece of the puzzle (ie, phenotype, environment, gene, and analysis of GxE interaction) are put forward, and tentative solutions are proposed. New perspectives to integrate various types of data generated by new sequencing technologies and to progress toward a systems biology approach of disease are outlined. The future of a molecular network-based approach of disease to which GxE interactions are related requires space for innovative and multidisciplinary research. Assembling the various parts of a puzzle in a complex system could well occur in a way that might not necessarily follow the rules of logic. PMID:23195523

  7. Gene-environment interactions and obesity: recent developments and future directions

    PubMed Central

    2015-01-01

    Obesity, a major public health concern, is a multifactorial disease caused by both environmental and genetic factors. Although recent genome-wide association studies have identified many loci related to obesity or body mass index, the identified variants explain only a small proportion of the heritability of obesity. Better understanding of the interplay between genetic and environmental factors is the basis for developing effective personalized obesity prevention and management strategies. This article reviews recent advances in identifying gene-environment interactions related to obesity and describes epidemiological designs and newly developed statistical approaches to characterizing and discovering gene-environment interactions on obesity risk. PMID:25951849

  8. Gene-Environment Interactions Between Depressive Symptoms and Smoking Quantity.

    PubMed

    Keskitalo-Vuokko, Kaisu; Korhonen, Tellervo; Kaprio, Jaakko

    2016-08-01

    We investigated genetic and environmental correlations and gene by environment interactions (GxE) between depressive symptoms measured by the Beck Depression Inventory (BDI) and quantity smoked measured by number of cigarettes smoked per day (CPD) using quantitative genetic modeling. The population-based sample consisted of 12,063 twin individuals from the Finnish Twin Cohort Study. Bivariate Cholesky decomposition revealed that the phenotypic correlation (r = 0.09) between BDI and CPD was explained by shared genetic (r g = 0.18) and environmental (r e = 0.08) factors. GxE models incorporating moderator effects were built by using CPD as trait and BDI as moderator and vice versa. The importance of the genetic variance component increased with increasing moderator value in both models. Thus, the influence of genetic effects on variance of smoking quantity was enhanced in individuals with elevated depression score and vice versa; the genetic effects on depression variance were potentiated among heavy smokers. In conclusion, shared genetic and environmental factors as well as GxE underlie the association of smoking with depression. PMID:27161145

  9. Identifying gene-environment interactions in schizophrenia: contemporary challenges for integrated, large-scale investigations.

    PubMed

    van Os, Jim; Rutten, Bart P; Myin-Germeys, Inez; Delespaul, Philippe; Viechtbauer, Wolfgang; van Zelst, Catherine; Bruggeman, Richard; Reininghaus, Ulrich; Morgan, Craig; Murray, Robin M; Di Forti, Marta; McGuire, Philip; Valmaggia, Lucia R; Kempton, Matthew J; Gayer-Anderson, Charlotte; Hubbard, Kathryn; Beards, Stephanie; Stilo, Simona A; Onyejiaka, Adanna; Bourque, Francois; Modinos, Gemma; Tognin, Stefania; Calem, Maria; O'Donovan, Michael C; Owen, Michael J; Holmans, Peter; Williams, Nigel; Craddock, Nicholas; Richards, Alexander; Humphreys, Isla; Meyer-Lindenberg, Andreas; Leweke, F Markus; Tost, Heike; Akdeniz, Ceren; Rohleder, Cathrin; Bumb, J Malte; Schwarz, Emanuel; Alptekin, Köksal; Üçok, Alp; Saka, Meram Can; Atbaşoğlu, E Cem; Gülöksüz, Sinan; Gumus-Akay, Guvem; Cihan, Burçin; Karadağ, Hasan; Soygür, Haldan; Cankurtaran, Eylem Şahin; Ulusoy, Semra; Akdede, Berna; Binbay, Tolga; Ayer, Ahmet; Noyan, Handan; Karadayı, Gülşah; Akturan, Elçin; Ulaş, Halis; Arango, Celso; Parellada, Mara; Bernardo, Miguel; Sanjuán, Julio; Bobes, Julio; Arrojo, Manuel; Santos, Jose Luis; Cuadrado, Pedro; Rodríguez Solano, José Juan; Carracedo, Angel; García Bernardo, Enrique; Roldán, Laura; López, Gonzalo; Cabrera, Bibiana; Cruz, Sabrina; Díaz Mesa, Eva Ma; Pouso, María; Jiménez, Estela; Sánchez, Teresa; Rapado, Marta; González, Emiliano; Martínez, Covadonga; Sánchez, Emilio; Olmeda, Ma Soledad; de Haan, Lieuwe; Velthorst, Eva; van der Gaag, Mark; Selten, Jean-Paul; van Dam, Daniella; van der Ven, Elsje; van der Meer, Floor; Messchaert, Elles; Kraan, Tamar; Burger, Nadine; Leboyer, Marion; Szoke, Andrei; Schürhoff, Franck; Llorca, Pierre-Michel; Jamain, Stéphane; Tortelli, Andrea; Frijda, Flora; Vilain, Jeanne; Galliot, Anne-Marie; Baudin, Grégoire; Ferchiou, Aziz; Richard, Jean-Romain; Bulzacka, Ewa; Charpeaud, Thomas; Tronche, Anne-Marie; De Hert, Marc; van Winkel, Ruud; Decoster, Jeroen; Derom, Catherine; Thiery, Evert; Stefanis, Nikos C; Sachs, Gabriele; Aschauer, Harald; Lasser, Iris; Winklbaur, Bernadette; Schlögelhofer, Monika; Riecher-Rössler, Anita; Borgwardt, Stefan; Walter, Anna; Harrisberger, Fabienne; Smieskova, Renata; Rapp, Charlotte; Ittig, Sarah; Soguel-dit-Piquard, Fabienne; Studerus, Erich; Klosterkötter, Joachim; Ruhrmann, Stephan; Paruch, Julia; Julkowski, Dominika; Hilboll, Desiree; Sham, Pak C; Cherny, Stacey S; Chen, Eric Y H; Campbell, Desmond D; Li, Miaoxin; Romeo-Casabona, Carlos María; Emaldi Cirión, Aitziber; Urruela Mora, Asier; Jones, Peter; Kirkbride, James; Cannon, Mary; Rujescu, Dan; Tarricone, Ilaria; Berardi, Domenico; Bonora, Elena; Seri, Marco; Marcacci, Thomas; Chiri, Luigi; Chierzi, Federico; Storbini, Viviana; Braca, Mauro; Minenna, Maria Gabriella; Donegani, Ivonne; Fioritti, Angelo; La Barbera, Daniele; La Cascia, Caterina Erika; Mulè, Alice; Sideli, Lucia; Sartorio, Rachele; Ferraro, Laura; Tripoli, Giada; Seminerio, Fabio; Marinaro, Anna Maria; McGorry, Patrick; Nelson, Barnaby; Amminger, G Paul; Pantelis, Christos; Menezes, Paulo R; Del-Ben, Cristina M; Gallo Tenan, Silvia H; Shuhama, Rosana; Ruggeri, Mirella; Tosato, Sarah; Lasalvia, Antonio; Bonetto, Chiara; Ira, Elisa; Nordentoft, Merete; Krebs, Marie-Odile; Barrantes-Vidal, Neus; Cristóbal, Paula; Kwapil, Thomas R; Brietzke, Elisa; Bressan, Rodrigo A; Gadelha, Ary; Maric, Nadja P; Andric, Sanja; Mihaljevic, Marina; Mirjanic, Tijana

    2014-07-01

    Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G × E), however, so far, thorough replication of findings is rare and G × E research still faces several conceptual and methodological challenges. In this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G × E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G × E in schizophrenia. While such investigations are now well underway, new challenges emerge for G × E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype. PMID:24860087

  10. Identifying Gene-Environment Interactions in Schizophrenia: Contemporary Challenges for Integrated, Large-scale Investigations

    PubMed Central

    2014-01-01

    Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G × E), however, so far, thorough replication of findings is rare and G × E research still faces several conceptual and methodological challenges. In this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G × E research, drawing on the example of a large, international, multi–center study into the identification and translational application of G × E in schizophrenia. While such investigations are now well underway, new challenges emerge for G × E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype. PMID:24860087

  11. Confirmatory and Competitive Evaluation of Alternative Gene-Environment Interaction Hypotheses

    ERIC Educational Resources Information Center

    Belsky, Jay; Pluess, Michael; Widaman, Keith F.

    2013-01-01

    Background: Most gene-environment interaction (GXE) research, though based on clear, vulnerability-oriented hypotheses, is carried out using exploratory rather than hypothesis-informed statistical tests, limiting power and making formal evaluation of competing GXE propositions difficult. Method: We present and illustrate a new regression technique…

  12. How Gene-Environment Interaction Affects Children's Anxious and Fearful Behavior. Science Briefs

    ERIC Educational Resources Information Center

    National Scientific Council on the Developing Child, 2007

    2007-01-01

    "Science Briefs" summarize the findings and implications of a recent study in basic science or clinical research. This brief reports on the study "Evidence for a Gene-Environment Interaction in Predicting Behavioral Inhibition in Middle Childhood" (N. A. Fox, K E. Nichols, H. A. Henderson, K. Rubin, L. Schmidt, D. Hamer, M. Ernst, and D. S.…

  13. A Platform for the Remote Conduct of Gene-Environment Interaction Studies

    PubMed Central

    Gallacher, John; Collins, Rory; Elliott, Paul; Palmer, Stephen; Burton, Paul; Mitchell, Clive; John, Gareth; Lyons, Ronan

    2013-01-01

    Background Gene-environment interaction studies offer the prospect of robust causal inference through both gene identification and instrumental variable approaches. As such they are a major and much needed development. However, conducting these studies using traditional methods, which require direct participant contact, is resource intensive. The ability to conduct gene-environment interaction studies remotely would reduce costs and increase capacity. Aim To develop a platform for the remote conduct of gene-environment interaction studies. Methods A random sample of 15,000 men and women aged 50+ years and living in Cardiff, South Wales, of whom 6,012 were estimated to have internet connectivity, were mailed inviting them to visit a web-site to join a study of successful ageing. Online consent was obtained for questionnaire completion, cognitive testing, re-contact, record linkage and genotyping. Cognitive testing was conducted using the Cardiff Cognitive Battery. Bio-sampling was randomised to blood spot, buccal cell or no request. Results A heterogeneous sample of 663 (4.5% of mailed sample and 11% of internet connected sample) men and women (47% female) aged 50–87 years (median = 61 yrs) from diverse backgrounds (representing the full range of deprivation scores) was recruited. Bio-samples were donated by 70% of those agreeing to do so. Self report questionnaires and cognitive tests showed comparable distributions to those collected using face-to-face methods. Record linkage was achieved for 99.9% of participants. Conclusion This study has demonstrated that remote methods are suitable for the conduct of gene-environment interaction studies. Up-scaling these methods provides the opportunity to increase capacity for large-scale gene-environment interaction studies. PMID:23349852

  14. Gene-Environment Interactions in Cancer Epidemiology: A National Cancer Institute Think Tank Report

    PubMed Central

    Hutter, Carolyn M.; Mechanic, Leah E.; Chatterjee, Nilanjan; Kraft, Peter; Gillander, Elizabeth M.

    2014-01-01

    Cancer risk is determined by a complex interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified hundreds of common (minor allele frequency [MAF]>0.05) and less common (0.01gene-environment interactions, into epidemiologic studies of cancer. To help address these questions, and to better inform research priorities and allocation of resources, the National Cancer Institute sponsored a “Gene-Environment Think Tank” on January 10th–011th, 2012. The objective of the Think Tank was to facilitate discussions on: 1) the state of the science; 2) the goals of gene-environment interaction studies in cancer epidemiology; and 3) opportunities for developing novel study designs and analysis tools. This report summarizes the Think Tank discussion, with a focus on contemporary approaches to the analysis of gene-environment interactions. Selecting the appropriate methods requires first identifying the relevant scientific question and rationale, with an important distinction made between analyses aiming to characterize the joint effects of putative or established genetic and environmental factors and analyses aiming to discover novel risk factors or novel interaction effects. Other discussion items include measurement error, statistical power, significance and replication. Additional designs, exposure assessments, and analytical approaches need to be considered as we move from the current small number of success stories to a fuller understanding of the interplay of genetic and environmental factors. PMID:24123198

  15. Genetics, environment, and gene-environment interactions in the development of systemic rheumatic diseases

    PubMed Central

    Sparks, Jeffrey A.; Costenbader, Karen H.

    2014-01-01

    Understanding disease susceptibility factors and gene-environment interactions may offer valuable insights into the biological mechanisms for the etiology of rheumatic diseases. Defining the contributions of genetic and environmental factors to the pathogenesis of rheumatic diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and ankylosing spondylitis (AS), may have important implications for understanding risk prediction, pathogenic mechanisms, cellular pathways, drug discovery, and prevention strategies. However, rheumatic diseases offer distinct challenges to researchers due to heterogeneity in disease phenotypes, low disease incidence, and geographic variation in both genetic and environmental factors. Emerging research areas, including epigenetics, metabolomics, and the microbiome, may provide additional links between genetic and environmental risk factors in rheumatic disease pathogenesis. This article reviews the methods used to establish genetic and environmental risk factors and to study gene-environment interactions in rheumatic diseases and provides specific examples of successes and challenges for identifying gene-environment interactions in RA, SLE, and AS. Finally, we describe how emerging research strategies may build upon previous discoveries as well as future challenges. PMID:25437282

  16. The genetics of music accomplishment: evidence for gene-environment correlation and interaction.

    PubMed

    Hambrick, David Z; Tucker-Drob, Elliot M

    2015-02-01

    Theories of skilled performance that emphasize training history, such as K. Anders Ericsson and colleagues' deliberate-practice theory, have received a great deal of recent attention in both the scientific literature and the popular press. Twin studies, however, have demonstrated evidence for moderate-to-strong genetic influences on skilled performance. Focusing on musical accomplishment in a sample of over 800 pairs of twins, we found evidence for gene-environment correlation, in the form of a genetic effect on music practice. However, only about one quarter of the genetic effect on music accomplishment was explained by this genetic effect on music practice, suggesting that genetically influenced factors other than practice contribute to individual differences in music accomplishment. We also found evidence for gene-environment interaction, such that genetic effects on music accomplishment were most pronounced among those engaging in music practice, suggesting that genetic potentials for skilled performance are most fully expressed and fostered by practice. PMID:24957535

  17. Gene-Environment Interactions in Stress Response Contribute Additively to a Genotype-Environment Interaction

    PubMed Central

    Matsui, Takeshi; Ehrenreich, Ian M.

    2016-01-01

    How combinations of gene-environment interactions collectively give rise to genotype-environment interactions is not fully understood. To shed light on this problem, we genetically dissected an environment-specific poor growth phenotype in a cross of two budding yeast strains. This phenotype is detectable when certain segregants are grown on ethanol at 37°C (‘E37’), a condition that differs from the standard culturing environment in both its carbon source (ethanol as opposed to glucose) and temperature (37°C as opposed to 30°C). Using recurrent backcrossing with phenotypic selection, we identified 16 contributing loci. To examine how these loci interact with each other and the environment, we focused on a subset of four loci that together can lead to poor growth in E37. We measured the growth of all 16 haploid combinations of alleles at these loci in all four possible combinations of carbon source (ethanol or glucose) and temperature (30 or 37°C) in a nearly isogenic population. This revealed that the four loci act in an almost entirely additive manner in E37. However, we also found that these loci have weaker effects when only carbon source or temperature is altered, suggesting that their effect magnitudes depend on the severity of environmental perturbation. Consistent with such a possibility, cloning of three causal genes identified factors that have unrelated functions in stress response. Thus, our results indicate that polymorphisms in stress response can show effects that are intensified by environmental stress, thereby resulting in major genotype-environment interactions when multiple of these variants co-occur. PMID:27437938

  18. Genome-wide gene-environment interactions on quantitative traits using family data.

    PubMed

    Sitlani, Colleen M; Dupuis, Josée; Rice, Kenneth M; Sun, Fangui; Pitsillides, Achilleas N; Cupples, L Adrienne; Psaty, Bruce M

    2016-07-01

    Gene-environment interactions may provide a mechanism for targeting interventions to those individuals who would gain the most benefit from them. Searching for interactions agnostically on a genome-wide scale requires large sample sizes, often achieved through collaboration among multiple studies in a consortium. Family studies can contribute to consortia, but to do so they must account for correlation within families by using specialized analytic methods. In this paper, we investigate the performance of methods that account for within-family correlation, in the context of gene-environment interactions with binary exposures and quantitative outcomes. We simulate both cross-sectional and longitudinal measurements, and analyze the simulated data taking family structure into account, via generalized estimating equations (GEE) and linear mixed-effects models. With sufficient exposure prevalence and correct model specification, all methods perform well. However, when models are misspecified, mixed modeling approaches have seriously inflated type I error rates. GEE methods with robust variance estimates are less sensitive to model misspecification; however, when exposures are infrequent, GEE methods require modifications to preserve type I error rate. We illustrate the practical use of these methods by evaluating gene-drug interactions on fasting glucose levels in data from the Framingham Heart Study, a cohort that includes related individuals. PMID:26626313

  19. Gene-Gene and Gene-Environment Interactions in Ulcerative Colitis

    PubMed Central

    Wang, Ming-Hsi; Fiocchi, Claudio; Zhu, Xiaofeng; Ripke, Stephan; Kamboh, M. Ilyas; Rebert, Nancy; Duerr, Richard H.; Achkar, Jean-Paul

    2014-01-01

    Genome-wide association studies (GWAS) have identified at least 133 ulcerative colitis (UC) associated loci. The role of genetic factors in clinical practice is not clearly defined. The relevance of genetic variants to disease pathogenesis is still uncertain because of not characterized gene-gene and gene-environment interactions. We examined the predictive value of combining the 133 UC risk loci with genetic interactions in an ongoing inflammatory bowel disease (IBD) GWAS. The Wellcome Trust Case-Control Consortium (WTCCC) IBD GWAS was used as a replication cohort. We applied logic regression (LR), a novel adaptive regression methodology, to search for high order interactions. Exploratory genotype correlations with UC sub-phenotypes (extent of disease, need of surgery, age of onset, extra-intestinal manifestations and primary sclerosing cholangitis (PSC)) were conducted. The combination of 133 UC loci yielded good UC risk predictability (area under the curve [AUC] of 0.86). A higher cumulative allele score predicted higher UC risk. Through LR, several lines of evidence for genetic interactions were identified and successfully replicated in the WTCCC cohort. The genetic interactions combined with the gene-smoking interaction significantly improved predictability in the model (AUC, from 0.86 to 0.89, P=3.26E-05). Explained UC variance increased from 37% to 42% after adding the interaction terms. A within case analysis found suggested genetic association with PSC. Our study demonstrates that the LR methodology allows the identification and replication of high order genetic interactions in UC GWAS datasets. UC risk can be predicted by a 133 loci and improved by adding gene-gene and gene-environment interactions. PMID:24241240

  20. From 'omics' to complex disease: a systems biology approach to gene-environment interactions in cancer

    PubMed Central

    2010-01-01

    Background Cancer is a complex disease that involves a sequence of gene-environment interactions in a progressive process that cannot occur without dysfunction in multiple systems, including DNA repair, apoptotic and immune functions. Epigenetic mechanisms, responding to numerous internal and external cues in a dynamic ongoing exchange, play a key role in mediating environmental influences on gene expression and tumor development. Hypothesis The hypothesis put forth in this paper addresses the limited success of treatment outcomes in clinical oncology. It states that improvement in treatment efficacy requires a new paradigm that focuses on reversing systemic dysfunction and tailoring treatments to specific stages in the process. It requires moving from a reductionist framework of seeking to destroy aberrant cells and pathways to a transdisciplinary systems biology approach aimed at reversing multiple levels of dysfunction. Conclusion Because there are many biological pathways and multiple epigenetic influences working simultaneously in the expression of cancer phenotypes, studying individual components in isolation does not allow an adequate understanding of phenotypic expression. A systems biology approach using new modeling techniques and nonlinear mathematics is needed to investigate gene-environment interactions and improve treatment efficacy. A broader array of study designs will also be required, including prospective molecular epidemiology, immune competent animal models and in vitro/in vivo translational research that more accurately reflects the complex process of tumor initiation and progression. PMID:20420667

  1. Gene-Environment Interaction Research and Transgenic Mouse Models of Alzheimer's Disease

    PubMed Central

    Chouliaras, L.; Sierksma, A. S. R.; Kenis, G.; Prickaerts, J.; Lemmens, M. A. M.; Brasnjevic, I.; van Donkelaar, E. L.; Martinez-Martinez, P.; Losen, M.; De Baets, M. H.; Kholod, N.; van Leeuwen, F.; Hof, P. R.; van Os, J.; Steinbusch, H. W. M.; van den Hove, D. L. A.; Rutten, B. P. F.

    2010-01-01

    The etiology of the sporadic form of Alzheimer's disease (AD) remains largely unknown. Recent evidence has suggested that gene-environment interactions (GxE) may play a crucial role in its development and progression. Whereas various susceptibility loci have been identified, like the apolipoprotein E4 allele, these cannot fully explain the increasing prevalence of AD observed with aging. In addition to such genetic risk factors, various environmental factors have been proposed to alter the risk of developing AD as well as to affect the rate of cognitive decline in AD patients. Nevertheless, aside from the independent effects of genetic and environmental risk factors, their synergistic participation in increasing the risk of developing AD has been sparsely investigated, even though evidence points towards such a direction. Advances in the genetic manipulation of mice, modeling various aspects of the AD pathology, have provided an excellent tool to dissect the effects of genes, environment, and their interactions. In this paper we present several environmental factors implicated in the etiology of AD that have been tested in transgenic animal models of the disease. The focus lies on the concept of GxE and its importance in a multifactorial disease like AD. Additionally, possible mediating mechanisms and future challenges are discussed. PMID:20953364

  2. Culture as a mediator of gene-environment interaction: Cultural consonance, childhood adversity, a 2A serotonin receptor polymorphism, and depression in urban Brazil.

    PubMed

    Dressler, William W; Balieiro, Mauro C; Ferreira de Araújo, Luiza; Silva, Wilson A; Ernesto Dos Santos, José

    2016-07-01

    Research on gene-environment interaction was facilitated by breakthroughs in molecular biology in the late 20th century, especially in the study of mental health. There is a reliable interaction between candidate genes for depression and childhood adversity in relation to mental health outcomes. The aim of this paper is to explore the role of culture in this process in an urban community in Brazil. The specific cultural factor examined is cultural consonance, or the degree to which individuals are able to successfully incorporate salient cultural models into their own beliefs and behaviors. It was hypothesized that cultural consonance in family life would mediate the interaction of genotype and childhood adversity. In a study of 402 adult Brazilians from diverse socioeconomic backgrounds, conducted from 2011 to 2014, the interaction of reported childhood adversity and a polymorphism in the 2A serotonin receptor was associated with higher depressive symptoms. Further analysis showed that the gene-environment interaction was mediated by cultural consonance in family life, and that these effects were more pronounced in lower social class neighborhoods. The findings reinforce the role of the serotonergic system in the regulation of stress response and learning and memory, and how these processes in turn interact with environmental events and circumstances. Furthermore, these results suggest that gene-environment interaction models should incorporate a wider range of environmental experience and more complex pathways to better understand how genes and the environment combine to influence mental health outcomes. PMID:27270123

  3. Bayesian Variable Selection for Hierarchical Gene-Environment and Gene-Gene Interactions

    PubMed Central

    Liu, Changlu; Ma, Jianzhong; Amos, Christopher I.

    2014-01-01

    We propose a Bayesian hierarchical mixture model framework that allows us to investigate the genetic and environmental effects, gene by gene interactions and gene by environment interactions in the same model. Our approach incorporates the natural hierarchical structure between the main effects and interaction effects into a mixture model, such that our methods tend to remove the irrelevant interaction effects more effectively, resulting in more robust and parsimonious models. We consider both strong and weak hierarchical models. For a strong hierarchical model, both of the main effects between interacting factors must be present for the interactions to be considered in the model development, while for a weak hierarchical model, only one of the two main effects is required to be present for the interaction to be evaluated. Our simulation results show that the proposed strong and weak hierarchical mixture models work well in controlling false positive rates and provide a powerful approach for identifying the predisposing effects and interactions in gene-environment interaction studies, in comparison with the naive model that does not impose this hierarchical constraint in most of the scenarios simulated. We illustrated our approach using data for lung cancer and cutaneous melanoma. PMID:25154630

  4. Gene-Environment Interactions, Folate Metabolism and the Embryonic Nervous System

    PubMed Central

    Ross, M. Elizabeth

    2010-01-01

    Formation of brain and spinal cord requires the successful closure of neural ectoderm into an embryonic neural tube. Defects in this process result in anencephaly or spina bifida, which together constitute a leading cause of mortality and morbidity in children, affecting all ethnic and socioeconomic groups. The subject of intensive research for decades, neural tube defects (NTDs) are understood to arise from complex interactions of genes and environmental conditions, though systems-level details are still elusive. Despite the variety of underlying causes, a single intervention, folic acid supplementation given in the first gestational month can measurably reduce the occurrence of NTDs in a population. Evidence for and the scope of gene-environment interactions in the genesis of NTDs are discussed. A systems-based approach is now possible toward studies of genetic and environmental influences underlying NTDs that will enable the assessment of individual risk and personalized optimization of prevention. PMID:20836042

  5. The role of gene-environment interactions in the development of food allergy.

    PubMed

    Neeland, Melanie R; Martino, David J; Allen, Katrina J

    2015-01-01

    The rates of IgE-mediated food allergy have increased globally, particularly in developed countries. The rising incidence is occurring more rapidly than changes to the genome sequence would allow, suggesting that environmental exposures that alter the immune response play an important role. Genetic factors may also be used to predict an increased predisposition to these environmental risk factors, giving rise to the concept of gene-environment interactions, whereby differential risk of environmental exposures is mediated through the genome. Increasing evidence also suggests a role for epigenetic mechanisms, which are sensitive to environmental exposures, in the development of food allergy. This paper discusses the current state of knowledge regarding the environmental and genetic risk factors for food allergy and how environmental exposures may interact with immune genes to modify disease risk or outcome. PMID:26357960

  6. Environmental and gene-environment interactions and risk of rheumatoid arthritis

    PubMed Central

    Karlson, Elizabeth W.; Deane, Kevin

    2012-01-01

    Multiple environmental factors including hormones, dietary factors, infections and exposure to tobacco smoke as well as gene-environment interactions have been associated with increased risk for rheumatoid arthritis (RA). Importantly, the growing understanding of the prolonged period prior to the first onset of symptoms of RA suggests that these environmental and genetic factors are likely acting to drive the development of RA-related autoimmunity long before the appearance of the first joint symptoms and clinical findings that are characteristic of RA. Herein we will review these factors and interactions, especially those that have been investigated in a prospective fashion prior to the symptomatic onset of RA. We will also discuss how these factors may be explored in future study to further the understanding of the pathogenesis of RA, and ultimately perhaps develop preventive measures for this disease. PMID:22819092

  7. MAOA genotype, social exclusion and aggression: an experimental test of a gene-environment interaction.

    PubMed

    Gallardo-Pujol, D; Andrés-Pueyo, A; Maydeu-Olivares, A

    2013-02-01

    In 2002, Caspi and colleagues provided the first epidemiological evidence that genotype may moderate individuals' responses to environmental determinants. However, in a correlational study great care must be taken to ensure the proper estimation of the causal relationship. Here, a randomized experiment was performed to test the hypothesis that the MAOA gene promoter polymorphism (MAOA-LPR) interacts with environmental adversity in determining aggressive behavior using laboratory analogs of real-life conditions. A sample of 57 Caucasian male students of Catalan and Spanish origin was recruited at the University of Barcelona. Ostracism, or social exclusion, was induced as environmental adversity using the Cyberball software. Laboratory aggression was assessed with the Point Subtraction Aggression Paradigm (PSAP), which was used as an analog of antisocial behavior. We also measured aggressiveness by means of the reduced version of the Aggression Questionnaire. The MAOA-LPR polymorphism showed a significant effect on the number of aggressive responses in the PSAP (F(1,53) = 4.63, P = 0.03, partial η(2) = 0.08), as well as social exclusion (F(1,53) = 8.03, P = 0.01, partial η(2) = 0.13). Most notably, however, we found that the MAOA-LPR polymorphism interacts significantly with social exclusion in order to provoke aggressive behavior (F(1,53) = 4.42, P = 0.04, partial η(2) = 0.08), remarkably, the low-activity allele of the MAOA-LPR polymorphism carriers in the ostracized group show significantly higher aggression scores than the rest. Our results support the notion that gene-environment interactions can be successfully reproduced within a laboratory using analogs and an appropriate design. We provide guidelines to test gene-environment interactions hypotheses under controlled, experimental settings. PMID:23067570

  8. Gene-Environment Interaction Effects on the Development of Immune Responses in the 1st Year of Life

    PubMed Central

    Hoffjan, Sabine; Nicolae, Dan; Ostrovnaya, Irina; Roberg, Kathy; Evans, Michael; Mirel, Daniel B.; Steiner, Lori; Walker, Karen; Shult, Peter; Gangnon, Ronald E.; Gern, James E.; Martinez, Fernando D.; Lemanske, Robert F.; Ober, Carole

    2005-01-01

    Asthma is a common disease that results from both genetic and environmental risk factors. Children attending day care in the 1st year of life have lower risks for developing asthma, although the mechanism for this “day care” effect is largely unknown. We investigated the interactions between day care exposure in the 1st 6 mo of life and genotypes for 72 polymorphisms at 45 candidate loci and their effects on cytokine response profiles and on the development of atopic phenotypes in the 1st year of life in the Childhood Onset of Asthma (COAST) cohort of children. Six interactions (at four polymorphisms in three loci) with “day care” that had an effect on early-life immune phenotypes were significant at P<.001. The estimated false-discovery rate was 33%, indicating that an estimated four P values correspond to true associations. Moreover, the “day care” effect at some loci was accounted for by the increased number of viral infections among COAST children attending day care, whereas interactions at other loci were independent of the number of viral infections, indicating the presence of additional risk factors associated with day care environment. This study identified significant gene-environment interactions influencing the early patterning of the immune system and the subsequent development of asthma and highlights the importance of considering environmental risk factors in genetic analyses. PMID:15726497

  9. Key Considerations and Methods in the Study of Gene-Environment Interactions.

    PubMed

    Simon, Paul H G; Sylvestre, Marie-Pierre; Tremblay, Johanne; Hamet, Pavel

    2016-08-01

    With increased involvement of genetic data in most epidemiological investigations, gene-environment (G × E) interactions now stand as a topic, which must be meticulously assessed and thoroughly understood. The level, mode, and outcomes of interactions between environmental factors and genetic traits have the capacity to modulate disease risk. These must, therefore, be carefully evaluated as they have the potential to offer novel insights on the "missing heritability problem", reaching beyond our current limitations. First, we review a definition of G × E interactions. We then explore how concepts such as the early manifestation of the genetic components of a disease, the heterogeneity of complex traits, the clear definition of epidemiological strata, and the effect of varying physiological conditions can affect our capacity to detect (or miss) G × E interactions. Lastly, we discuss the shortfalls of regression models to study G × E interactions and how other methods such as the ReliefF algorithm, pattern recognition methods, or the LASSO (Least Absolute Shrinkage and Selection Operator) method can enable us to more adequately model G × E interactions. Overall, we present the elements to consider and a path to follow when studying genetic determinants of disease in order to uncover potential G × E interactions. PMID:27037711

  10. Putting the Genome in Context: Gene-Environment Interactions in Type 2 Diabetes.

    PubMed

    Franks, Paul W; Paré, Guillaume

    2016-07-01

    The genome is often the conduit through which environmental exposures convey their effects on health and disease. Whilst not all diseases act by directly perturbing the genome, the phenotypic responses are often genetically determined. Hence, whilst diseases are often defined has having differing degrees of genetic determination, genetic and environmental factors are, with few exceptions, inseparable features of most diseases, not least type 2 diabetes. It follows that to optimize diabetes, prevention and treatment will require that the etiological roles of genetic and environmental risk factors be jointly considered. As we discuss here, studies focused on quantifying gene-environment and gene-treatment interactions are gathering momentum and may eventually yield data that helps guide health-related choices and medical interventions for type 2 diabetes and other complex diseases. PMID:27155607

  11. Local Area Disadvantage and Gambling Involvement and Disorder: Evidence for Gene-Environment Correlation and Interaction

    PubMed Central

    Slutske, Wendy S.; Deutsch, Arielle R.; Statham, Dixie B.; Martin, Nicholas G.

    2015-01-01

    Previous research has demonstrated that local area characteristics (such as disadvantage and gambling outlet density) and genetic risk factors are associated with gambling involvement and disordered gambling. These two lines of research were brought together in the present study by examining the extent to which genetic contributions to individual differences in gambling involvement and disorder contributed to being exposed to, and were also accentuated by, local area disadvantage. Participants were members of the national community-based Australian Twin Registry who completed a telephone interview in which the past-year frequency of gambling and symptoms of disordered gambling were assessed. Indicators of local area disadvantage were based on census data matched to the participants' postal codes. Univariate biometric model-fitting revealed that exposure to area disadvantage was partially explained by genetic factors. Bivariate biometric model-fitting was conducted to examine the evidence for gene-environment interaction while accounting for gene-environment correlation. These analyses demonstrated that: (a) a small portion of the genetic propensity to gamble was explained by moving to or remaining in a disadvantaged area, and (b) the remaining genetic and unique environmental variation in the frequency of participating in electronic machine gambling (among men and women) and symptoms of disordered gambling (among women) was greater in more disadvantaged localities. As the gambling industry continues to grow, it will be important to take into account the multiple contexts in which problematic gambling behavior can emerge -- from genes to geography -- as well as the ways in which such contexts may interact with each other. PMID:26147321

  12. Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease

    PubMed Central

    Chou, Vivian P.; Ko, Novie; Holman, Theodore R.; Manning-Boğ, Amy B.

    2014-01-01

    Lipoxygenase (LOX) activity has been implicated in neurodegenerative disorders such as Alzheimer's disease, but its effects in Parkinson's disease (PD) pathogenesis are less understood. Gene-environment interaction models have utility in unmasking the impact of specific cellular pathways in toxicity that may not be observed using a solely genetic or toxicant disease model alone. To evaluate if distinct LOX isozymes selectively contribute to PD-related neurodegeneration, transgenic (i.e. 5-LOX and 12/15-LOX deficient) mice can be challenged with a toxin that mimics cell injury and death in the disorder. Here we describe the use of a neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces a nigrostriatal lesion to elucidate the distinct contributions of LOX isozymes to neurodegeneration related to PD. The use of MPTP in mouse, and nonhuman primate, is well-established to recapitulate the nigrostriatal damage in PD. The extent of MPTP-induced lesioning is measured by HPLC analysis of dopamine and its metabolites and semi-quantitative Western blot analysis of striatum for tyrosine hydroxylase (TH), the rate-limiting enzyme for the synthesis of dopamine. To assess inflammatory markers, which may demonstrate LOX isozyme-selective sensitivity, glial fibrillary acidic protein (GFAP) and Iba-1 immunohistochemistry are performed on brain sections containing substantia nigra, and GFAP Western blot analysis is performed on striatal homogenates. This experimental approach can provide novel insights into gene-environment interactions underlying nigrostriatal degeneration and PD. PMID:24430802

  13. A Fast Multiple-Kernel Method With Applications to Detect Gene-Environment Interaction.

    PubMed

    Marceau, Rachel; Lu, Wenbin; Holloway, Shannon; Sale, Michèle M; Worrall, Bradford B; Williams, Stephen R; Hsu, Fang-Chi; Tzeng, Jung-Ying

    2015-09-01

    Kernel machine (KM) models are a powerful tool for exploring associations between sets of genetic variants and complex traits. Although most KM methods use a single kernel function to assess the marginal effect of a variable set, KM analyses involving multiple kernels have become increasingly popular. Multikernel analysis allows researchers to study more complex problems, such as assessing gene-gene or gene-environment interactions, incorporating variance-component based methods for population substructure into rare-variant association testing, and assessing the conditional effects of a variable set adjusting for other variable sets. The KM framework is robust, powerful, and provides efficient dimension reduction for multifactor analyses, but requires the estimation of high dimensional nuisance parameters. Traditional estimation techniques, including regularization and the "expectation-maximization (EM)" algorithm, have a large computational cost and are not scalable to large sample sizes needed for rare variant analysis. Therefore, under the context of gene-environment interaction, we propose a computationally efficient and statistically rigorous "fastKM" algorithm for multikernel analysis that is based on a low-rank approximation to the nuisance effect kernel matrices. Our algorithm is applicable to various trait types (e.g., continuous, binary, and survival traits) and can be implemented using any existing single-kernel analysis software. Through extensive simulation studies, we show that our algorithm has similar performance to an EM-based KM approach for quantitative traits while running much faster. We also apply our method to the Vitamin Intervention for Stroke Prevention (VISP) clinical trial, examining gene-by-vitamin effects on recurrent stroke risk and gene-by-age effects on change in homocysteine level. PMID:26139508

  14. CardioGxE, a catalog of gene-environment interactions for cardiometabolic traits

    PubMed Central

    2014-01-01

    Background Genetic understanding of complex traits has developed immensely over the past decade but remains hampered by incomplete descriptions of contribution to phenotypic variance. Gene-environment (GxE) interactions are one of these contributors and in the guise of diet and physical activity are important modulators of cardiometabolic phenotypes and ensuing diseases. Results We mined the scientific literature to collect GxE interactions from 386 publications for blood lipids, glycemic traits, obesity anthropometrics, vascular measures, inflammation and metabolic syndrome, and introduce CardioGxE, a gene-environment interaction resource. We then analyzed the genes and SNPs supporting cardiometabolic GxEs in order to demonstrate utility of GxE SNPs and to discern characteristics of these important genetic variants. We were able to draw many observations from our extensive analysis of GxEs. 1) The CardioGxE SNPs showed little overlap with variants identified by main effect GWAS, indicating the importance of environmental interactions with genetic factors on cardiometabolic traits. 2) These GxE SNPs were enriched in adaptation to climatic and geographical features, with implications on energy homeostasis and response to physical activity. 3) Comparison to gene networks responding to plasma cholesterol-lowering or regression of atherosclerotic plaques showed that GxE genes have a greater role in those responses, particularly through high-energy diets and fat intake, than do GWAS-identified genes for the same traits. Other aspects of the CardioGxE dataset were explored. Conclusions Overall, we demonstrate that SNPs supporting cardiometabolic GxE interactions often exhibit transcriptional effects or are under positive selection. Still, not all such SNPs can be assigned potential functional or regulatory roles often because data are lacking in specific cell types or from treatments that approximate the environmental factor of the GxE. With research on metabolic related

  15. The Influence of Gene-Gene and Gene-Environment Interactions on the Risk of Asbestosis

    PubMed Central

    Franko, A.; Dolžan, V.; Arnerić, N.; Dodič-Fikfak, M.

    2013-01-01

    This study investigated the influence of gene-gene and gene-environment interactions on the risk of developing asbestosis. The study comprised 262 cases with asbestosis and 265 controls with no asbestos-related disease previously studied for MnSOD, ECSOD, CAT, GSTT1, GSTM1, GSTP1, and iNOS polymorphisms. Data on cumulative asbestos and smoking were available for all subjects. To assess gene-gene and gene-environmental interactions, logistic regression was used. The associations between MnSOD Ala −9Val polymorphism and the risk of asbestosis and between iNOS genotypes and asbestosis were modified by CAT –262 C > T polymorphism (P = 0.038; P = 0.031). A strong interaction was found between GSTM1-null polymorphism and smoking (P = 0.007), iNOS (CCTTT)n polymorphism and smoking (P = 0.054), and between iNOS (CCTTT)n polymorphism and cumulative asbestos exposure (P = 0.037). The findings of this study suggest that the interactions between different genotypes, genotypes and smoking, and between genotypes and asbestos exposure have an important influence on the development of asbestosis and should be seriously considered in future research on occupational/environmental asbestos-related diseases. PMID:23984360

  16. Gene-Environment Interactions across Development: Exploring DRD2 Genotype and Prenatal Smoking Effects on Self-Regulation

    ERIC Educational Resources Information Center

    Wiebe, Sandra A.; Espy, Kimberly Andrews; Stopp, Christian; Respass, Jennifer; Stewart, Peter; Jameson, Travis R.; Gilbert, David G.; Huggenvik, Jodi I.

    2009-01-01

    Genetic factors dynamically interact with both pre- and postnatal environmental influences to shape development. Considerable attention has been devoted to gene-environment interactions (G x E) on important outcomes (A. Caspi & T. E. Moffitt, 2006). It is also important to consider the possibility that these G x E effects may vary across…

  17. Identification of New Genetic Susceptibility Loci for Breast Cancer Through Consideration of Gene-Environment Interactions

    PubMed Central

    Schoeps, Anja; Rudolph, Anja; Seibold, Petra; Dunning, Alison M.; Milne, Roger L.; Bojesen, Stig E.; Swerdlow, Anthony; Andrulis, Irene; Brenner, Hermann; Behrens, Sabine; Orr, Nicholas; Jones, Michael; Ashworth, Alan; Li, Jingmei; Cramp, Helen; Connley, Dan; Czene, Kamila; Darabi, Hatef; Chanock, Stephen J.; Lissowska, Jolanta; Figueroa, Jonine D.; Knight, Julia; Glendon, Gord; Mulligan, Anna M.; Dumont, Martine; Severi, Gianluca; Baglietto, Laura; Olson, Janet; Vachon, Celine; Purrington, Kristen; Moisse, Matthieu; Neven, Patrick; Wildiers, Hans; Spurdle, Amanda; Kosma, Veli-Matti; Kataja, Vesa; Hartikainen, Jaana M.; Hamann, Ute; Ko, Yon-Dschun; Dieffenbach, Aida K.; Arndt, Volker; Stegmaier, Christa; Malats, Núria; Arias Perez, JoséI.; Benítez, Javier; Flyger, Henrik; Nordestgaard, Børge G.; Truong, Théresè; Cordina-Duverger, Emilie; Menegaux, Florence; Silva, Isabel dos Santos; Fletcher, Olivia; Johnson, Nichola; Häberle, Lothar; Beckmann, Matthias W.; Ekici, Arif B.; Braaf, Linde; Atsma, Femke; van den Broek, Alexandra J.; Makalic, Enes; Schmidt, Daniel F.; Southey, Melissa C.; Cox, Angela; Simard, Jacques; Giles, Graham G.; Lambrechts, Diether; Mannermaa, Arto; Brauch, Hiltrud; Guénel, Pascal; Peto, Julian; Fasching, Peter A.; Hopper, John; Flesch-Janys, Dieter; Couch, Fergus; Chenevix-Trench, Georgia; Pharoah, Paul D. P.; Garcia-Closas, Montserrat; Schmidt, Marjanka K.; Hall, Per; Easton, Douglas F.; Chang-Claude, Jenny

    2014-01-01

    Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 × 10−07), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m2 (OR = 1.26, 95% CI 1.15–1.38) but not in women with a BMI of 30 kg/m2 or higher (OR = 0.89, 95% CI 0.72–1.11, P for interaction = 3.2 × 10−05). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci. PMID:24248812

  18. Gene environment interaction studies in depression and suicidal behavior: An update.

    PubMed

    Mandelli, Laura; Serretti, Alessandro

    2013-12-01

    Increasing evidence supports the involvement of both heritable and environmental risk factors in major depression (MD) and suicidal behavior (SB). Studies investigating gene-environment interaction (G × E) may be useful for elucidating the role of biological mechanisms in the risk for mental disorders. In the present paper, we review the literature regarding the interaction between genes modulating brain functions and stressful life events in the etiology of MD and SB and discuss their potential added benefit compared to genetic studies only. Within the context of G × E investigation, thus far, only a few reliable results have been obtained, although some genes have consistently shown interactive effects with environmental risk in MD and, to a lesser extent, in SB. Further investigation is required to disentangle the direct and mediated effects that are common or specific to MD and SB. Since traditional G × E studies overall suffer from important methodological limitations, further effort is required to develop novel methodological strategies with an interdisciplinary approach. PMID:23886513

  19. A Nonlinear Model for Gene-Based Gene-Environment Interaction.

    PubMed

    Sa, Jian; Liu, Xu; He, Tao; Liu, Guifen; Cui, Yuehua

    2016-01-01

    A vast amount of literature has confirmed the role of gene-environment (G×E) interaction in the etiology of complex human diseases. Traditional methods are predominantly focused on the analysis of interaction between a single nucleotide polymorphism (SNP) and an environmental variable. Given that genes are the functional units, it is crucial to understand how gene effects (rather than single SNP effects) are influenced by an environmental variable to affect disease risk. Motivated by the increasing awareness of the power of gene-based association analysis over single variant based approach, in this work, we proposed a sparse principle component regression (sPCR) model to understand the gene-based G×E interaction effect on complex disease. We first extracted the sparse principal components for SNPs in a gene, then the effect of each principal component was modeled by a varying-coefficient (VC) model. The model can jointly model variants in a gene in which their effects are nonlinearly influenced by an environmental variable. In addition, the varying-coefficient sPCR (VC-sPCR) model has nice interpretation property since the sparsity on the principal component loadings can tell the relative importance of the corresponding SNPs in each component. We applied our method to a human birth weight dataset in Thai population. We analyzed 12,005 genes across 22 chromosomes and found one significant interaction effect using the Bonferroni correction method and one suggestive interaction. The model performance was further evaluated through simulation studies. Our model provides a system approach to evaluate gene-based G×E interaction. PMID:27271617

  20. A Nonlinear Model for Gene-Based Gene-Environment Interaction

    PubMed Central

    Sa, Jian; Liu, Xu; He, Tao; Liu, Guifen; Cui, Yuehua

    2016-01-01

    A vast amount of literature has confirmed the role of gene-environment (G×E) interaction in the etiology of complex human diseases. Traditional methods are predominantly focused on the analysis of interaction between a single nucleotide polymorphism (SNP) and an environmental variable. Given that genes are the functional units, it is crucial to understand how gene effects (rather than single SNP effects) are influenced by an environmental variable to affect disease risk. Motivated by the increasing awareness of the power of gene-based association analysis over single variant based approach, in this work, we proposed a sparse principle component regression (sPCR) model to understand the gene-based G×E interaction effect on complex disease. We first extracted the sparse principal components for SNPs in a gene, then the effect of each principal component was modeled by a varying-coefficient (VC) model. The model can jointly model variants in a gene in which their effects are nonlinearly influenced by an environmental variable. In addition, the varying-coefficient sPCR (VC-sPCR) model has nice interpretation property since the sparsity on the principal component loadings can tell the relative importance of the corresponding SNPs in each component. We applied our method to a human birth weight dataset in Thai population. We analyzed 12,005 genes across 22 chromosomes and found one significant interaction effect using the Bonferroni correction method and one suggestive interaction. The model performance was further evaluated through simulation studies. Our model provides a system approach to evaluate gene-based G×E interaction. PMID:27271617

  1. Genes-environment interactions in obesity- and diabetes-associated pancreatic cancer: A GWAS data analysis

    PubMed Central

    Tang, Hongwei; Wei, Peng; Duell, Eric J.; Risch, Harvey A.; Olson, Sara H.; Bueno-de-Mesquita, H. Bas; Gallinger, Steven; Holly, Elizabeth A.; Petersen, Gloria M.; Bracci, Paige M.; McWilliams, Robert R.; Jenab, Mazda; Riboli, Elio; Tjønneland, Anne; Boutron-Ruault, Marie Christine; Kaaks, Rudolf; Trichopoulos, Dimitrios; Panico, Salvatore; Sund, Malin; Peeters, Petra H.M; Khaw, Kay-Tee; Amos, Christopher I; Li, Donghui

    2013-01-01

    Background Obesity and diabetes are potentially alterable risk factors for pancreatic cancer. Genetic factors that modify the associations of obesity and diabetes with pancreatic cancer have previously not been examined at the genome-wide level. Methods Using GWAS genotype and risk factor data from the Pancreatic Cancer Case Control Consortium, we conducted a discovery study of 2,028 cases and 2,109 controls to examine gene-obesity and gene-diabetes interactions in relation to pancreatic cancer risk by employing the likelihood ratio test (LRT) nested in logistic regression models and Ingenuity Pathway Analysis (IPA). Results After adjusting for multiple comparisons, a significant interaction of the chemokine signaling pathway with obesity (P = 3.29 × 10−6) and a near significant interaction of calcium signaling pathway with diabetes (P = 1.57 × 10−4) in modifying the risk of pancreatic cancer was observed. These findings were supported by results from IPA analysis of the top genes with nominal interactions. The major contributing genes to the two top pathways include GNGT2, RELA, TIAM1 and GNAS. None of the individual genes or SNPs except one SNP remained significant after adjusting for multiple testing. Notably, SNP rs10818684 of the PTGS1 gene showed an interaction with diabetes (P = 7.91 × 10−7) at a false discovery rate of 6%. Conclusions Genetic variations in inflammatory response and insulin resistance may affect the risk of obesity and diabetes-related pancreatic cancer. These observations should be replicated in additional large datasets. Impact Gene-environment interaction analysis may provide new insights into the genetic susceptibility and molecular mechanisms of obesity- and diabetes-related pancreatic cancer. PMID:24136929

  2. A unified set-based test with adaptive filtering for gene-environment interaction analyses.

    PubMed

    Liu, Qianying; Chen, Lin S; Nicolae, Dan L; Pierce, Brandon L

    2016-06-01

    In genome-wide gene-environment interaction (GxE) studies, a common strategy to improve power is to first conduct a filtering test and retain only the SNPs that pass the filtering in the subsequent GxE analyses. Inspired by two-stage tests and gene-based tests in GxE analysis, we consider the general problem of jointly testing a set of parameters when only a few are truly from the alternative hypothesis and when filtering information is available. We propose a unified set-based test that simultaneously considers filtering on individual parameters and testing on the set. We derive the exact distribution and approximate the power function of the proposed unified statistic in simplified settings, and use them to adaptively calculate the optimal filtering threshold for each set. In the context of gene-based GxE analysis, we show that although the empirical power function may be affected by many factors, the optimal filtering threshold corresponding to the peak of the power curve primarily depends on the size of the gene. We further propose a resampling algorithm to calculate P-values for each gene given the estimated optimal filtering threshold. The performance of the method is evaluated in simulation studies and illustrated via a genome-wide gene-gender interaction analysis using pancreatic cancer genome-wide association data. PMID:26496228

  3. A unified set-based test with adaptive filtering for gene-environment interaction analyses

    PubMed Central

    Liu, Qianying; Chen, Lin S.; Nicolae, Dan L.; Pierce, Brandon L.

    2015-01-01

    Summary In genome-wide gene-environment interaction (GxE) studies, a common strategy to improve power is to first conduct a filtering test and retain only the SNPs that pass the filtering in the subsequent GxE analyses. Inspired by two-stage tests and gene-based tests in GxE analysis, we consider the general problem of jointly testing a set of parameters when only a few are truly from the alternative hypothesis and when filtering information is available. We propose a unified set-based test that simultaneously considers filtering on individual parameters and testing on the set. We derive the exact distribution and approximate the power function of the proposed unified statistic in simplified settings, and use them to adaptively calculate the optimal filtering threshold for each set. In the context of gene-based GxE analysis, we show that although the empirical power function may be affected by many factors, the optimal filtering threshold corresponding to the peak of the power curve primarily depends on the size of the gene. We further propose a resampling algorithm to calculate p-values for each gene given the estimated optimal filtering threshold. The performance of the method is evaluated in simulation studies and illustrated via a genome-wide gene-gender interaction analysis using pancreatic cancer genome-wide association data. PMID:26496228

  4. Heavy metals, organic solvents, and multiple sclerosis: An exploratory look at gene-environment interactions.

    PubMed

    Napier, Melanie D; Poole, Charles; Satten, Glen A; Ashley-Koch, Allison; Marrie, Ruth Ann; Williamson, Dhelia M

    2016-01-01

    Exposure to heavy metals and organic solvents are potential etiologic factors for multiple sclerosis (MS), but their interaction with MS-associated genes is under-studied. The authors explored the relationship between environmental exposure to lead, mercury, and solvents and 58 single-nucleotide polymorphisms (SNPs) in MS-associated genes. Data from a population-based case-control study of 217 prevalent MS cases and 496 age-, race-, gender-, and geographically matched controls were used to fit conditional logistic regression models of the association between the chemical, gene, and MS, adjusting for education and ancestry. MS cases were more likely than controls to report lead (odds ratio [OR] = 2.03; 95% confidence interval [CI]: 1.07, 3.86) and mercury exposure (OR = 2.06; 95% CI: 1.08, 3.91). Findings of potential gene-environment interactions between SNPs in TNF-α, TNF-β, TCA-β, VDR, MBP, and APOE, and lead, mercury, or solvents should be considered cautiously due to limited sample size. PMID:25137520

  5. Genome-wide analysis of gestational gene-environment interactions in the developing kidney

    PubMed Central

    Yan, Lei; Yao, Xiao; Bachvarov, Dimcho; Saifudeen, Zubaida

    2014-01-01

    The G protein-coupled bradykinin B2 receptor (Bdkrb2) plays an important role in regulation of blood pressure under conditions of excess salt intake. Our previous work has shown that Bdkrb2 also plays a developmental role since Bdkrb2−/− embryos, but not their wild-type or heterozygous littermates, are prone to renal dysgenesis in response to gestational high salt intake. Although impaired terminal differentiation and apoptosis are consistent findings in the Bdkrb2−/− mutant kidneys, the developmental pathways downstream of gene-environment interactions leading to the renal phenotype remain unknown. Here, we performed genome-wide transcriptional profiling on embryonic kidneys from salt-stressed Bdkrb2+/+ and Bdkrb2−/− embryos. The results reveal significant alterations in key pathways regulating Wnt signaling, apoptosis, embryonic development, and cell-matrix interactions. In silico analysis reveal that nearly 12% of differentially regulated genes harbor one or more Pax2 DNA-binding sites in their promoter region. Further analysis shows that metanephric kidneys of salt-stressed Bdkrb2−/− have a significant downregulation of Pax2 gene expression. This was corroborated in Bdkrb2−/−;Pax2GFP+/tg mice, demonstrating that Pax2 transcriptional activity is significantly repressed by gestational salt-Bdkrb2 interactions. We conclude that gestational gene (Bdkrb2) and environment (salt) interactions cooperate to impact gene expression programs in the developing kidney. Suppression of Pax2 likely contributes to the defects in epithelial survival, growth, and differentiation in salt-stressed BdkrB2−/− mice. PMID:25005792

  6. Powerful Set-Based Gene-Environment Interaction Testing Framework for Complex Diseases.

    PubMed

    Jiao, Shuo; Peters, Ulrike; Berndt, Sonja; Bézieau, Stéphane; Brenner, Hermann; Campbell, Peter T; Chan, Andrew T; Chang-Claude, Jenny; Lemire, Mathieu; Newcomb, Polly A; Potter, John D; Slattery, Martha L; Woods, Michael O; Hsu, Li

    2015-12-01

    Identification of gene-environment interaction (G × E) is important in understanding the etiology of complex diseases. Based on our previously developed Set Based gene EnviRonment InterAction test (SBERIA), in this paper we propose a powerful framework for enhanced set-based G × E testing (eSBERIA). The major challenge of signal aggregation within a set is how to tell signals from noise. eSBERIA tackles this challenge by adaptively aggregating the interaction signals within a set weighted by the strength of the marginal and correlation screening signals. eSBERIA then combines the screening-informed aggregate test with a variance component test to account for the residual signals. Additionally, we develop a case-only extension for eSBERIA (coSBERIA) and an existing set-based method, which boosts the power not only by exploiting the G-E independence assumption but also by avoiding the need to specify main effects for a large number of variants in the set. Through extensive simulation, we show that coSBERIA and eSBERIA are considerably more powerful than existing methods within the case-only and the case-control method categories across a wide range of scenarios. We conduct a genome-wide G × E search by applying our methods to Illumina HumanExome Beadchip data of 10,446 colorectal cancer cases and 10,191 controls and identify two novel interactions between nonsteroidal anti-inflammatory drugs (NSAIDs) and MINK1 and PTCHD3. PMID:26095235

  7. Detecting Gene-Environment Interactions for a Quantitative Trait in a Genome-Wide Association Study.

    PubMed

    Zhang, Pingye; Lewinger, Juan Pablo; Conti, David; Morrison, John L; Gauderman, W James

    2016-07-01

    A genome-wide association study (GWAS) typically is focused on detecting marginal genetic effects. However, many complex traits are likely to be the result of the interplay of genes and environmental factors. These SNPs may have a weak marginal effect and thus unlikely to be detected from a scan of marginal effects, but may be detectable in a gene-environment (G × E) interaction analysis. However, a genome-wide interaction scan (GWIS) using a standard test of G × E interaction is known to have low power, particularly when one corrects for testing multiple SNPs. Two 2-step methods for GWIS have been previously proposed, aimed at improving efficiency by prioritizing SNPs most likely to be involved in a G × E interaction using a screening step. For a quantitative trait, these include a method that screens on marginal effects [Kooperberg and Leblanc, 2008] and a method that screens on variance heterogeneity by genotype [Paré et al., 2010] In this paper, we show that the Paré et al. approach has an inflated false-positive rate in the presence of an environmental marginal effect, and we propose an alternative that remains valid. We also propose a novel 2-step approach that combines the two screening approaches, and provide simulations demonstrating that the new method can outperform other GWIS approaches. Application of this method to a G × Hispanic-ethnicity scan for childhood lung function reveals a SNP near the MARCO locus that was not identified by previous marginal-effect scans. PMID:27230133

  8. Education and alcohol use: A study of gene-environment interaction in young adulthood.

    PubMed

    Barr, Peter B; Salvatore, Jessica E; Maes, Hermine; Aliev, Fazil; Latvala, Antti; Viken, Richard; Rose, Richard J; Kaprio, Jaakko; Dick, Danielle M

    2016-08-01

    The consequences of heavy alcohol use remain a serious public health problem. Consistent evidence has demonstrated that both genetic and social influences contribute to alcohol use. Research on gene-environment interaction (GxE) has also demonstrated that these social and genetic influences do not act independently. Instead, certain environmental contexts may limit or exacerbate an underlying genetic predisposition. However, much of the work on GxE and alcohol use has focused on adolescence and less is known about the important environmental contexts in young adulthood. Using data from the young adult wave of the Finnish Twin Study, FinnTwin12 (N = 3402), we used biometric twin modeling to test whether education moderated genetic risk for alcohol use as assessed by drinking frequency and intoxication frequency. Education is important because it offers greater access to personal resources and helps determine one's position in the broader stratification system. Results from the twin models show that education did not moderate genetic variance components and that genetic risk was constant across levels of education. Instead, education moderated environmental variance so that under conditions of low education, environmental influences explained more of the variation in alcohol use outcomes. The implications and limitations of these results are discussed. PMID:27367897

  9. Shame and Guilt-Proneness in Adolescents: Gene-Environment Interactions.

    PubMed

    Szentágotai-Tătar, Aurora; Chiș, Adina; Vulturar, Romana; Dobrean, Anca; Cândea, Diana Mirela; Miu, Andrei C

    2015-01-01

    Rooted in people's preoccupation with how they are perceived and evaluated, shame and guilt are self-conscious emotions that play adaptive roles in social behavior, but can also contribute to psychopathology when dysregulated. Shame and guilt-proneness develop during childhood and adolescence, and are influenced by genetic and environmental factors that are little known to date. This study investigated the effects of early traumatic events and functional polymorphisms in the brain-derived neurotrophic factor (BDNF) gene and the serotonin transporter gene promoter (5-HTTLPR) on shame and guilt in adolescents. A sample of N = 271 healthy adolescents between 14 and 17 years of age filled in measures of early traumatic events and proneness to shame and guilt, and were genotyped for the BDNF Val66Met and 5-HTTLPR polymorphisms. Results of moderator analyses indicated that trauma intensity was positively associated with guilt-proneness only in carriers of the low-expressing Met allele of BDNF Val66Met. This is the first study that identifies a gene-environment interaction that significantly contributes to guilt proneness in adolescents, with potential implications for developmental psychopathology. PMID:26230319

  10. Cognitive endophenotypes, gene-environment interactions and experience-dependent plasticity in animal models of schizophrenia.

    PubMed

    Burrows, Emma L; Hannan, Anthony J

    2016-04-01

    Schizophrenia is a devastating brain disorder caused by a complex and heterogeneous combination of genetic and environmental factors. In order to develop effective new strategies to prevent and treat schizophrenia, valid animal models are required which accurately model the disorder, and ideally provide construct, face and predictive validity. The cognitive deficits in schizophrenia represent some of the most debilitating symptoms and are also currently the most poorly treated. Therefore it is crucial that animal models are able to capture the cognitive dysfunction that characterizes schizophrenia, as well as the negative and psychotic symptoms. The genomes of mice have, prior to the recent gene-editing revolution, proven the most easily manipulable of mammalian laboratory species, and hence most genetic targeting has been performed using mouse models. Importantly, when key environmental factors of relevance to schizophrenia are experimentally manipulated, dramatic changes in the phenotypes of these animal models are often observed. We will review recent studies in rodent models which provide insight into gene-environment interactions in schizophrenia. We will focus specifically on environmental factors which modulate levels of experience-dependent plasticity, including environmental enrichment, cognitive stimulation, physical activity and stress. The insights provided by this research will not only help refine the establishment of optimally valid animal models which facilitate development of novel therapeutics, but will also provide insight into the pathogenesis of schizophrenia, thus identifying molecular and cellular targets for future preclinical and clinical investigations. PMID:26687973

  11. [Gene-environment-interaction of ODD and Conduct Disorder Versus "Anethic Psychopathy"].

    PubMed

    Schepker, Renate; Schmeck, Klaus; Kölch, Michael; Schepker, Klaus

    2015-01-01

    Gene-environment-interaction of ODD and Conduct Disorder Versus »Anethic Psychopathy«. In 1934, Kramer and von der Leyen demonstrated in a sophisticated longitudinal study with eleven conduct disordered and neglected children labelled as »anethic psychopaths« that »anethic traits« subsided in a favourable educational setting. Sound prognoses, due to the diversity of environmental factors, were found to be impossible. On the contrary they stated that negative labelling led to an affirmation of a negative prognosis. In theory, they supposed a genetic predisposition resulting in a heightened sensitivity to the environment. This early theory of epigenetics radically contradicted the Nazi dogma of hereditability and ostracism and the selection procedures in mainstream psychiatry at that time. The debate ended with von der Leyen's suicide and the prohibition of medical work and publication towards Kramer. Even after the end of the Nazi policy of »eradication of the socially debased«, this early theory was not taken on again, nor dignified. PMID:25968413

  12. Shame and Guilt-Proneness in Adolescents: Gene-Environment Interactions

    PubMed Central

    Szentágotai-Tătar, Aurora; Chiș, Adina; Vulturar, Romana; Dobrean, Anca; Cândea, Diana Mirela; Miu, Andrei C.

    2015-01-01

    Rooted in people’s preoccupation with how they are perceived and evaluated, shame and guilt are self-conscious emotions that play adaptive roles in social behavior, but can also contribute to psychopathology when dysregulated. Shame and guilt-proneness develop during childhood and adolescence, and are influenced by genetic and environmental factors that are little known to date. This study investigated the effects of early traumatic events and functional polymorphisms in the brain-derived neurotrophic factor (BDNF) gene and the serotonin transporter gene promoter (5-HTTLPR) on shame and guilt in adolescents. A sample of N = 271 healthy adolescents between 14 and 17 years of age filled in measures of early traumatic events and proneness to shame and guilt, and were genotyped for the BDNF Val66Met and 5-HTTLPR polymorphisms. Results of moderator analyses indicated that trauma intensity was positively associated with guilt-proneness only in carriers of the low-expressing Met allele of BDNF Val66Met. This is the first study that identifies a gene-environment interaction that significantly contributes to guilt proneness in adolescents, with potential implications for developmental psychopathology. PMID:26230319

  13. A database of gene-environment interactions pertaining to blood lipid traits, cardiovascular disease and type 2 diabetes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    As the role of the environment – diet, exercise, alcohol and tobacco use and sleep among others – is accorded a more prominent role in modifying the relationship between genetic variants and clinical measures of disease, consideration of gene-environment (GxE) interactions is a must. To facilitate i...

  14. Gene-Environment Interaction in Externalizing Problems among Adolescents: Evidence from the Pelotas 1993 Birth Cohort Study

    ERIC Educational Resources Information Center

    Kieling, Christian; Hutz, Mara H.; Genro, Julia P.; Polanczyk, Guilherme V.; Anselmi, Luciana; Camey, Suzi; Hallal, Pedro C.; Barros, Fernando C.; Victora, Cesar G.; Menezes, Ana M. B.; Rohde, Luis Augusto

    2013-01-01

    Background: The study of gene-environment interactions (G by E) is one of the most promising strategies to uncover the origins of mental disorders. Replication of initial findings, however, is essential because there is a strong possibility of publication bias in the literature. In addition, there is a scarcity of research on the topic originated…

  15. Gene-environment interactions in common mental disorders: an update and strategy for a genome-wide search.

    PubMed

    Uher, Rudolf

    2014-01-01

    A decade of research has demonstrated the explanatory potential of interplay between genetic variants and environmental factors in the development of common mental disorders. Initial findings have undergone tests of replicability and specificity. Some gene-environment interactions have been confirmed, some have not replicated and yet other turned out to be more specific than initially thought. Specific and complementary roles of genetic factors have been delineated: a common functional length polymorphism in the serotonin transporter gene (5-HTTLPR) moderated the effect of childhood maltreatment on chronic depression in adulthood, but did not substantially influence the effects of adult stressful life events on the onset of new depressive episodes; in contrast, a common functional polymorphism in the brain-derived neurotrophic factor gene (BDNF) moderated the effect of stressful life events in adulthood in triggering new depressive episodes, but did not influence the effects of childhood maltreatment. Molecular mechanisms underlying gene-environment interactions are being uncovered, including DNA methylation and other epigenetic modifications. New gene-environment interactions continue to be reported, still largely from hypothesis-driven research. Statistical and biological prioritization strategies are proposed to facilitate a systematic discovery of novel gene-environment interactions in genome-wide analyses. PMID:24323294

  16. Characterization of gene-environment interactions for colorectal cancer susceptibility loci

    PubMed Central

    Hutter, Carolyn M.; Chang-Claude, Jenny; Slattery, Martha L.; Pflugeisen, Bethann M.; Lin, Yi; Duggan, David; Nan, Hongmei; Lemire, Mathieu; Rangrej, Jagadish; Figueiredo, Jane C.; Jiao, Shuo; Harrison, Tabitha A.; Liu, Yan; Chen, Lin S.; Stelling, Deanna L.; Warnick, Greg S.; Hoffmeister, Michael; Küry, Sébastien; Fuchs, Charles S.; Giovannucci, Edward; Hazra, Aditi; Kraft, Peter; Hunter, David J.; Gallinger, Steven; Zanke, Brent W.; Brenner, Hermann; Frank, Bernd; Ma, Jing; Ulrich, Cornelia M.; White, Emily; Newcomb, Polly A.; Kooperberg, Charles; LaCroix, Andrea Z.; Prentice, Ross L.; Jackson, Rebecca D.; Schoen, Robert E.; Chanock, Stephen J.; Berndt, Sonja I.; Hayes, Richard B.; Caan, Bette J.; Potter, John D.; Hsu, Li; Bézieau, Stéphane; Chan, Andrew T.; Hudson, Thomas J.; Peters, Ulrike

    2012-01-01

    Genome-wide association studies (GWAS) have identified over a dozen loci associated with colorectal cancer (CRC) risk. Here we examined potential effect-modification between single nucleotide polymorphisms (SNPs) at 10 of these loci and probable or established environmental risk factors for CRC in 7,016 CRC cases and 9,723 controls from nine cohort and case-control studies. We used meta-analysis of an efficient empirical-Bayes estimator to detect potential multiplicative interactions between each of the SNPs [rs16892766 at 8q23.3 (EIF3H/UTP23); rs6983267 at 8q24 (MYC); rs10795668 at 10p14 (FLJ3802842); rs3802842 at11q23 (LOC120376); rs4444235 at 14q22.2 (BMP4); rs4779584 at15q13 (GREM1); rs9929218 at16q22.1 (CDH1); rs4939827 at18q21 (SMAD7); rs10411210 at19q13.1 (RHPN2); and rs961253 at 20p12.3 (BMP2)] and select major CRC risk factors (sex, body mass index, height, smoking status, aspirin/non-steroidal anti-inflammatory drug use, alcohol use, and dietary intake of calcium, folate, red meat, processed meat, vegetables, fruit, and fiber). The strongest statistical evidence for a gene-environment interaction across studies was for vegetable consumption and rs16892766, located on chromosome 8q23.3, near the EIF3H and UTP23 genes (nominal p-interaction =1.3×10–4; adjusted p-value 0.02). The magnitude of the main effect of the SNP increased with increasing levels of vegetable consumption. No other interactions were statistically significant after adjusting for multiple comparisons. Overall, the association of most CRC susceptibility loci identified in initial GWAS appears to be invariant to the other risk factors considered; however, our results suggest potential modification of the rs16892766 effect by vegetable consumption. PMID:22367214

  17. G x E: a NIAAA workshop on gene-environment interactions.

    PubMed

    Gunzerath, Lorraine; Goldman, David

    2003-03-01

    The National Institute on Alcohol Abuse and Alcoholism (NIAAA) sponsored a May 2002 workshop on gene-environment interaction (G x E) research to identify potential roadblocks to further research and to propose solutions to those roadblocks, to optimize investigative opportunities and multidisciplinary or multi-institution collaborations, and to explore ways that NIAAA can facilitate G x E studies. Sessions included panels on animal models; phenotypes; genetic findings in humans; study designs and analytical methods; and assessment of environmental risk. Key among the identified challenges to progress in G x E research were issues of study design and sampling strategies; logistic and methodological costs and constraints; availability and understanding of data analysis techniques; potential stigmatization of study populations; and organizational/bureaucratic structures that are inadequate to address the unique needs of large-scale, multicenter, longitudinal projects. Participants proposed a series of recommendations to address these issues. Session coordinators included: Gayle Boyd, Kendall Bryant, Page Chiapella, Vivian Faden, David Goldman, and Antonio Noronha. Session participants included: Laura Almasy, Henri Begleiter, Raul Caetano, Bruce Dudek, Mary Dufour, Cindy Ehlers, Mary-Anne Enoch, Joel Gelernter, David Goldman, Bridget Grant, Lorraine Gunzerath, Deborah Hasin, Andrew Heath, Victor Hesselbrock, J. Dee Higley, Shirley Hill, Kerry Jang, Raynard S. Kington, Rick Kittles, George Koob, Kenneth Leonard, Ting-Kai Li, Jeffrey Long, William McBride, Matthew McGue, Kathleen Merikangas, Tamara Phillips, Bernice Porjesz, Carol Prescott, Theodore Reich, John Rice, Richard Rose, Charmaine Royal, Arnold Sameroff, Marc Schuckit, Kenneth Sher, Renee Sieving, Robert Taylor, Michael Windle, and Robert Zucker. PMID:12658122

  18. Toward a 3D model of human brain development for studying gene/environment interactions

    PubMed Central

    2013-01-01

    This project aims to establish and characterize an in vitro model of the developing human brain for the purpose of testing drugs and chemicals. To accurately assess risk, a model needs to recapitulate the complex interactions between different types of glial cells and neurons in a three-dimensional platform. Moreover, human cells are preferred over cells from rodents to eliminate cross-species differences in sensitivity to chemicals. Previously, we established conditions to culture rat primary cells as three-dimensional aggregates, which will be humanized and evaluated here with induced pluripotent stem cells (iPSCs). The use of iPSCs allows us to address gene/environment interactions as well as the potential of chemicals to interfere with epigenetic mechanisms. Additionally, iPSCs afford us the opportunity to study the effect of chemicals during very early stages of brain development. It is well recognized that assays for testing toxicity in the developing brain must consider differences in sensitivity and susceptibility that arise depending on the time of exposure. This model will reflect critical developmental processes such as proliferation, differentiation, lineage specification, migration, axonal growth, dendritic arborization and synaptogenesis, which will probably display differences in sensitivity to different types of chemicals. Functional endpoints will evaluate the complex cell-to-cell interactions that are affected in neurodevelopment through chemical perturbation, and the efficacy of drug intervention to prevent or reverse phenotypes. The model described is designed to assess developmental neurotoxicity effects on unique processes occurring during human brain development by leveraging human iPSCs from diverse genetic backgrounds, which can be differentiated into different cell types of the central nervous system. Our goal is to demonstrate the feasibility of the personalized model using iPSCs derived from individuals with neurodevelopmental disorders

  19. Gene-environment interaction in problematic substance use: interaction between DRD4 and insecure attachments.

    PubMed

    Olsson, Craig A; Moyzis, Robert K; Williamson, Elizabeth; Ellis, Justine A; Parkinson-Bates, Mandy; Patton, George C; Dwyer, Terry; Romaniuk, Helena; Moore, Elya E

    2013-07-01

    To investigate the combined effect of an exon III variable number tandem repeat in the dopamine receptor gene (DRD4) and insecure attachment style on risk for tobacco, cannabis and alcohol use problems in young adulthood. It was hypothesized that (1) individuals with 5, 6, 7 or 8 repeats (labelled 7R+) would be at increased risk for problematic drug use, and (2) risk for drug use would be further increased in individuals with 7R+ repeats who also have a history of insecure parent-child attachment relations. Data were drawn from the Victorian Adolescent Health Cohort Study, an eight-wave longitudinal study of adolescent and young adult development. DRD4 genotypes were available for 839 participants. Risk attributable to the combined effects of 7R+ genotype and insecure attachments was evaluated within a sufficient causes framework under the assumptions of additive interaction using a two-by-four table format with a common reference group. 7R+ alleles were associated with higher tobacco, cannabis and alcohol use (binging). Insecure attachments were associated with higher tobacco and cannabis use but lower alcohol use. For tobacco, there was evidence of interaction for anxious but not avoidant attachments. For cannabis, there was evidence of interaction for both anxious and avoidant attachments, although the interaction for anxious attachments was more substantial. There is no evidence of interaction for binge drinking. Results are consistent with a generic reward deficit hypothesis of drug addiction for which the 7R+ disposition may play a role. Interaction between 7R+ alleles and attachment insecurity may intensify risk for problematic tobacco and cannabis use. PMID:22126256

  20. A model of gene-gene and gene-environment interactions and its implications for targeting environmental interventions by genotype

    PubMed Central

    Wallace, Helen M

    2006-01-01

    Background The potential public health benefits of targeting environmental interventions by genotype depend on the environmental and genetic contributions to the variance of common diseases, and the magnitude of any gene-environment interaction. In the absence of prior knowledge of all risk factors, twin, family and environmental data may help to define the potential limits of these benefits in a given population. However, a general methodology to analyze twin data is required because of the potential importance of gene-gene interactions (epistasis), gene-environment interactions, and conditions that break the 'equal environments' assumption for monozygotic and dizygotic twins. Method A new model for gene-gene and gene-environment interactions is developed that abandons the assumptions of the classical twin study, including Fisher's (1918) assumption that genes act as risk factors for common traits in a manner necessarily dominated by an additive polygenic term. Provided there are no confounders, the model can be used to implement a top-down approach to quantifying the potential utility of genetic prediction and prevention, using twin, family and environmental data. The results describe a solution space for each disease or trait, which may or may not include the classical twin study result. Each point in the solution space corresponds to a different model of genotypic risk and gene-environment interaction. Conclusion The results show that the potential for reducing the incidence of common diseases using environmental interventions targeted by genotype may be limited, except in special cases. The model also confirms that the importance of an individual's genotype in determining their risk of complex diseases tends to be exaggerated by the classical twin studies method, owing to the 'equal environments' assumption and the assumption of no gene-environment interaction. In addition, if phenotypes are genetically robust, because of epistasis, a largely environmental

  1. Plasma selenium levels and oxidative stress biomarkers: a gene-environment interaction population-based study.

    PubMed

    Galan-Chilet, Inmaculada; Tellez-Plaza, Maria; Guallar, Eliseo; De Marco, Griselda; Lopez-Izquierdo, Raul; Gonzalez-Manzano, Isabel; Carmen Tormos, M; Martin-Nuñez, Gracia M; Rojo-Martinez, Gemma; Saez, Guillermo T; Martín-Escudero, Juan C; Redon, Josep; Javier Chaves, F

    2014-09-01

    The role of selenium exposure in preventing chronic disease is controversial, especially in selenium-repleted populations. At high concentrations, selenium exposure may increase oxidative stress. Studies evaluating the interaction of genetic variation in genes involved in oxidative stress pathways and selenium are scarce. We evaluated the cross-sectional association of plasma selenium concentrations with oxidative stress levels, measured as oxidized to reduced glutathione ratio (GSSG/GSH), malondialdehyde (MDA), and 8-oxo-7,8-dihydroguanine (8-oxo-dG) in urine, and the interacting role of genetic variation in oxidative stress candidate genes, in a representative sample of 1445 men and women aged 18-85 years from Spain. The geometric mean of plasma selenium levels in the study sample was 84.76 µg/L. In fully adjusted models the geometric mean ratios for oxidative stress biomarker levels comparing the highest to the lowest quintiles of plasma selenium levels were 0.61 (0.50-0.76) for GSSG/GSH, 0.89 (0.79-1.00) for MDA, and 1.06 (0.96-1.18) for 8-oxo-dG. We observed nonlinear dose-responses of selenium exposure and oxidative stress biomarkers, with plasma selenium concentrations above ~110 μg/L being positively associated with 8-oxo-dG, but inversely associated with GSSG/GSH and MDA. In addition, we identified potential risk genotypes associated with increased levels of oxidative stress markers with high selenium levels. Our findings support that high selenium levels increase oxidative stress in some biological processes. More studies are needed to disentangle the complexity of selenium biology and the relevance of potential gene-selenium interactions in relation to health outcomes in human populations. PMID:25017966

  2. Progress in the epidemiological understanding of gene-environment interactions in major diseases: cancer

    PubMed Central

    Clavel, Jacqueline

    2007-01-01

    Cancer epidemiology has undergone marked development since the nineteen-fifties. One of the most spectacular and specific contributions was the demonstration of the massive effect of smoking on the occurrence of lung, larynx and bladder cancer. Major chemical, physical and biological carcinogenic agents have been identified in the working environment and in the overall environment. The chain of events from environmental exposures to cancer requires hundreds of polymorphic genes coding for proteins involved in the transport and metabolism of xenobiotics, or in repair, or in an immune or inflammatory response. The multifactorial and multistage characteristics of cancer create the theoretical conditions for statistical interactions which have been exceptionnally detected. Over the last two decades, a considerable mass of data has been generated, mostly addressing the interactions between smoking and xenobiotic-metabolizing enzymes in smoking-related cancers. They are sometimes considered disappointing but they actually brought a lot of information and raised many methodological issues. In parallel, the number of polymorphisms which can be considered candidate per function increased so much that multiple testing has become a major issue, and genome wide screening approaches have more and more gained in interest. Facing the resulting complexity, some instruments are being set up: our studies are now equipped with carefully sampled biological collections, high-throughput genotyping systems are becoming available, work on statistical methodologies is ongoing, bioinformatics databases are growing larger and access to them is becoming simpler; international consortiums are being organized. The roles of environmental and genetic factors are being jointly elucidated. The basic rules of epidemiology, which are demanding with respect to sampling, with respect to the histological and molecular criteria for cancer classification, with respect to the evaluation of environmental

  3. A latent variable approach to study gene-environment interactions in the presence of multiple correlated exposures

    PubMed Central

    Kang, Shan; Mukherjee, Bhramar

    2015-01-01

    Summary Many existing cohort studies initially designed to investigate disease risk as a function of environmental exposures have collected genomic data in recent years with the objective of testing for gene-environment interaction (G × E) effects. In environmental epidemiology, interest in G × E arises primarily after a significant effect of the environmental exposure has been documented. Cohort studies often collect rich exposure data, as a result, assessing G × E effects in the presence of multiple exposure markers further increases the burden of multiple testing, an issue already present in both genetic and environment health studies. Latent variable (LV) models have been used in environmental epidemiology to reduce dimensionality of the exposure data, gain power by reducing multiplicity issues via condensing exposure data, and avoid collinearity problems due to presence of multiple correlated exposures. We extend the LV framework to characterize gene-environment interaction in presence of multiple correlated exposures and genotype categories. Further, similar to what has been done in case-control G × E studies, we use the assumption of gene-environment (G-E) independence to boost the power of tests for interaction. The consequences of making this assumption, or the issue of how to explicitly model G-E association has not been previously investigated in LV models. We postulate a hierarchy of assumptions about the LV model regarding the different forms of G-E dependence and show that making such assumptions may influence inferential results on the G, E, and G × E parameters. We implement a class of shrinkage estimators to data adaptively trade-off between the most restrictive to most flexible form of G-E dependence assumption and note that such class of compromise estimators can serve as a benchmark of model adequacy in LV models. We demonstrate the methods with an example from the Early Life Exposures in Mexico City to Neuro-Toxicants (ELEMENT) study of

  4. Genotype-Based Bayesian Analysis of Gene-Environment Interactions with Multiple Genetic Markers and Misclassification in Environmental Factors

    PubMed Central

    Lobach, Iryna; Fan, Ruzong

    2015-01-01

    A key component to understanding etiology of complex diseases, such as cancer, diabetes, alcohol dependence, is to investigate gene-environment interactions. This work is motivated by the following two concerns in the analysis of gene-environment interactions. First, multiple genetic markers in moderate linkage disequilibrium may be involved in susceptibility to a complex disease. Second, environmental factors may be subject to misclassification. We develop a genotype based Bayesian pseudolikelihood approach that accommodates linkage disequilibrium in genetic markers and misclassification in environmental factors. Since our approach is genotype based, it allows the observed genetic information to enter the model directly thus eliminating the need to infer haplotype phase and simplifying computations. Bayesian approach allows shrinking parameter estimates towards prior distribution to improve estimation and inference when environmental factors are subject to misclassification. Simulation experiments demonstrated that our method produced parameter estimates that are nearly unbiased even for small sample sizes. An application of our method is illustrated using a case-control study of interaction between early onset of drinking and genes involved in dopamine pathway. PMID:26180529

  5. Gene-Environment Interactions Target Mitogen-activated Protein 3 Kinase 1 (MAP3K1) Signaling in Eyelid Morphogenesis*

    PubMed Central

    Mongan, Maureen; Meng, Qinghang; Wang, Jingjing; Kao, Winston W.-Y.; Puga, Alvaro; Xia, Ying

    2015-01-01

    Gene-environment interactions determine the biological outcomes through mechanisms that are poorly understood. Mouse embryonic eyelid closure is a well defined model to study the genetic control of developmental programs. Using this model, we investigated how exposure to dioxin-like environmental pollutants modifies the genetic risk of developmental abnormalities. Our studies reveal that mitogen-activated protein 3 kinase 1 (MAP3K1) signaling is a focal point of gene-environment cross-talk. Dioxin exposure, acting through the aryl hydrocarbon receptor (AHR), blocked eyelid closure in genetic mutants in which MAP3K1 signaling was attenuated but did not disturb this developmental program in either wild type or mutant mice with attenuated epidermal growth factor receptor or WNT signaling. Exposure also markedly inhibited c-Jun phosphorylation in Map3k1+/− embryonic eyelid epithelium, suggesting that dioxin-induced AHR pathways can synergize with gene mutations to inhibit MAP3K1 signaling. Our studies uncover a novel mechanism through which the dioxin-AHR axis interacts with the MAP3K1 signaling pathways during fetal development and provide strong empirical evidence that specific gene alterations can increase the risk of developmental abnormalities driven by environmental pollutant exposure. PMID:26109068

  6. High-throughput phenotypic profiling of gene-environment interactions by quantitative growth curve analysis in Saccharomyces cerevisiae.

    PubMed

    Weiss, Andrew; Delproposto, James; Giroux, Craig N

    2004-04-01

    Cell-based assays are widely used in high-throughput screening to determine the effects of toxicants and drugs on their biological targets. To enable a functional genomics modeling of gene-environment interactions, quantitative assays are required both for gene expression and for the phenotypic responses to environmental challenge. To address this need, we describe an automated high-throughput methodology that provides phenotypic profiling of the cellular responses to environmental stress in Saccharomyces cerevisiae. Standardized assay conditions enable the use of a single metric value to quantify yeast microculture growth curves. This assay format allows precise control of both genetic and environmental determinants of the cellular responses to oxidative stress, a common mechanism of environmental insult. These yeast-cell-based assays are validated with hydrogen peroxide, a simple direct-acting oxidant. Phenotypic profiling of the oxidative stress response of a yap1 mutant strain demonstrates the mechanistic analysis of genetic susceptibility to oxidative stress. As a proof of concept for analysis of more complex gene-environment interactions, we describe a combinatorial assay design for phenotypic profiling of the cellular responses to tert-butyl hydroperoxide, a complex oxidant that is actively metabolized by its target cells. Thus, the yeast microculture assay format supports comprehensive applications in toxicogenomics. PMID:15033507

  7. Gene-Environment Interactions Target Mitogen-activated Protein 3 Kinase 1 (MAP3K1) Signaling in Eyelid Morphogenesis.

    PubMed

    Mongan, Maureen; Meng, Qinghang; Wang, Jingjing; Kao, Winston W-Y; Puga, Alvaro; Xia, Ying

    2015-08-01

    Gene-environment interactions determine the biological outcomes through mechanisms that are poorly understood. Mouse embryonic eyelid closure is a well defined model to study the genetic control of developmental programs. Using this model, we investigated how exposure to dioxin-like environmental pollutants modifies the genetic risk of developmental abnormalities. Our studies reveal that mitogen-activated protein 3 kinase 1 (MAP3K1) signaling is a focal point of gene-environment cross-talk. Dioxin exposure, acting through the aryl hydrocarbon receptor (AHR), blocked eyelid closure in genetic mutants in which MAP3K1 signaling was attenuated but did not disturb this developmental program in either wild type or mutant mice with attenuated epidermal growth factor receptor or WNT signaling. Exposure also markedly inhibited c-Jun phosphorylation in Map3k1(+/-) embryonic eyelid epithelium, suggesting that dioxin-induced AHR pathways can synergize with gene mutations to inhibit MAP3K1 signaling. Our studies uncover a novel mechanism through which the dioxin-AHR axis interacts with the MAP3K1 signaling pathways during fetal development and provide strong empirical evidence that specific gene alterations can increase the risk of developmental abnormalities driven by environmental pollutant exposure. PMID:26109068

  8. The emergence of biobanks: practical design considerations for large population-based studies of gene-environment interactions.

    PubMed

    Davis, Robert L; Khoury, Muin J

    2007-01-01

    The completion of the human genome project has spurred new thinking about launching large-scale cohort studies; as proposed, these studies will differ from past large-scale cohort studies and will focus primarily on how genetic variation interacts with environmental exposures to affect the risk for common human diseases. There is no single 'best design' for large-scale studies of gene-environment interactions. Some studies are best performed in cohort studies where unbiased information can be collected on individuals years before disease onset. Other studies may be most efficiently done with a case-control design using currently available automated data. Population-based biobanks with nested case-control or case-cohort studies offer distinct advantages to some of the resource-intensive large-scale cohort studies under consideration, and may be more acceptable to many of the countries around the world currently considering such projects. PMID:17575463

  9. Gene environment interaction in urinary bladder cancer with special reference to organochlorine pesticide: a case control study.

    PubMed

    Sharma, Tusha; Jain, Smita; Verma, Ankur; Sharma, Nivedita; Gupta, Sanjay; Arora, Vinod Kumar; Dev Banerjee, Basu

    2013-01-01

    Urinary bladder cancer (UBC) is a common disease worldwide with a higher incidence rate in developed countries. Organochlorine pesticides (OCPs), potent endocrine disrupters, are found to be associated with several cancers such as prostate, breast, bladder, etc. Glutathione S-transferase (GST) is a polymorphic supergene family involved in the detoxification of numerous environmental toxins including OCPs. The present study was carried out in UBC subjects (n=50) and healthy control subjects (n=50) with an aim to determine the role of GSTM1 and GSTT1 polymorphism and its implication on the OCP detoxification or bioaccumulation which may increase the risk of UBC in humans. This study was also designed to identify the "gene-environment interaction" specifically between gene polymorphism in xenobiotic metabolizing genetic enzyme(s) and blood OCP levels. GSTM1/GSTT1 gene polymorphism was analysed by using multiplex PCR. OCPs levels in whole blood were estimated by Gas chromatography equipped with electron capture detector. The results demonstrated a significant (p< 0.05) increase in frequency of GSTM1^{-}/GSTT1^{-} (null) genotype in UBC cases without interfering the distribution of other GSTT1/GSTM1 genotypes. The blood levels of alpha (α), Beta (β), Gamma (γ), total - Hexachlorcyclohexane (HCH) and para-para - dichlorodiphenyltrichloroetane (p,p'-DDT) were found to be significantly (p< 0.05) high in UBC cases as compared to controls. Multiple regression analysis revealed a significant interaction between β-HCH and GSTM1^{-} genotype (p< 0.05) as well as in β-HCH and GSTT1^{-} genotype (p< 0.05) respectively. These findings indicate that "gene-environment interaction" may play a key role in increasing the risk for UBC in individuals who are genetically more susceptible due to presence of GSTM1/GSTT1 null deletion during their routine encounter with or exposure to OCPs. PMID:24240585

  10. Next-generation analysis of cataracts: determining knowledge driven gene-gene interactions using biofilter, and gene-environment interactions using the Phenx Toolkit*.

    PubMed

    Pendergrass, Sarah A; Verma, Shefali S; Hall, Molly A; Holzinger, Emily R; Moore, Carrie B; Wallace, John R; Dudek, Scott M; Huggins, Wayne; Kitchner, Terrie; Waudby, Carol; Berg, Richard; Mccarty, Catherine A; Ritchie, Marylyn D

    2015-01-01

    Investigating the association between biobank derived genomic data and the information of linked electronic health records (EHRs) is an emerging area of research for dissecting the architecture of complex human traits, where cases and controls for study are defined through the use of electronic phenotyping algorithms deployed in large EHR systems. For our study, cataract cases and controls were identified within the Marshfield Personalized Medicine Research Project (PMRP) biobank and linked EHR, which is a member of the NHGRI-funded electronic Medical Records and Genomics (eMERGE) Network. Our goal was to explore potential gene-gene and gene-environment interactions within these data for 527,953 and 527,936 single nucleotide polymorphisms (SNPs) for gene-gene and gene-environment analyses, respectively, with minor allele frequency > 1%, in order to explore higher level associations with cataract risk beyond investigations of single SNP-phenotype associations. To build our SNP-SNP interaction models we utilized a prior-knowledge driven filtering method called Biofilter to minimize the multiple testing burden of exploring the vast array of interaction models possible from our extensive number of SNPs. Using Biofilter, we developed 57,376 prior-knowledge directed SNP-SNP models to test for association with cataract status. We selected models that required 6 sources of external domain knowledge. We identified 13 statistically significant SNP-SNP models with an interaction with p-value < 1 × 10(-4), as well as an overall model with p-value < 0.01 associated with cataract status. We also conducted gene-environment interaction analyses for all GWAS SNPs and a set of environmental factors from the PhenX Toolkit: smoking, UV exposure, and alcohol use;these environmental factors have been previously associated with the formation of cataracts. We found a total of 782 gene-environment models that exhibit an interaction with a p-value < 1 × 10(-4) associatedwith cataract

  11. Gene-Environment Interactions Controlling Energy and Glucose Homeostasis and the Developmental Origins of Obesity

    PubMed Central

    Bouret, Sebastien; Levin, Barry E.; Ozanne, Susan E.

    2015-01-01

    Obesity and type 2 diabetes mellitus (T2DM) often occur together and affect a growing number of individuals in both the developed and developing worlds. Both are associated with a number of other serious illnesses that lead to increased rates of mortality. There is likely a polygenic mode of inheritance underlying both disorders, but it has become increasingly clear that the pre- and postnatal environments play critical roles in pushing predisposed individuals over the edge into a disease state. This review focuses on the many genetic and environmental variables that interact to cause predisposed individuals to become obese and diabetic. The brain and its interactions with the external and internal environment are a major focus given the prominent role these interactions play in the regulation of energy and glucose homeostasis in health and disease. PMID:25540138

  12. Gene-gene and gene-environment interactions defining lipid-related traits

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Steps towards reducing chronic disease progression are continuously being taken through the form of genomic research. Studies over the last year have highlighted more and more polymorphisms, pathways and interactions responsible for metabolic disorders such as cardiovascular disease, obesity and dys...

  13. Gene-gene and gene-environment interactions defining lipid-related traits

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Purpose of review Steps towards reducing chronic disease progression are continuously being taken through the form of genomic research. Studies over the last year have highlighted more and more polymorphisms, pathways and interactions responsible for metabolic disorders such as cardiovascular diseas...

  14. What Gene-Environment Interactions Can Tell Us about Social Competence in Typical and Atypical Populations

    ERIC Educational Resources Information Center

    Iarocci, Grace; Yager, Jodi; Elfers, Theo

    2007-01-01

    Social competence is a complex human behaviour that is likely to involve a system of genes that interacts with a myriad of environmental risk and protective factors. The search for its genetic and environmental origins and influences is equally complex and will require a multidimensional conceptualization and multiple methods and levels of…

  15. GENE-ENVIRONMENT INTERACTION AND THE GNB3 GENE IN THE ATHEROSCLEROSIS RISK IN COMMUNITIES STUDY

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The purpose of this study was to investigate the interaction between the G-protein beta-3 (GNB3) 825C>T polymorphism and physical activity in relation to prevalent obesity and hypertension. The GNB3 825C>T genotype was measured in a sample of 14 716 African Americans (AAs) and whites from the Athero...

  16. Gene-environment interaction between the oxytocin receptor (OXTR) gene and parenting behaviour on children's theory of mind.

    PubMed

    Wade, Mark; Hoffmann, Thomas J; Jenkins, Jennifer M

    2015-12-01

    Theory of mind (ToM) is the ability to interpret and understand human behaviour by representing the mental states of others. Like many human capacities, ToM is thought to develop through both complex biological and socialization mechanisms. However, no study has examined the joint effect of genetic and environmental influences on ToM. This study examined how variability in the oxytocin receptor gene (OXTR) and parenting behavior--two widely studied factors in ToM development-interacted to predict ToM in pre-school-aged children. Participants were 301 children who were part of an ongoing longitudinal birth cohort study. ToM was assessed at age 4.5 using a previously validated scale. Parenting was assessed through observations of mothers' cognitively sensitive behaviours. Using a family-based association design, it was suggestive that a particular variant (rs11131149) interacted with maternal cognitive sensitivity on children's ToM (P = 0.019). More copies of the major allele were associated with higher ToM as a function of increasing cognitive sensitivity. A sizeable 26% of the variability in ToM was accounted for by this interaction. This study provides the first empirical evidence of gene-environment interactions on ToM, supporting the notion that genetic factors may be modulated by potent environmental influences early in development. PMID:25977357

  17. Linking Genes to Cardiovascular Diseases: Gene Action and Gene-Environment Interactions.

    PubMed

    Pasipoularides, Ares

    2015-12-01

    A unique myocardial characteristic is its ability to grow/remodel in order to adapt; this is determined partly by genes and partly by the environment and the milieu intérieur. In the "post-genomic" era, a need is emerging to elucidate the physiologic functions of myocardial genes, as well as potential adaptive and maladaptive modulations induced by environmental/epigenetic factors. Genome sequencing and analysis advances have become exponential lately, with escalation of our knowledge concerning sometimes controversial genetic underpinnings of cardiovascular diseases. Current technologies can identify candidate genes variously involved in diverse normal/abnormal morphomechanical phenotypes, and offer insights into multiple genetic factors implicated in complex cardiovascular syndromes. The expression profiles of thousands of genes are regularly ascertained under diverse conditions. Global analyses of gene expression levels are useful for cataloging genes and correlated phenotypes, and for elucidating the role of genes in maladies. Comparative expression of gene networks coupled to complex disorders can contribute insights as to how "modifier genes" influence the expressed phenotypes. Increasingly, a more comprehensive and detailed systematic understanding of genetic abnormalities underlying, for example, various genetic cardiomyopathies is emerging. Implementing genomic findings in cardiology practice may well lead directly to better diagnosing and therapeutics. There is currently evolving a strong appreciation for the value of studying gene anomalies, and doing so in a non-disjointed, cohesive manner. However, it is challenging for many-practitioners and investigators-to comprehend, interpret, and utilize the clinically increasingly accessible and affordable cardiovascular genomics studies. This survey addresses the need for fundamental understanding in this vital area. PMID:26545598

  18. Using mouse models of autism spectrum disorders to study the neurotoxicology of gene-environment interactions

    PubMed Central

    Schwartzer, Jared J.; Koenig, Claire M.; Berman, Robert F

    2012-01-01

    To better study the role of genetics in autism, mouse models have been developed which mimic the genetics of specific autism spectrum and related disorders. These models have facilitated research on the role genetic susceptibility factors in the pathogenesis of autism in the absence of environmental factors. Inbred mouse strains have been similarly studied to assess the role of environmental agents on neurodevelopment, typically without the complications of genetic heterogeneity of the human population. What has not been as actively pursued, however, is the methodical study of the interaction between these factors (e.g., gene and environmental interactions in neurodevelopment). This review suggests that a genetic predisposition paired with exposure to environmental toxicants play an important role in the etiology of neurodevelopmental disorders including autism, and may contribute to the largely unexplained rise in the number of children diagnosed with autism worldwide. Specifically, descriptions of the major mouse models of autism and toxic mechanisms of prevalent environmental chemicals are provided followed by a discussion of current and future research strategies to evaluate the role of gene and environment interactions in neurodevelopmental disorders. PMID:23010509

  19. Gene-environment interactions on mental development in African American, Dominican, and Caucasian Mothers and Newborns

    PubMed Central

    Wang, Shuang; Chanock, Stephen; Tang, Deliang; Li, Zhigang; Edwards, Susan; Jedrychowski, Wieslaw; Perera, Frederica P.

    2009-01-01

    The health impact of environmental toxins has gained increasing recognition over the years. Polycyclic aromatic hydrocarbons (PAHs) and environmental tobacco smoke (ETS) are known to affect nervous system development in children, but no studies have investigated how polymorphisms in PAH metabolic or detoxification genes affect child cognitive development following PAH exposure during pregnancy. In two parallel prospective cohort studies of nonsmoking African American and Dominican mothers and children in New York City and of Caucasian mothers and children in Krakow, Poland, we explored the effect of gene-PAH interaction on child mental development index (MDI), as measured by the Bayley Scales of Infant Development-Revised (BSID-II). Genes known to play important roles in the metabolic activation or detoxification of PAHs were selected. Genetic variations in these genes could influence susceptibility to adverse effects of PAHs in polluted air. We explored the effects of interactions between prenatal PAH exposure and 21 polymorphisms or haplotypes in these genes on MDI at 12, 24, and 36 months among 547 newborns and 806 mothers from three different ethnic groups: African Americans, Dominicans, and Caucasians. PAHs were measured by personal air monitoring of mothers during pregnancy. Significant interaction effects between haplotypes and PAHs were observed in mothers and their newborns in all three ethnic groups after Bonferroni correction for multiple comparisons. The strongest and most consistent effect observed was between PAH and haplotype ACCGGC of the CYP1B1 gene. PMID:19860743

  20. Gene-environment interaction on neural mechanisms of orthographic processing in Chinese children

    PubMed Central

    Su, Mengmeng; Wang, Jiuju; Maurer, Urs; Zhang, Yuping; Li, Jun; McBride-Chang, Catherine; Tardif, Twila; Liu, Youyi; Shu, Hua

    2015-01-01

    The ability to process and identify visual words requires efficient orthographic processing of print, consisting of letters in alphabetic languages or characters in Chinese. The N170 is a robust neural marker for orthographic processes. Both genetic and environmental factors, such as home literacy, have been shown to influence orthographic processing at the behavioral level, but their relative contributions and interactions are not well understood. The present study aimed to reveal possible gene-by-environment interactions on orthographic processing at the behavioral and neural level in a normal children sample. Sixty 12 year old Chinese children from a 10-year longitudinal sample underwent an implicit visual-word color decision task on real words and stroke combinations. The ERP analysis focused on the increase of the occipito-temporal N170 to words compared to stroke combinations. The genetic analysis focused on two SNPs (rs1419228, rs1091047) in the gene DCDC2 based on previous findings linking these 2 SNPs to orthographic coding. Home literacy was measured previously as the number of children's books at home, when the children were at the age of 3. Relative to stroke combinations, real words evoked greater N170 in bilateral posterior brain regions. A significant interaction between rs1091047 and home literacy was observed on the changes of N170 comparing real words to stroke combinations in the left hemisphere. Particularly, children carrying the major allele “G” showed a similar N170 effect irrespective of their environment, while children carrying the minor allele “C” showed a smaller N170 effect in low home-literacy environment than those in good environment. PMID:26294811

  1. Gene-environment interaction of reelin and stress in cognitive behaviours in mice: Implications for schizophrenia.

    PubMed

    Schroeder, Anna; Buret, Laetitia; Hill, Rachel A; van den Buuse, Maarten

    2015-01-01

    Cognitive deficits are a particularly debilitating symptom group in schizophrenia. We investigated the effect of a 'two hit' combination of two factors implicated in schizophrenia development, reelin deficiency and stress, on cognitive behaviours in mice. Male and female heterozygous reelin mice (HRM) and wild-type (WT) controls received the stress hormone, corticosterone (CORT), during early adulthood to simulate chronic stress. The Y-maze, novel object recognition task (NORT), social interaction task and prepulse inhibition (PPI) were used to assess short-term spatial memory, visual non-spatial memory, social recognition memory and sensory gating, respectively. Reelin protein expression was measured in the prefrontal cortex (PFC) and hippocampus. CORT induced spatial memory deficits in male and female HRM but not in WT controls suggesting increased vulnerability of HRM to the effects of stress on cognition. By contrast, CORT disrupted PPI only in male WT mice, but not in male HRM, suggesting a protective role of reelin deficiency against effects of stress on PPI. Male HRM performed worse in the social recognition memory task compared to wild-type controls, irrespective of CORT treatment. No differences were detected in the NORT. Reelin protein expression was increased in the PFC of female CORT-treated HRM but there were no group differences in the hippocampus. Overall, these findings extend our understanding of the role of reelin-stress interactions in schizophrenia. PMID:25845740

  2. Gene-Environment Interaction of ApoE Genotype and Combat Exposure on PTSD

    PubMed Central

    Lyons, Michael J.; Genderson, Margo; Grant, Michael D.; Logue, Mark; Zink, Tyler; McKenzie, Ruth; Franz, Carol E.; Panizzon, Matthew; Lohr, James B.; Jerskey, Beth; Kremen, William S.

    2015-01-01

    Factors determining who develops PTSD following trauma are not well understood. The €4 allele of the apolipoprotein E (apoE) gene is associated with dementia and unfavorable outcome following brain insult. PTSD is also associated with dementia. Given evidence that psychological trauma adversely affects the brain, we hypothesized that the apoE genotype moderates effects of psychological trauma on PTSD pathogenesis. To investigate the moderation of the relationship between PTSD symptoms and combat exposure, we used 172 participants with combat trauma sustained during the Vietnam War. PTSD symptoms were the dependent variable and number of combat experiences, apoE genotype, and the combat experiences × apoE genotype interaction were predictors. We also examined the outcome of a diagnosis of PTSD (n = 39) versus no PTSD diagnosis (n = 131). The combat × apoE genotype interaction was significant for both PTSD symptoms (P = .014) and PTSD diagnosis (P = .009). ApoE genotype moderates the relationship between combat exposure and PTSD symptoms. Although the pathophysiology of PTSD is not well understood, the €4 allele is related to reduced resilience of the brain to insult. Our results are consistent with the €4 allele influencing the effects of psychological trauma on the brain, thereby affecting the risk of PTSD. PMID:24132908

  3. Gene-environment interaction in programming hippocampal plasticity: focus on adult neurogenesis

    PubMed Central

    Koehl, Muriel

    2015-01-01

    Interactions between genes and environment are a critical feature of development and both contribute to shape individuality. They are at the core of vulnerability resiliency for mental illnesses. During the early postnatal period, several brain structures involved in cognitive and emotional processing, such as the hippocampus, still develop and it is likely that interferences with this neuronal development, which is genetically determined, might lead to long-lasting structural and functional consequences and increase the risk of developing psychopathology. One particular target is adult neurogenesis, which is involved in the regulation of cognitive and emotional processes. Insights into the dynamic interplay between genes and environmental factors in setting up individual rates of neurogenesis have come from laboratory studies exploring experience-dependent changes in adult neurogenesis as a function of individual’s genetic makeup. These studies have implications for our understanding of the mechanisms regulating adult neurogenesis, which could constitute a link between environmental challenges and psychopathology. PMID:26300723

  4. Gene-environment interactions in severe intraventricular hemorrhage of preterm neonates

    PubMed Central

    Ment, Laura R.; Ådén, Ulrika; Lin, Aiping; Kwon, Soo Hyun; Choi, Murim; Hallman, Mikko; Lifton, Richard P.; Zhang, Heping; Bauer, Charles R.

    2014-01-01

    Intraventricular hemorrhage (IVH) of the preterm neonate is a complex developmental disorder, with contributions from both the environment and the genome. IVH, or hemorrhage into the germinal matrix of the developing brain with secondary periventricular infarction, occurs in that critical period of time before the 32nd – 33rd week post-conception and has been attributed to changes in cerebral blood flow to the immature germinal matrix microvasculature. Emerging data suggest that genes subserving coagulation, inflammatory and vascular pathways, and their interactions with environmental triggers may influence both the incidence and severity of cerebral injury and are the subject of this review. Polymorphisms in the Factor V Leiden gene are associated with the atypical timing of IVH suggesting an as yet unknown environmental trigger. The methylenetetra-hydrofolate reeducates (MTHFR) variants render neonates more vulnerable to cerebral injury in the presence of perinatal hypoxia. The present study demonstrates that the MTHFR 677C>T polymorphism and low 5 minute Apgar score additively increase the risk of IVH. Finally, review of published preclinical data suggests the stressors of delivery result in hemorrhage in the presence of mutations in collagen 4A1 (COL4A1), a major structural protein of the developing cerebral vasculature. Maternal genetics and fetal environment may also play a role. PMID:24192699

  5. Gene-environment interactions and intermediate phenotypes: early trauma and depression.

    PubMed

    Hornung, Orla P; Heim, Christine M

    2014-01-01

    This review focuses on current research developments in the study of gene by early life stress (ELS) interactions and depression. ELS refers to aversive experiences during childhood and adolescence such as sexual, physical or emotional abuse, emotional or physical neglect as well as parental loss. Previous research has focused on investigating and characterizing the specific role of ELS within the pathogenesis of depression and linking these findings to neurobiological changes of the brain, especially the stress response system. The latest findings highlight the role of genetic factors that increase vulnerability or, likewise, promote resilience to depression after childhood trauma. Considering intermediate phenotypes has further increased our understanding of the complex relationship between early trauma and depression. Recent findings with regard to epigenetic changes resulting from adverse environmental events during childhood promote current endeavors to identify specific target areas for prevention and treatment schemes regarding the long-term impact of ELS. Taken together, the latest research findings have underscored the essential role of genotypes and epigenetic processes within the development of depression after childhood trauma, thereby building the basis for future research and clinical interventions. PMID:24596569

  6. Gene-gene, gene-environment, gene-nutrient interactions and single nucleotide polymorphisms of inflammatory cytokines

    PubMed Central

    Nadeem, Amina; Mumtaz, Sadaf; Naveed, Abdul Khaliq; Aslam, Muhammad; Siddiqui, Arif; Lodhi, Ghulam Mustafa; Ahmad, Tausif

    2015-01-01

    Inflammation plays a significant role in the etiology of type 2 diabetes mellitus (T2DM). The rise in the pro-inflammatory cytokines is the essential step in glucotoxicity and lipotoxicity induced mitochondrial injury, oxidative stress and beta cell apoptosis in T2DM. Among the recognized markers are interleukin (IL)-6, IL-1, IL-10, IL-18, tissue necrosis factor-alpha (TNF-α), C-reactive protein, resistin, adiponectin, tissue plasminogen activator, fibrinogen and heptoglobins. Diabetes mellitus has firm genetic and very strong environmental influence; exhibiting a polygenic mode of inheritance. Many single nucleotide polymorphisms (SNPs) in various genes including those of pro and anti-inflammatory cytokines have been reported as a risk for T2DM. Not all the SNPs have been confirmed by unifying results in different studies and wide variations have been reported in various ethnic groups. The inter-ethnic variations can be explained by the fact that gene expression may be regulated by gene-gene, gene-environment and gene-nutrient interactions. This review highlights the impact of these interactions on determining the role of single nucleotide polymorphism of IL-6, TNF-α, resistin and adiponectin in pathogenesis of T2DM. PMID:25987962

  7. Gene-environment interactions in determining differences in genetic susceptibility to cancer in subsites of the head and neck.

    PubMed

    Maurya, Shailendra S; Katiyar, Tridiv; Dhawan, Ankur; Singh, Sudhir; Jain, Swatantra K; Pant, Mohan C; Parmar, Devendra

    2015-04-01

    Genetic differences in susceptibility to cancer in subsites of the head and neck were investigated in a case-control study involving 750 cases of cancers of the oral cavity, larynx, or pharynx, and an equal number of healthy controls. The prevalence of variant genotypes of cytochrome P450 (CYP) 1A1, 1B1, 2E1, or glutathione-S-transferase M1 (null) in cases suggests that polymorphisms in drug metabolizing enzymes (DMEs) modify cancer risk within subsites of the head and neck. Tobacco or alcohol use was found to increase the risk in cases of laryngeal, pharyngeal, or oral cavity cancers. Interaction between genetic variation in DMEs and tobacco smoke (or smoking) exposures conferred significant risk for laryngeal cancer. Likewise, strong associations of the polymorphic genotypes of DMEs with cases of pharyngeal and oral cavity cancer who were tobacco chewers or alcohol users demonstrate that gene-environment interactions may explain differences in genetic susceptibility for cancers of the oral cavity, larynx, and pharynx. PMID:25399842

  8. Gene-gene, gene-environment, gene-nutrient interactions and single nucleotide polymorphisms of inflammatory cytokines.

    PubMed

    Nadeem, Amina; Mumtaz, Sadaf; Naveed, Abdul Khaliq; Aslam, Muhammad; Siddiqui, Arif; Lodhi, Ghulam Mustafa; Ahmad, Tausif

    2015-05-15

    Inflammation plays a significant role in the etiology of type 2 diabetes mellitus (T2DM). The rise in the pro-inflammatory cytokines is the essential step in glucotoxicity and lipotoxicity induced mitochondrial injury, oxidative stress and beta cell apoptosis in T2DM. Among the recognized markers are interleukin (IL)-6, IL-1, IL-10, IL-18, tissue necrosis factor-alpha (TNF-α), C-reactive protein, resistin, adiponectin, tissue plasminogen activator, fibrinogen and heptoglobins. Diabetes mellitus has firm genetic and very strong environmental influence; exhibiting a polygenic mode of inheritance. Many single nucleotide polymorphisms (SNPs) in various genes including those of pro and anti-inflammatory cytokines have been reported as a risk for T2DM. Not all the SNPs have been confirmed by unifying results in different studies and wide variations have been reported in various ethnic groups. The inter-ethnic variations can be explained by the fact that gene expression may be regulated by gene-gene, gene-environment and gene-nutrient interactions. This review highlights the impact of these interactions on determining the role of single nucleotide polymorphism of IL-6, TNF-α, resistin and adiponectin in pathogenesis of T2DM. PMID:25987962

  9. Genetic risk for violent behavior and environmental exposure to disadvantage and violent crime: the case for gene-environment interaction.

    PubMed

    Barnes, J C; Jacobs, Bruce A

    2013-01-01

    Despite mounds of evidence to suggest that neighborhood structural factors predict violent behavior, almost no attention has been given to how these influences work synergistically (i.e., interact) with an individual's genetic propensity toward violent behavior. Indeed, two streams of research have, heretofore, flowed independently of one another. On one hand, criminologists have underscored the importance of neighborhood context in the etiology of violence. On the other hand, behavioral geneticists have argued that individual-level genetic propensities are important for understanding violence. The current study seeks to integrate these two compatible frameworks by exploring gene-environment interactions (GxE). Two GxEs were examined and supported by the data (i.e., the National Longitudinal Study of Adolescent Health). Using a scale of genetic risk based on three dopamine genes, the analysis revealed that genetic risk had a greater influence on violent behavior when the individual was also exposed to neighborhood disadvantage or when the individual was exposed to higher violent crime rates. The relevance of these findings for criminological theorizing was considered. PMID:22829212

  10. The Association between Gene-Environment Interactions and Diseases Involving the Human GST Superfamily with SNP Variants.

    PubMed

    Hollman, Antoinesha L; Tchounwou, Paul B; Huang, Hung-Chung

    2016-04-01

    Exposure to environmental hazards has been associated with diseases in humans. The identification of single nucleotide polymorphisms (SNPs) in human populations exposed to different environmental hazards, is vital for detecting the genetic risks of some important human diseases. Several studies in this field have been conducted on glutathione S-transferases (GSTs), a phase II detoxification superfamily, to investigate its role in the occurrence of diseases. Human GSTs consist of cytosolic and microsomal superfamilies that are further divided into subfamilies. Based on scientific search engines and a review of the literature, we have found a large amount of published articles on human GST super- and subfamilies that have greatly assisted in our efforts to examine their role in health and disease. Because of its polymorphic variations in relation to environmental hazards such as air pollutants, cigarette smoke, pesticides, heavy metals, carcinogens, pharmaceutical drugs, and xenobiotics, GST is considered as a significant biomarker. This review examines the studies on gene-environment interactions related to various diseases with respect to single nucleotide polymorphisms (SNPs) found in the GST superfamily. Overall, it can be concluded that interactions between GST genes and environmental factors play an important role in human diseases. PMID:27043589

  11. The Association between Gene-Environment Interactions and Diseases Involving the Human GST Superfamily with SNP Variants

    PubMed Central

    Hollman, Antoinesha L.; Tchounwou, Paul B.; Huang, Hung-Chung

    2016-01-01

    Exposure to environmental hazards has been associated with diseases in humans. The identification of single nucleotide polymorphisms (SNPs) in human populations exposed to different environmental hazards, is vital for detecting the genetic risks of some important human diseases. Several studies in this field have been conducted on glutathione S-transferases (GSTs), a phase II detoxification superfamily, to investigate its role in the occurrence of diseases. Human GSTs consist of cytosolic and microsomal superfamilies that are further divided into subfamilies. Based on scientific search engines and a review of the literature, we have found a large amount of published articles on human GST super- and subfamilies that have greatly assisted in our efforts to examine their role in health and disease. Because of its polymorphic variations in relation to environmental hazards such as air pollutants, cigarette smoke, pesticides, heavy metals, carcinogens, pharmaceutical drugs, and xenobiotics, GST is considered as a significant biomarker. This review examines the studies on gene-environment interactions related to various diseases with respect to single nucleotide polymorphisms (SNPs) found in the GST superfamily. Overall, it can be concluded that interactions between GST genes and environmental factors play an important role in human diseases. PMID:27043589

  12. Gene-environment interactions between JAZF1 and occupational and household lead exposure in prostate cancer among African American men

    PubMed Central

    Neslund-Dudas, Christine; Levin, Albert M.; Beebe-Dimmer, Jennifer L.; Bock, Cathryn H.; Nock, Nora L.; Rundle, Andrew; Jankowski, Michelle; Krajenta, Richard; Dou, Q. Ping; Mitra, Bharati; Tang, Deliang; Rebbeck, Timothy R.; Rybicki, Benjamin A.

    2014-01-01

    Purpose A single nucleotide polymorphism, rs10486567, in JAZF1 has consistently been associated with increased risk of prostate cancer. The physical interaction of zinc finger proteins, such as JAZF1, with heavy metals may play a role in carcinogenesis. This study assessed potential gene-environment statistical interactions (GxE) between rs10486567 and heavy metals in prostate cancer. Methods In a case-only study of 228 African American prostate cancer cases, GxE between rs10486567 and sources of cadmium (Cd) and lead (Pb) were assessed. Unconditional logistic regression was used to estimate interaction odds ratios and GEE was used for models containing nested data. Case-control validation of IORs was performed, using 82 controls frequency matched to cases on age-race. Results Among cases, a potential GxE interaction was observed between rs10486567 CC genotype and living in a Census tract with a high proportion of housing built before 1950, a proxy for household Pb exposure, when compared to CT or TT carriers (OR 1.81; 95% CI 1.04-3.16; p=0.036). A stronger GxE interaction was observed when both housing and occupational Pb exposure were taken into account (OR 2.62; 95% CI 1.03-6.68; p=0.04). Case-control stratified analyses showed the odds of being a CC carrier was higher in cases compared to controls among men living in areas with older housing (OR 2.03; CI 0.99-4.19; p=0.05) or having high occupational Pb exposure (OR 2.50; CI 1.01-6.18; p=0.05). Conclusions In African American men, the association between JAZF1 rs10486567 and prostate cancer may be modified by exposure to heavy metals such as Pb. PMID:24801046

  13. I Just Ran a Thousand Analyses: Benefits of Multiple Testing in Understanding Equivocal Evidence on Gene-Environment Interactions

    PubMed Central

    Heininga, Vera E.; Oldehinkel, Albertine J.; Veenstra, René; Nederhof, Esther

    2015-01-01

    Background In psychiatric genetics research, the volume of ambivalent findings on gene-environment interactions (G x E) is growing at an accelerating pace. In response to the surging suspicions of systematic distortion, we challenge the notion of chance capitalization as a possible contributor. Beyond qualifying multiple testing as a mere methodological issue that, if uncorrected, leads to chance capitalization, we advance towards illustrating the potential benefits of multiple tests in understanding equivocal evidence in genetics literature. Method We focused on the interaction between the serotonin-transporter-linked promotor region (5-HTTLPR) and childhood adversities with regard to depression. After testing 2160 interactions with all relevant measures available within the Dutch population study of adolescents TRAILS, we calculated percentages of significant (p < .05) effects for several subsets of regressions. Using chance capitalization (i.e. overall significance rate of 5% alpha and randomly distributed findings) as a competing hypothesis, we expected more significant effects in the subsets of regressions involving: 1) interview-based instead of questionnaire-based measures; 2) abuse instead of milder childhood adversities; and 3) early instead of later adversities. Furthermore, we expected equal significance percentages across 4) male and female subsamples, and 5) various genotypic models of 5-HTTLPR. Results We found differences in the percentages of significant interactions among the subsets of analyses, including those regarding sex-specific subsamples and genetic modeling, but often in unexpected directions. Overall, the percentage of significant interactions was 7.9% which is only slightly above the 5% that might be expected based on chance. Conclusion Taken together, multiple testing provides a novel approach to better understand equivocal evidence on G x E, showing that methodological differences across studies are a likely reason for heterogeneity in

  14. BAYESIAN METHODS FOR GENETIC ASSOCIATION ANALYSIS WITH HETEROGENEOUS SUBGROUPS: FROM META-ANALYSES TO GENE-ENVIRONMENT INTERACTIONS

    PubMed Central

    Wen, Xiaoquan; Stephens, Matthew

    2015-01-01

    Genetic association analyses often involve data from multiple potentially-heterogeneous subgroups. The expected amount of heterogeneity can vary from modest (e.g. a typical meta-analysis), to large (e.g. a strong gene-environment interaction). However, existing statistical tools are limited in their ability to address such heterogeneity. Indeed, most genetic association meta-analyses use a “fixed effects” analysis, which assumes no heterogeneity. Here we develop and apply Bayesian association methods to address this problem. These methods are easy to apply (in the simplest case, requiring only a point estimate for the genetic effect, and its standard error, from each subgroup), and effectively include standard frequentist meta-analysis methods, including the usual “fixed effects” analysis, as special cases. We apply these tools to two large genetic association studies: one a meta-analysis of genome-wide association studies from the Global Lipids consortium, and the second a cross-population analysis for expression quantitative trait loci (eQTLs). In the Global Lipids data we find, perhaps surprisingly, that effects are generally quite homogeneous across studies. In the eQTL study we find that eQTLs are generally shared among different continental groups, and discuss consequences of this for study design. PMID:26413181

  15. Genetic gating of human fear learning and extinction: possible implications for gene-environment interaction in anxiety disorder.

    PubMed

    Lonsdorf, Tina B; Weike, Almut I; Nikamo, Pernilla; Schalling, Martin; Hamm, Alfons O; Ohman, Arne

    2009-02-01

    Pavlovian fear conditioning is a widely used model of the acquisition and extinction of fear. Neural findings suggest that the amygdala is the core structure for fear acquisition, whereas prefrontal cortical areas are given pivotal roles in fear extinction. Forty-eight volunteers participated in a fear-conditioning experiment, which used fear potentiation of the startle reflex as the primary measure to investigate the effect of two genetic polymorphisms (5-HTTLPR and COMTval158met) on conditioning and extinction of fear. The 5-HTTLPR polymorphism, located in the serotonin transporter gene, is associated with amygdala reactivity and neuroticism, whereas the COMTval158met polymorphism, which is located in the gene coding for catechol-O-methyltransferase (COMT), a dopamine-degrading enzyme, affects prefrontal executive functions. Our results show that only carriers of the 5-HTTLPR s allele exhibited conditioned startle potentiation, whereas carriers of the COMT met/met genotype failed to extinguish conditioned fear. These results may have interesting implications for understanding gene-environment interactions in the development and treatment of anxiety disorders. PMID:19175757

  16. Molecular pathways: gene-environment interactions regulating dietary fiber induction of proliferation and apoptosis via butyrate for cancer prevention.

    PubMed

    Bultman, Scott J

    2014-02-15

    Gene-environment interactions are so numerous and biologically complicated that it can be challenging to understand their role in cancer. However, dietary fiber and colorectal cancer prevention may represent a tractable model system. Fiber is fermented by colonic bacteria into short-chain fatty acids such as butyrate. One molecular pathway that has emerged involves butyrate having differential effects depending on its concentration and the metabolic state of the cell. Low-moderate concentrations, which are present near the base of colonic crypts, are readily metabolized in the mitochondria to stimulate cell proliferation via energetics. Higher concentrations, which are present near the lumen, exceed the metabolic capacity of the colonocyte. Unmetabolized butyrate enters the nucleus and functions as a histone deacetylase (HDAC) inhibitor that epigenetically regulates gene expression to inhibit cell proliferation and induce apoptosis as the colonocytes exfoliate into the lumen. Butyrate may therefore play a role in normal homeostasis by promoting turnover of the colonic epithelium. Because cancerous colonocytes undergo the Warburg effect, their preferred energy source is glucose instead of butyrate. Consequently, even moderate concentrations of butyrate accumulate in cancerous colonocytes and function as HDAC inhibitors to inhibit cell proliferation and induce apoptosis. These findings implicate a bacterial metabolite with metaboloepigenetic properties in tumor suppression. PMID:24270685

  17. Gene-environment interaction from international cohorts: impact on development and evolution of occupational and environmental lung and airway disease.

    PubMed

    Gaffney, Adam; Christiani, David C

    2015-06-01

    Environmental and occupational pulmonary diseases impose a substantial burden of morbidity and mortality on the global population. However, it has been long observed that only some of those who are exposed to pulmonary toxicants go on to develop disease; increasingly, it is being recognized that genetic differences may underlie some of this person-to-person variability. Studies performed throughout the globe are demonstrating important gene-environment interactions for diseases as diverse as chronic beryllium disease, coal workers' pneumoconiosis, silicosis, asbestosis, byssinosis, occupational asthma, and pollution-associated asthma. These findings have, in many instances, elucidated the pathogenesis of these highly complex diseases. At the same time, however, translation of this research into clinical practice has, for good reasons, proceeded slowly. No genetic test has yet emerged with sufficiently robust operating characteristics to be clearly useful or practicable in an occupational or environmental setting. In addition, occupational genetic testing raises serious ethical and policy concerns. Therefore, the primary objective must remain ensuring that the workplace and the environment are safe for all. PMID:26024343

  18. Enacting the molecular imperative: How gene-environment interaction research links bodies and environments in the post-genomic age.

    PubMed

    Darling, Katherine Weatherford; Ackerman, Sara L; Hiatt, Robert H; Lee, Sandra Soo-Jin; Shim, Janet K

    2016-04-01

    Despite a proclaimed shift from 'nature versus nurture' to 'genes and environment' paradigms within biomedical and genomic science, capturing the environment and identifying gene-environment interactions (GEIs) has remained a challenge. What does 'the environment' mean in the post-genomic age? In this paper, we present qualitative data from a study of 33 principal investigators funded by the U.S. National Institutes of Health to conduct etiological research on three complex diseases (cancer, cardiovascular disease and diabetes). We examine their research practices and perspectives on the environment through the concept of molecularization: the social processes and transformations through which phenomena (diseases, identities, pollution, food, racial/ethnic classifications) are re-defined in terms of their molecular components and described in the language of molecular biology. We show how GEI researchers' expansive conceptualizations of the environment ultimately yield to the imperative to molecularize and personalize the environment. They seek to 'go into the body' and re-work the boundaries between bodies and environments. In the process, they create epistemic hinges to facilitate a turn from efforts to understand social and environmental exposures outside the body, to quantifying their effects inside the body. GEI researchers respond to these emergent imperatives with a mixture of excitement, ambivalence and frustration. We reflect on how GEI researchers struggle to make meaning of molecules in their work, and how they grapple with molecularization as a methodological and rhetorical imperative as well as a process transforming biomedical research practices. PMID:26994357

  19. Identifying novel interventional strategies for psychiatric disorders: integrating genomics, 'enviromics' and gene-environment interactions in valid preclinical models.

    PubMed

    McOmish, Caitlin E; Burrows, Emma L; Hannan, Anthony J

    2014-10-01

    Psychiatric disorders affect a substantial proportion of the population worldwide. This high prevalence, combined with the chronicity of the disorders and the major social and economic impacts, creates a significant burden. As a result, an important priority is the development of novel and effective interventional strategies for reducing incidence rates and improving outcomes. This review explores the progress that has been made to date in establishing valid animal models of psychiatric disorders, while beginning to unravel the complex factors that may be contributing to the limitations of current methodological approaches. We propose some approaches for optimizing the validity of animal models and developing effective interventions. We use schizophrenia and autism spectrum disorders as examples of disorders for which development of valid preclinical models, and fully effective therapeutics, have proven particularly challenging. However, the conclusions have relevance to various other psychiatric conditions, including depression, anxiety and bipolar disorders. We address the key aspects of construct, face and predictive validity in animal models, incorporating genetic and environmental factors. Our understanding of psychiatric disorders is accelerating exponentially, revealing extraordinary levels of genetic complexity, heterogeneity and pleiotropy. The environmental factors contributing to individual, and multiple, disorders also exhibit breathtaking complexity, requiring systematic analysis to experimentally explore the environmental mediators and modulators which constitute the 'envirome' of each psychiatric disorder. Ultimately, genetic and environmental factors need to be integrated via animal models incorporating the spatiotemporal complexity of gene-environment interactions and experience-dependent plasticity, thus better recapitulating the dynamic nature of brain development, function and dysfunction. PMID:24846457

  20. Gene-Environment Interaction Effects of Peer Deviance, Parental Knowledge and Stressful Life Events on Adolescent Alcohol Use

    PubMed Central

    Cooke, Megan E.; Meyers, Jacquelyn L.; Latvala, Antti; Korhonen, Tellervo; Rose, Richard J.; Kaprio, Jaakko; Salvatore, Jessica E.; Dick, Danielle M.

    2016-01-01

    The purpose of this study was to address two methodological issues that have called into question whether previously reported gene-environment interaction (GxE) effects for adolescent alcohol use are “real.” These issues are (1) the potential correlation between the environmental moderator and the outcome across twins and (2) non-linear transformations of the behavioral outcome. Three environments that have been previously reported on (peer deviance, parental knowledge, and potentially stressful life events) were examined here. For each moderator (peer deviance, parental knowledge, and potentially stressful life events), a series of models was fit to both a raw and transformed measure of monthly adolescent alcohol use in a sample that included 825 DZ and 803 MZ twin pairs. The results showed that the moderating effect of peer deviance was robust to transformation, and that although the significance of moderating effects of parental knowledge and potentially stressful life events were dependent on the scale of the adolescent alcohol use outcome, the overall results were consistent across transformation. In addition, the findings did not vary across statistical models. The consistency of the peer deviance results and the shift of the parental knowledge and potentially stressful life events results between trending and significant, shed some light on why previous findings for certain moderators have been inconsistent and emphasize the importance of considering both methodological issues and previous findings when conducting and interpreting GxE analyses. PMID:26290350

  1. Genotype-based association models of complex diseases to detect gene-gene and gene-environment interactions

    PubMed Central

    Fan, Ruzong; Manga, Prashiela

    2015-01-01

    A central problem in genetic epidemiology is to identify and rank genetic markers involved in a disease. Complex diseases, such as cancer, hypertension, diabetes, are thought to be caused by an interaction of a panel of genetic factors, that can be identified by markers, which modulate environmental factors. Moreover, the effect of each genetic marker may be small. Hence, the association signal may be missed unless a large sample is considered, or a priori biomedical data are used. Recent advances generated a vast variety of a priori information, including linkage maps and information about gene regulatory dependence assembled into curated pathway databases. We propose a genotype-based approach that takes into account linkage disequilibrium (LD) information between genetic markers that are in moderate LD while modeling gene-gene and gene-environment interactions. A major advantage of our method is that the observed genetic information enters a model directly thus eliminating the need to estimate haplotype-phase. Our approach results in an algorithm that is inexpensive computationally and does not suffer from bias induced by haplotype-phase ambiguity. We investigated our model in a series of simulation experiments and demonstrated that the proposed approach results in estimates that are nearly unbiased and have small variability. We applied our method to the analysis of data from a melanoma case-control study and investigated interaction between a set of pigmentation genes and environmental factors defined by age and gender. Furthermore, an application of our method is demonstrated using a study of Alcohol Dependence. PMID:26191336

  2. Epigenetic Genes and Emotional Reactivity to Daily Life Events: A Multi-Step Gene-Environment Interaction Study

    PubMed Central

    Pishva, Ehsan; Drukker, Marjan; Viechtbauer, Wolfgang; Decoster, Jeroen; Collip, Dina; van Winkel, Ruud; Wichers, Marieke; Jacobs, Nele; Thiery, Evert; Derom, Catherine; Geschwind, Nicole; van den Hove, Daniel; Lataster, Tineke; Myin-Germeys, Inez; van Os, Jim

    2014-01-01

    Recent human and animal studies suggest that epigenetic mechanisms mediate the impact of environment on development of mental disorders. Therefore, we hypothesized that polymorphisms in epigenetic-regulatory genes impact stress-induced emotional changes. A multi-step, multi-sample gene-environment interaction analysis was conducted to test whether 31 single nucleotide polymorphisms (SNPs) in epigenetic-regulatory genes, i.e. three DNA methyltransferase genes DNMT1, DNMT3A, DNMT3B, and methylenetetrahydrofolate reductase (MTHFR), moderate emotional responses to stressful and pleasant stimuli in daily life as measured by Experience Sampling Methodology (ESM). In the first step, main and interactive effects were tested in a sample of 112 healthy individuals. Significant associations in this discovery sample were then investigated in a population-based sample of 434 individuals for replication. SNPs showing significant effects in both the discovery and replication samples were subsequently tested in three other samples of: (i) 85 unaffected siblings of patients with psychosis, (ii) 110 patients with psychotic disorders, and iii) 126 patients with a history of major depressive disorder. Multilevel linear regression analyses showed no significant association between SNPs and negative affect or positive affect. No SNPs moderated the effect of pleasant stimuli on positive affect. Three SNPs of DNMT3A (rs11683424, rs1465764, rs1465825) and 1 SNP of MTHFR (rs1801131) moderated the effect of stressful events on negative affect. Only rs11683424 of DNMT3A showed consistent directions of effect in the majority of the 5 samples. These data provide the first evidence that emotional responses to daily life stressors may be moderated by genetic variation in the genes involved in the epigenetic machinery. PMID:24967710

  3. Next-generation analysis of cataracts: determining knowledge driven gene-gene interactions using Biofilter, and gene-environment interactions using the PhenX Toolkit.

    PubMed

    Pendergrass, Sarah A; Verma, Shefali S; Holzinger, Emily R; Moore, Carrie B; Wallace, John; Dudek, Scott M; Huggins, Wayne; Kitchner, Terrie; Waudby, Carol; Berg, Richard; McCarty, Catherine A; Ritchie, Marylyn D

    2013-01-01

    Investigating the association between biobank derived genomic data and the information of linked electronic health records (EHRs) is an emerging area of research for dissecting the architecture of complex human traits, where cases and controls for study are defined through the use of electronic phenotyping algorithms deployed in large EHR systems. For our study, 2580 cataract cases and 1367 controls were identified within the Marshfield Personalized Medicine Research Project (PMRP) Biobank and linked EHR, which is a member of the NHGRI-funded electronic Medical Records and Genomics (eMERGE) Network. Our goal was to explore potential gene-gene and gene-environment interactions within these data for 529,431 single nucleotide polymorphisms (SNPs) with minor allele frequency > 1%, in order to explore higher level associations with cataract risk beyond investigations of single SNP-phenotype associations. To build our SNP-SNP interaction models we utilized a prior-knowledge driven filtering method called Biofilter to minimize the multiple testing burden of exploring the vast array of interaction models possible from our extensive number of SNPs. Using the Biofilter, we developed 57,376 prior-knowledge directed SNP-SNP models to test for association with cataract status. We selected models that required 6 sources of external domain knowledge. We identified 5 statistically significant models with an interaction term with p-value < 0.05, as well as an overall model with p-value < 0.05 associated with cataract status. We also conducted gene-environment interaction analyses for all GWAS SNPs and a set of environmental factors from the PhenX Toolkit: smoking, UV exposure, and alcohol use; these environmental factors have been previously associated with the formation of cataracts. We found a total of 288 models that exhibit an interaction term with a p-value ≤ 1×10(-4) associated with cataract status. Our results show these approaches enable advanced searches for epistasis

  4. The Interacting Effect of the BDNF Val66Met Polymorphism and Stressful Life Events on Adolescent Depression Is Not an Artifact of Gene-Environment Correlation: Evidence from a Longitudinal Twin Study

    ERIC Educational Resources Information Center

    Chen, Jie; Li, Xinying; McGue, Matt

    2013-01-01

    Background: Confounding introduced by gene-environment correlation (rGE) may prevent one from observing a true gene-environment interaction (G × E) effect on psychopathology. The present study investigated the interacting effect of the BDNF Val66Met polymorphism and stressful life events (SLEs) on adolescent depression while controlling for the…

  5. Research Review: Gene-Environment Interaction Research in Youth Depression--A Systematic Review with Recommendations for Future Research

    ERIC Educational Resources Information Center

    Dunn, Erin C.; Uddin, Monica; Subramanian, S. V.; Smoller, Jordan W.; Galea, Sandro; Koenen, Karestan C.

    2011-01-01

    Background: Depression is a major public health problem among youth, currently estimated to affect as many as 9% of US children and adolescents. The recognition that both genes (nature) and environments (nurture) are important for understanding the etiology of depression has led to a rapid growth in research exploring gene-environment interactions…

  6. Multiple Analytical Approaches Reveal Distinct Gene-Environment Interactions in Smokers and Non Smokers in Lung Cancer

    PubMed Central

    Ihsan, Rakhshan; Chauhan, Pradeep Singh; Mishra, Ashwani Kumar; Yadav, Dhirendra Singh; Kaushal, Mishi; Sharma, Jagannath Dev; Zomawia, Eric; Verma, Yogesh; Kapur, Sujala; Saxena, Sunita

    2011-01-01

    with SULT1A1 Arg213His and EPHX1 Tyr113His in smokers and SULT1A1 Arg213His with GSTP1 Ile105Val and CYP1A1*2C in nonsmokers. These results identified distinct gene-gene and gene environment interactions in smokers and non-smokers, which confirms the importance of multifactorial interaction in risk assessment of lung cancer. PMID:22206016

  7. Power Analysis for Population-Based Longitudinal Studies Investigating Gene-Environment Interactions in Chronic Diseases: A Simulation Study

    PubMed Central

    Ma, Jinhui; Thabane, Lehana; Beyene, Joseph; Raina, Parminder

    2016-01-01

    very low (≥0.1) and the disease of interest was not rare (such as diabetes and dementia). The CLSA had enough power to detect a large effect of the gene-environment interaction only when both risk exposures had relatively high prevalence (0.2) and the disease of interest was very common (such as diabetes). The minimum detectable hazard ratios (MDHR) of the CLSA for the environmental and genetic risk exposures obtained from this simulation study were larger than those calculated according to the conventional sample size calculation method. For example, the MDHR for the environmental risk exposure was 1.15 according to the conventional method if the prevalence of the risk exposure was 0.1 and the disease of interest was dementia. In contrast, the MDHR was 1.61 if the same exposure was measured every 3 years with a misclassification rate of 0.1 according to this simulation study. With a given sample size, higher statistical power could be achieved by increasing the measuring frequency in participants with high risk of declining health status or changing risk exposures, and by increasing measurement accuracy of diseases and risk exposures. A properly designed simulation-based sample size calculation is superior to conventional methods when rigorous sample size calculation is necessary. PMID:26901422

  8. Underlying Mechanisms of Gene-Environment Interactions in Externalizing Behavior: A Systematic Review and Search for Theoretical Mechanisms.

    PubMed

    Weeland, Joyce; Overbeek, Geertjan; de Castro, Bram Orobio; Matthys, Walter

    2015-12-01

    Over the last decade, several candidate genes (i.e., MAOA, DRD4, DRD2, DAT1, 5-HTTLPR, and COMT) have been extensively studied as potential moderators of the detrimental effects of postnatal family adversity on child externalizing behaviors, such as aggression and conduct disorder. Many studies on such candidate gene by environment interactions (i.e., cG × E) have been published, and the first part of this paper offers a systematic review and integration of their findings (n = 53). The overview shows a set of heterogeneous findings. However, because of large differences between studies in terms of sample composition, conceptualizations, and power, it is difficult to determine if different findings indeed illustrate inconsistent cG × E findings or if findings are simply incomparable. In the second part of the paper, therefore, we argue that one way to help resolve this problem is the development of theory-driven a priori hypotheses on which biopsychosocial mechanisms might underlie cG × E. Such a theoretically based approach can help us specify our research strategies, create more comparable findings, and help us interpret different findings between studies. In accordance, we describe three possible explanatory mechanisms, based on extant literature on the concepts of (1) emotional reactivity, (2) reward sensitivity, and (3) punishment sensitivity. For each mechanism, we discuss the link between the putative mechanism and externalizing behaviors, the genetic polymorphism, and family adversity. Possible research strategies to test these mechanisms, and implications for interventions, are discussed. PMID:26537239

  9. The Cumulative Effect of Gene-Gene and Gene-Environment Interactions on the Risk of Prostate Cancer in Chinese Men

    PubMed Central

    Liu, Ming; Shi, Xiaohong; Yang, Fan; Wang, Jianye; Xu, Yong; Wei, Dong; Yang, Kuo; Zhang, Yaoguang; Wang, Xin; Liang, Siying; Chen, Xin; Sun, Liang; Zhu, Xiaoquan; Zhao, Chengxiao; Zhu, Ling; Tang, Lei; Zheng, Chenguang; Yang, Ze

    2016-01-01

    Prostate cancer (PCa) is a multifactorial disease involving complex genetic and environmental factors interactions. Gene-gene and gene-environment interactions associated with PCa in Chinese men are less studied. We explored the association between 36 SNPs and PCa in 574 subjects from northern China. Body mass index (BMI), smoking, and alcohol consumption were determined through self-administered questionnaires in 134 PCa patients. Then gene-gene and gene-environment interactions among the PCa-associated SNPs were analyzed using the generalized multifactor dimensionality reduction (GMDR) and logistic regression methods. Allelic and genotypic association analyses showed that six variants were associated with PCa and the cumulative effect suggested men who carried any combination of 1, 2, or ≥3 risk genotypes had a gradually increased PCa risk (odds ratios (ORs) = 1.79–4.41). GMDR analysis identified the best gene-gene interaction model with scores of 10 for both the cross-validation consistency and sign tests. For gene-environment interactions, rs6983561 CC and rs16901966 GG in individuals with a BMI ≥ 28 had ORs of 7.66 (p = 0.032) and 5.33 (p = 0.046), respectively. rs7679673 CC + CA and rs12653946 TT in individuals that smoked had ORs of 2.77 (p = 0.007) and 3.11 (p = 0.024), respectively. rs7679673 CC in individuals that consumed alcohol had an OR of 4.37 (p = 0.041). These results suggest that polymorphisms, either individually or by interacting with other genes or environmental factors, contribute to an increased risk of PCa. PMID:26828504

  10. Is the Gene-Environment Interaction Paradigm Relevant to Genome-Wide Studies? The Case of Education and Body Mass Index

    PubMed Central

    Boardman, Jason D.; Domingue, Benjamin W.; Blalock, Casey L.; Haberstick, Brett C.; Harris, Kathleen Mullan; McQueen, Matthew B.

    2014-01-01

    This study uses data from the Framingham Heart Study to examine the relevance of the gene-environment interaction paradigm for genome-wide association studies (GWAS). We use completed college education as our environmental measure and estimate the interactive effect of genotype and education on body mass index (BMI) using 260,402 single-nucleotide polymorphisms (SNPs). Our results highlight the sensitivity of parameter estimates obtained from GWAS models and the difficulty of framing genome-wide results using the existing gene-environment interaction typology. We argue that SNP-environment interactions across the human genome are not likely to provide consistent evidence regarding genetic influences on health that differ by environment. Nevertheless, genome-wide data contain rich information about individual respondents, and we demonstrate the utility of this type of data. We highlight the fact that GWAS is just one use of genome-wide data, and we encourage demographers to develop methods that incorporate this vast amount of information from respondents into their analyses. PMID:24281739

  11. Enhancing the gene-environment interaction framework through a quasi-experimental research design: evidence from differential responses to September 11.

    PubMed

    Fletcher, Jason M

    2014-01-01

    This article uses a gene-environment interaction framework to examine the differential responses to an objective external stressor based on genetic variation in the production of depressive symptoms. This article advances the literature by utilizing a quasi-experimental environmental exposure design, as well as a regression discontinuity design, to control for seasonal trends, which limit the potential for gene-environment correlation and allow stronger causal claims. Replications are attempted for two prominent genes (5-HTT and MAOA), and three additional genes are explored (DRD2, DRD4, and DAT1). This article provides evidence of a main effect of 9/11 on reports of feelings of sadness and fails to replicate a common finding of interaction using 5-HTT but does show support for interaction with MAOA in men. It also provides new evidence that variation in the DRD4 gene modifies an individual's response to the exposure, with individuals with no 7-repeats found to have a muted response. PMID:24784984

  12. Rigorous tests of gene-environment interactions in a lab study of the oxytocin receptor gene (OXTR), alcohol exposure, and aggression.

    PubMed

    LoParo, Devon; Johansson, Ada; Walum, Hasse; Westberg, Lars; Santtila, Pekka; Waldman, Irwin

    2016-07-01

    Naturalistic studies of gene-environment interactions (G X E) have been plagued by several limitations, including difficulty isolating specific environmental risk factors from other correlated aspects of the environment, gene-environment correlation (rGE ), and the use of a single genetic variant to represent the influence of a gene. We present results from 235 Finnish young men in two lab studies of aggression and alcohol challenge that attempt to redress these limitations of the extant G X E literature. Specifically, we use a latent variable modeling approach in an attempt to more fully account for genetic variation across the oxytocin receptor gene (OXTR) and to robustly test its main effects on aggression and its interaction with alcohol exposure. We also modeled aggression as a latent variable comprising various indices, including the average and maximum levels of aggression, the earliest trial on which aggression was expressed, and the proportion of trials on which the minimum and maximum levels of aggression were expressed. The best fitting model for the genetic variation across OXTR included six factors derived from an exploratory factor analysis, roughly corresponding to six haplotype blocks. Aggression levels were higher on trials in which participants were administered alcohol, won, or were provoked. There was a significant main effect of OXTR on aggression across studies after controlling for covariates. The interaction of OXTR and alcohol was also significant across studies, such that OXTR had stronger effects on aggression in the alcohol administration condition. © 2015 Wiley Periodicals, Inc. PMID:26250573

  13. An empirical comparison of meta-analysis and mega-analysis of individual participant data for identifying gene-environment interactions

    PubMed Central

    Sung, Yun Ju; Schwander, Karen; Arnett, Donna K.; Kardia, Sharon L.R.; Rankinen, Tuomo; Bouchard, Claude; Boerwinkle, Eric; Hunt, Steven C.; Rao, Dabeeru C

    2015-01-01

    For analysis of the main effects of SNPs, meta-analysis of summary results from individual studies has been shown to provide comparable results as “mega-analysis” that jointly analyzes the pooled participant data from the available studies. This fact revolutionized the genetic analysis of complex traits through large GWAS consortia. Investigations of gene-environment (G×E) interactions are on the rise since they can potentially explain a part of the missing heritability and identify individuals at high risk for disease. However, for analysis of gene-environment interactions, it is not known whether these methods yield comparable results. In this empirical study, we report that the results from both methods were largely consistent for all four tests; the standard 1 degree of freedom (df) test of main effect only, the 1 df test of the main effect (in the presence of interaction effect), the 1 df test of the interaction effect, and the joint 2 df test of main and interaction effects. They provided similar effect size and standard error estimates, leading to comparable p-values. The genomic inflation factors and the number of SNPs with various thresholds were also comparable between the two approaches. Mega-analysis is not always feasible especially in very large and diverse consortia since pooling of raw data may be limited by the terms of the informed consent. Our study illustrates that meta-analysis can be an effective approach also for identifying interactions. To our knowledge, this is the first report investigating meta- versus mega-analyses for interactions. PMID:24719363

  14. Bayesian inference of gene-environment interaction from incomplete data: what happens when information on environment is disjoint from data on gene and disease?

    PubMed

    Gustafson, Paul; Burstyn, Igor

    2011-04-15

    Inference in gene-environment studies can sometimes exploit the assumption of mendelian randomization that genotype and environmental exposure are independent in the population under study. Moreover, in some such problems it is reasonable to assume that the disease risk for subjects without environmental exposure will not vary with genotype. When both assumptions can be invoked, we consider the prospects for inferring the dependence of disease risk on genotype and environmental exposure (and particularly the extent of any gene-environment interaction), without detailed data on environmental exposure. The data structure envisioned involves data on disease and genotype jointly, but only external information about the distribution of the environmental exposure in the population. This is relevant as for many environmental exposures individual-level measurements are costly and/or highly error-prone. Working in the setting where all relevant variables are binary, we examine the extent to which such data are informative about the interaction, via determination of the large-sample limit of the posterior distribution. The ideas are illustrated using data from a case-control study for bladder cancer involving smoking behaviour and the NAT2 genotype. PMID:21432881

  15. The Oxytocin Receptor Gene (OXTR) in Relation to State Levels of Loneliness in Adolescence: Evidence for Micro-Level Gene-Environment Interactions

    PubMed Central

    van Roekel, Eeske; Verhagen, Maaike; Scholte, Ron H. J.; Kleinjan, Marloes; Goossens, Luc; Engels, Rutger C. M. E.

    2013-01-01

    Previous research has shown that the rs53576 variant of the oxytocin receptor gene (OXTR) is associated with trait levels of loneliness, but results are inconsistent. The aim of the present study is to examine micro-level effects of the OXTR rs53576 variant on state levels of loneliness in early adolescents. In addition, gene-environment interactions are examined between this OXTR variant and positive and negative perceptions of company. Data were collected in 278 adolescents (58% girls), by means of the Experience Sampling Method (ESM). Sampling periods consisted of six days with nine assessments per day. A relation was found between the OXTR rs53576 variant and state loneliness, in girls only. Girls carrying an A allele had higher levels of state loneliness than girls carrying the GG genotype. In addition, adolescents with an A allele were more affected by negative perceptions of company than GG carriers, on weekend days only. No significant gene-environment interactions were found with positive company. Adolescents carrying an A allele were more susceptible to negative environments during weekend days than GG carriers. Our findings emphasize the importance of operationalizing the phenotype and the environment accurately. PMID:24223720

  16. MAOA, maltreatment, and gene-environment interaction predicting children's mental health: new evidence and a meta-analysis.

    PubMed

    Kim-Cohen, J; Caspi, A; Taylor, A; Williams, B; Newcombe, R; Craig, I W; Moffitt, T E

    2006-10-01

    Previous research on adults has shown that a functional polymorphism in the promoter region of the monoamine oxidase A (MAOA) gene moderates the impact of childhood maltreatment on risk for developing antisocial behavior. Thus far, attempts to replicate this finding have been mixed. The current study (i) presents new data investigating this finding in a sample of 975 seven-year-old boys, and (ii) evaluates the extant data by conducting a meta-analysis of published findings. We replicated the original finding by showing that the MAOA polymorphism moderates the development of psychopathology after exposure to physical abuse, we extended the finding to childhood closer in time to the maltreatment experience, and we ruled-out the possibility of a spurious finding by accounting for passive and evocative gene-environment correlation. Moreover, meta-analysis demonstrated that across studies, the association between maltreatment and mental health problems is significantly stronger in the group of males with the genotype conferring low vs high MAOA activity. These findings provide the strongest evidence to date suggesting that the MAOA gene influences vulnerability to environmental stress, and that this biological process can be initiated early in life. PMID:16801953

  17. Gene-environment interaction between the MMP9 C-1562T promoter variant and cigarette smoke in the pathogenesis of chronic obstructive pulmonary disease.

    PubMed

    Stankovic, Marija; Kojic, Snezana; Djordjevic, Valentina; Tomovic, Andrija; Nagorni-Obradovic, Ljudmila; Petrovic-Stanojevic, Natasa; Mitic-Milikic, Marija; Radojkovic, Dragica

    2016-07-01

    The aetiology of chronic obstructive pulmonary disease (COPD) is complex. While cigarette smoking is a well-established cause of COPD, a myriad of assessed genetic factors has given conflicting data. Since gene-environment interactions are thought to be implicated in aetiopathogenesis of COPD, we aimed to examine the matrix metalloproteinase (MMP) 9 C-1562T (rs3918242) functional variant and cigarette smoke in the pathogenesis of this disease. The distribution of the MMP9 C-1562T variant was analyzed in COPD patients and controls with normal pulmonary function from Serbia. Interaction between the C-1562T genetic variant and cigarette smoking was assessed using a case-control model. The response of the C-1562T promoter variant to cigarette smoke condensate (CSC) exposure was examined using a dual luciferase reporter assay. The frequency of T allele carriers was higher in the COPD group than in smoker controls (38.4% vs. 20%; OR = 2.7, P = 0.027). Interaction between the T allele and cigarette smoking was identified in COPD occurrence (OR = 4.38, P = 0.005) and severity (P = 0.001). A functional analysis of the C-1562T variant demonstrated a dose-dependent and allele-specific response (P < 0.01) to CSC. Significantly higher MMP9 promoter activity following CSC exposure was found for the promoter harboring the T allele compared to the promoter harboring the C allele (P < 0.05). Our study is the first to reveal an interaction between the MMP9-1562T allele and cigarette smoke in COPD, emphasising gene-environment interactions as a possible cause of lung damage in the pathogenesis of COPD. Environ. Mol. Mutagen. 57:447-454, 2016. © 2016 Wiley Periodicals, Inc. PMID:27270564

  18. The role of 5-HTT LPR and GNβ3 825C>T polymorphisms and gene-environment interactions in irritable bowel syndrome (IBS)

    PubMed Central

    Saito, Yuri A.; Larson, Joseph J.; Atkinson, Elizabeth J.; Ryu, Euijung; Almazar, Ann E.; Petersen, Gloria M.; Talley, Nicholas J.

    2014-01-01

    Background Smaller studies have evaluated SLC6A4 5-HTTLPR and GNβ3 825C>T polymorphisms in IBS, and interactions between 5-HTT LPR with life events have been reported in the psychiatric literature, but gene-environment studies in IBS are lacking. Aims To assess the association of two polymorphisms with IBS and age of onset; and to assess whether there are gene-environment interactions with IBS. Methods Outpatients with IBS and controls completed a validated questionnaire and provided blood for DNA. Comparisons of genotype/allele frequencies between cases and controls were performed with logistic regression. Linear regression was used to evaluate the association between the variants and age of onset. Environmental variables tested included abuse, parental alcohol abuse, parental psychiatric disorders, and gastrointestinal infections. Results Genotyping was performed in 385 cases and 262 controls with median age of 50 yrs (range: 18.0–70.0) and 498 (77%) females. The IBS subtype distribution among cases was: 102 (26%) D-IBS, 40 (10%) C-IBS, 125 (32%) M-IBS, 118 (31%) other. No association was observed between IBS or age of onset and both variants. Significant interactions were observed between GI infection and the GNβ3 825T allele. For those reporting gastrointestinal infection, the OR for IBS was 3.9 (95%CI: 1.2–12.7) whereas the OR was 0.86 (95% CI: 0.65–1.13) for those without prior infection. Conclusions There was a significant interaction between the GNβ3 polymorphism and infection in the development of IBS, suggesting that its etiology is the result of a combination of specific genetic and environmental risk factors. PMID:22855291

  19. Development of a Genotyping Microarray for Studying the Role of Gene-Environment Interactions in Risk for Lung Cancer

    PubMed Central

    Baldwin, Don A.; Sarnowski, Christopher P.; Reddy, Sabrina A.; Blair, Ian A.; Clapper, Margie; Lazarus, Philip; Li, Mingyao; Muscat, Joshua E.; Penning, Trevor M.; Vachani, Anil; Whitehead, Alexander S.

    2013-01-01

    A microarray (LungCaGxE), based on Illumina BeadChip technology, was developed for high-resolution genotyping of genes that are candidates for involvement in environmentally driven aspects of lung cancer oncogenesis and/or tumor growth. The iterative array design process illustrates techniques for managing large panels of candidate genes and optimizing marker selection, aided by a new bioinformatics pipeline component, Tagger Batch Assistant. The LungCaGxE platform targets 298 genes and the proximal genetic regions in which they are located, using ∼13,000 DNA single nucleotide polymorphisms (SNPs), which include haplotype linkage markers with a minimum allele frequency of 1% and additional specifically targeted SNPs, for which published reports have indicated functional consequences or associations with lung cancer or other smoking-related diseases. The overall assay conversion rate was 98.9%; 99.0% of markers with a minimum Illumina design score of 0.6 successfully generated allele calls using genomic DNA from a study population of 1873 lung-cancer patients and controls. PMID:24294113

  20. Gene-Gene and Gene-Environment Interactions Involving HLA-DRB1, PTPN22, and Smoking in Two Subsets of Rheumatoid Arthritis

    PubMed Central

    Källberg, Henrik; Padyukov, Leonid; Plenge, Robert M.; Rönnelid, Johan; Gregersen, Peter K.; van der Helm-van Mil, Annette H. M.; Toes, Rene E. M.; Huizinga, Tom W.; Klareskog, Lars; Alfredsson, Lars

    2007-01-01

    Gene-gene and gene-environment interactions are key features in the development of rheumatoid arthritis (RA) and other complex diseases. The aim of this study was to use and compare three different definitions of interaction between the two major genetic risk factors of RA—the HLA-DRB1 shared epitope (SE) alleles and the PTPN22 R620W allele—in three large case-control studies: the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study, the North American RA Consortium (NARAC) study, and the Dutch Leiden Early Arthritis Clinic study (in total, 1,977 cases and 2,405 controls). The EIRA study was also used to analyze interactions between smoking and the two genes. “Interaction” was defined either as a departure from additivity, as interaction in a multiplicative model, or in terms of linkage disequilibrium—for example, deviation from independence of penetrance of two unlinked loci. Consistent interaction, defined as departure from additivity, between HLA-DRB1 SE alleles and the A allele of PTPN22 R620W was seen in all three studies regarding anti-CCP–positive RA. Testing for multiplicative interactions demonstrated an interaction between the two genes only when the three studies were pooled. The linkage disequilibrium approach indicated a gene-gene interaction in EIRA and NARAC, as well as in the pooled analysis. No interaction was seen between smoking and PTPN22 R620W. A new pattern of interactions is described between the two major known genetic risk factors and the major environmental risk factor concerning the risk of developing anti-CCP–positive RA. The data extend the basis for a pathogenetic hypothesis for RA involving genetic and environmental factors. The study also raises and illustrates principal questions concerning ways to define interactions in complex diseases. PMID:17436241

  1. Aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 1B (ADH1B) polymorphisms exacerbate bladder cancer risk associated with alcohol drinking: gene-environment interaction.

    PubMed

    Masaoka, Hiroyuki; Ito, Hidemi; Soga, Norihito; Hosono, Satoyo; Oze, Isao; Watanabe, Miki; Tanaka, Hideo; Yokomizo, Akira; Hayashi, Norio; Eto, Masatoshi; Matsuo, Keitaro

    2016-06-01

    Although a range of chemical exposures (cigarette smoking and occupational exposure) are recognized risk factors for the development of bladder cancer (BCa), many epidemiological studies have demonstrated that alcohol drinking is not associated with BCa risk. Aldehyde dehydrogenase 2 (ALDH2; rs671, Glu504Lys) and alcohol dehydrogenase 1B (ADH1B; rs1229984, His47Arg) polymorphisms impact the accumulation of acetaldehyde, resulting in an increased risk of various cancers. To date, however, no studies evaluating the association between BCa risk and alcohol drinking have considered these polymorphisms. Here, we conducted a matched case-control study to investigate whether ALDH2 and ADH1B polymorphisms influence BCa risk associated with alcohol drinking. Cases were 74 BCa patients and controls were 740 first-visit outpatients without cancer at Aichi Cancer Center Hospital between January 2001 and December 2005. Odds ratio (OR), 95% confidence interval (CI) and gene-environment interaction were assessed by conditional logistic regression analysis with adjustment for potential confounders. Results showed that ALDH2 Glu/Lys was associated with a significantly increased risk of BCa compared with Glu/Glu (OR 2.03, 95% CI 1.14-3.62, P = 0.017). In contrast, ALDH2 Glu/Lys showed no increase in risk among the stratum of never drinkers compared with Glu/Glu, indicating a gene-environment interaction. ADH1B His/Arg had an OR of 1.98 (1.20-3.24, P = 0.007) compared with His/His. ADH1B Arg+ showed a similar OR and 95% CI. Individuals with ALDH2 Glu/Lys and ADH1B Arg+ had the highest risk of BCa compared with ALDH2 Glu/Glu and ADH1B His/His [OR 4.00 (1.81-8.87), P = 0.001]. PMID:26992901

  2. Gene Polymorphism Association with Type 2 Diabetes and Related Gene-Gene and Gene-Environment Interactions in a Uyghur Population.

    PubMed

    Xiao, Shan; Zeng, Xiaoyun; Fan, Yong; Su, Yinxia; Ma, Qi; Zhu, Jun; Yao, Hua

    2016-01-01

    BACKGROUND We investigated the association between 8 single-nucleotide polymorphisms (SNPs) at 3 genetic loci (CDKAL1, CDKN2A/2B and FTO) with type 2 diabetes (T2D) in a Uyghur population. MATERIAL AND METHODS A case-control study of 879 Uyghur patients with T2D and 895 non-diabetic Uyghur controls was conducted at the Hospital of Xinjiang Medical University between 2010 and 2013. Eight SNPs in CDKAL1, CDKN2A/2B and FTO were analyzed using Sequenom MassARRAY®SNP genotyping. Factors associated with T2D were assessed by logistic regression analyses. Gene-gene and gene-environment interactions were analyzed by generalized multifactor dimensionality reduction. RESULTS Genotype distributions of rs10811661 (CDKN2A/2B), rs7195539, rs8050136, and rs9939609 (FTO) and allele frequencies of rs8050136 and rs9939609 differed significantly between diabetes and control groups (all P<0.05). While rs10811661, rs8050136, and rs9939609 were eliminated after adjusting for covariates (P>0.05), rs7195539 distribution differed significantly in co-dominant and dominant models (P<0.05). In gene-gene interaction analysis, after adjusting for covariates the two-locus rs10811661-rs7195539 interaction model had a cross-validation consistency of 10/10 and the highest balanced accuracy of 0.5483 (P=0.014). In gene-environment interaction analysis, the 3-locus interaction model TG-HDL-family history of diabetes had a cross-validation consistency of 10/10 and the highest balanced accuracy of 0.7072 (P<0.001). The 4-locus interaction model, rs7195539-TG-HDL-family history of diabetes had a cross-validation consistency of 8/10 (P<0.001). CONCLUSIONS Polymorphisms in CDKN2A/2B and FTO, but not CDKAL1, may be associated with T2D, and alleles rs8050136 and rs9939609 are likely risk alleles for T2D in this population. There were potential interactions among CDKN2A/2B (rs10811661) - FTO (rs7195539) or FTO (rs7195539)-TG-HDL-family history of diabetes in the pathogenesis of T2D in a Uyghur population

  3. Gene Polymorphism Association with Type 2 Diabetes and Related Gene-Gene and Gene-Environment Interactions in a Uyghur Population

    PubMed Central

    Xiao, Shan; Zeng, Xiaoyun; Fan, Yong; Su, Yinxia; Ma, Qi; Zhu, Jun; Yao, Hua

    2016-01-01

    Background We investigated the association between 8 single-nucleotide polymorphisms (SNPs) at 3 genetic loci (CDKAL1, CDKN2A/2B and FTO) with type 2 diabetes (T2D) in a Uyghur population. Material/Methods A case-control study of 879 Uyghur patients with T2D and 895 non-diabetic Uyghur controls was conducted at the Hospital of Xinjiang Medical University between 2010 and 2013. Eight SNPs in CDKAL1, CDKN2A/2B and FTO were analyzed using Sequenom MassARRAY®SNP genotyping. Factors associated with T2D were assessed by logistic regression analyses. Gene-gene and gene-environment interactions were analyzed by generalized multifactor dimensionality reduction. Results Genotype distributions of rs10811661 (CDKN2A/2B), rs7195539, rs8050136, and rs9939609 (FTO) and allele frequencies of rs8050136 and rs9939609 differed significantly between diabetes and control groups (all P<0.05). While rs10811661, rs8050136, and rs9939609 were eliminated after adjusting for covariates (P>0.05), rs7195539 distribution differed significantly in co-dominant and dominant models (P<0.05). In gene-gene interaction analysis, after adjusting for covariates the two-locus rs10811661-rs7195539 interaction model had a cross-validation consistency of 10/10 and the highest balanced accuracy of 0.5483 (P=0.014). In gene-environment interaction analysis, the 3-locus interaction model TG-HDL-family history of diabetes had a cross-validation consistency of 10/10 and the highest balanced accuracy of 0.7072 (P<0.001). The 4-locus interaction model, rs7195539-TG-HDL-family history of diabetes had a cross-validation consistency of 8/10 (P<0.001). Conclusions Polymorphisms in CDKN2A/2B and FTO, but not CDKAL1, may be associated with T2D, and alleles rs8050136 and rs9939609 are likely risk alleles for T2D in this population. There were potential interactions among CDKN2A/2B (rs10811661) – FTO (rs7195539) or FTO (rs7195539)-TG-HDL-family history of diabetes in the pathogenesis of T2D in a Uyghur population. PMID

  4. Epistasis-list.org: A Curated Database of Gene-Gene and Gene-Environment Interactions in Human Epidemiology

    EPA Science Inventory

    The field of human genetics has experienced a paradigm shift in that common diseases are now thought to be due to the complex interactions among numerous genetic and environmental factors. This paradigm shift has prompted the development of myriad novel methods to detect such int...

  5. An investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors

    PubMed Central

    Rudolph, Anja; Milne, Roger L.; Truong, Thérèse; Knight, Julia A.; Seibold, Petra; Flesch-Janys, Dieter; Behrens, Sabine; Eilber, Ursula; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Dunning, Alison M.; Shah, Mitul; Munday, Hannah R.; Darabi, Hatef; Eriksson, Mikael; Brand, Judith S.; Olson, Janet; Vachon, Celine M.; Hallberg, Emily; Castelao, J. Esteban; Carracedo, Angel; Torres, Maria; Li, Jingmei; Humphreys, Keith; Cordina-Duverger, Emilie; Menegaux, Florence; Flyger, Henrik; Nordestgaard, Børge G.; Nielsen, Sune F.; Yesilyurt, Betul T.; Floris, Giuseppe; Leunen, Karin; Engelhardt, Ellen G.; Broeks, Annegien; Rutgers, Emiel J.; Glendon, Gord; Mulligan, Anna Marie; Cross, Simon; Reed, Malcolm; Gonzalez-Neira, Anna; Perez, José Ignacio Arias; Provenzano, Elena; Apicella, Carmel; Southey, Melissa C.; Spurdle, Amanda; Investigators, kConFab; Group, AOCS; Häberle, Lothar; Beckmann, Matthias W.; Ekici, Arif B.; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; McLean, Catriona; Baglietto, Laura; Chanock, Stephen J.; Lissowska, Jolanta; Sherman, Mark E.; Brüning, Thomas; Hamann, Ute; Ko, Yon-Dschun; Orr, Nick; Schoemaker, Minouk; Ashworth, Alan; Kosma, Veli-Matti; Kataja, Vesa; Hartikainen, Jaana M.; Mannermaa, Arto; Swerdlow, Anthony; Giles, Graham G.; Brenner, Hermann; Fasching, Peter A.; Chenevix-Trench, Georgia; Hopper, John; Benítez, Javier; Cox, Angela; Andrulis, Irene L.; Lambrechts, Diether; Gago-Dominguez, Manuela; Couch, Fergus; Czene, Kamila; Bojesen, Stig E.; Easton, Doug F.; Schmidt, Marjanka K.; Guénel, Pascal; Hall, Per; Pharoah, Paul D. P.; Garcia-Closas, Montserrat; Chang-Claude, Jenny

    2014-01-01

    A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator. Six SNPs showed interactions with associated p-values (pint) <1.1×10−3. None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER-negative BC risk in women ≥170cm (OR=1.22, p=0.017), but inversely associated with ER-negative BC risk in women <160cm (OR=0.83, p=0.039, pint=1.9×10−4). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR=0.85, p=2.0×10−4), and absent in women who had had just one (OR=0.96, p=0.19, pint = 6.1×10−4). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR=0.93, p=2.8×10−5), but no association was observed in current smokers (OR=1.07, p=0.14, pint = 3.4×10−4). In conclusion, recently identified breast cancer susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies. PMID:25227710

  6. Investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors.

    PubMed

    Rudolph, Anja; Milne, Roger L; Truong, Thérèse; Knight, Julia A; Seibold, Petra; Flesch-Janys, Dieter; Behrens, Sabine; Eilber, Ursula; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Dunning, Alison M; Shah, Mitul; Munday, Hannah R; Darabi, Hatef; Eriksson, Mikael; Brand, Judith S; Olson, Janet; Vachon, Celine M; Hallberg, Emily; Castelao, J Esteban; Carracedo, Angel; Torres, Maria; Li, Jingmei; Humphreys, Keith; Cordina-Duverger, Emilie; Menegaux, Florence; Flyger, Henrik; Nordestgaard, Børge G; Nielsen, Sune F; Yesilyurt, Betul T; Floris, Giuseppe; Leunen, Karin; Engelhardt, Ellen G; Broeks, Annegien; Rutgers, Emiel J; Glendon, Gord; Mulligan, Anna Marie; Cross, Simon; Reed, Malcolm; Gonzalez-Neira, Anna; Arias Perez, José Ignacio; Provenzano, Elena; Apicella, Carmel; Southey, Melissa C; Spurdle, Amanda; Häberle, Lothar; Beckmann, Matthias W; Ekici, Arif B; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; McLean, Catriona; Baglietto, Laura; Chanock, Stephen J; Lissowska, Jolanta; Sherman, Mark E; Brüning, Thomas; Hamann, Ute; Ko, Yon-Dschun; Orr, Nick; Schoemaker, Minouk; Ashworth, Alan; Kosma, Veli-Matti; Kataja, Vesa; Hartikainen, Jaana M; Mannermaa, Arto; Swerdlow, Anthony; Giles, Graham G; Brenner, Hermann; Fasching, Peter A; Chenevix-Trench, Georgia; Hopper, John; Benítez, Javier; Cox, Angela; Andrulis, Irene L; Lambrechts, Diether; Gago-Dominguez, Manuela; Couch, Fergus; Czene, Kamila; Bojesen, Stig E; Easton, Doug F; Schmidt, Marjanka K; Guénel, Pascal; Hall, Per; Pharoah, Paul D P; Garcia-Closas, Montserrat; Chang-Claude, Jenny

    2015-03-15

    A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator. Six SNPs showed interactions with associated p-values (pint ) <1.1 × 10(-3) . None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER-negative BC risk in women ≥170 cm (OR = 1.22, p = 0.017), but inversely associated with ER-negative BC risk in women <160 cm (OR = 0.83, p = 0.039, pint = 1.9 × 10(-4) ). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR = 0.85, p = 2.0 × 10(-4) ), and absent in women who had had just one (OR = 0.96, p = 0.19, pint = 6.1 × 10(-4) ). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR = 0.93, p = 2.8 × 10(-5) ), but no association was observed in current smokers (OR = 1.07, p = 0.14, pint = 3.4 × 10(-4) ). In conclusion, recently identified BC susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies. PMID:25227710

  7. The Influence of Gene-Environment Interactions on Alcohol Consumption and Alcohol Use Disorders: A Comprehensive Review

    PubMed Central

    Young-Wolff, Kelly C.; Enoch, Mary-Anne; Prescott, Carol A.

    2011-01-01

    Since 2005, a rapidly expanding literature has evaluated whether environmental factors such as socio-cultural context and environmental adversity interact with genetic influences on drinking behaviors. This article critically reviews empirical research on alcohol-related genotype-environment interactions (GxE) and provides a contextual framework for understanding how genetic factors combine with (or are shaped by) environmental influences to influence the development of drinking behaviors and alcohol use disorders. Collectively, evidence from twin, adoption, and molecular genetic studies indicates that the degree of importance of genetic influences on risk for drinking outcomes can vary in different populations and under different environmental circumstances. However, methodological limitations and lack of consistent replications in this literature make it difficult to draw firm conclusions regarding the nature and effect size of alcohol-related GxE. On the basis of this review, we describe several methodological challenges as they relate to current research on GxE in drinking behaviors and provide recommendations to aid future research. PMID:21530476

  8. Gene/environment interactions in the pathogenesis of autoimmunity: new insights on the role of Toll-like receptors.

    PubMed

    Gianchecchi, Elena; Fierabracci, Alessandra

    2015-11-01

    Autoimmune disorders are increasing worldwide. Although their pathogenesis has not been elucidated yet, a complex interaction of genetic and environmental factors is involved in their onset. Toll-like receptors (TLRs) represent a family of pattern recognition receptors involved in the recognition and in the defense of the host from invading microorganisms. They sense a wide range of pathogen associated molecular patterns (PAMPs) deriving from metabolic pathways selective of bacterial, viral, fungal and protozoan microorganisms. TLR activation plays a critical role in the activation of the downstream signaling pathway by interacting and recruiting several adaptor molecules. Although TLRs are involved in the protection of the host, several studies suggest that, in certain conditions, they play a critical role in the pathogenesis of autoimmune diseases. We review the most recent advances showing a correlation between some single nucleotide polymorphisms or copy number variations in TLR genes or in adaptor molecules involved in TLR signaling and the onset of several autoimmune conditions, such as Type I diabetes, autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy, rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis. In light of the foregoing we finally propose that molecules involved in TLR pathway may represent the targets for novel therapeutic treatments in order to stop autoimmune processes. PMID:26184547

  9. Gene-environment interactions in human health: case studies and strategies for developing new paradigms and research methodologies.

    PubMed

    Jackson, Fatimah L C

    2014-01-01

    THE SYNERGISTIC EFFECTS OF GENES AND THE ENVIRONMENT ON HEALTH ARE EXPLORED IN THREE CASE STUDIES: adult lactase persistence, autism spectrum disorders, and the metabolic syndrome, providing examples of the interactive complexities underlying these phenotypes. Since the phenotypes are the initial targets of evolutionary processes, understanding the specific environmental contexts of the genetic, epigenetic, and environmental changes associated with these phenotypes is essential in predicting their health implications. Robust databases must be developed on the local scale to deconstruct both the population substructure and the unique components of the environment that stimulate geographically specific changes in gene expression patterns. To produce these databases and make valid predictions, new, locally focused, and information-dense models are needed that incorporate data on evolutionary ecology, environmental complexity, local geographic patterns of gene expression, and population substructure. PMID:25221564

  10. Conceptual Shifts Needed to Understand the Dynamic Interactions of Genes, Environment, Epigenetics, Social Processes, and Behavioral Choices

    PubMed Central

    Niculescu, Mihai D.; Jackson, Robert T.

    2013-01-01

    Social and behavioral research in public health is often intimately tied to profound, but frequently neglected, biological influences from underlying genetic, environmental, and epigenetic events. The dynamic interplay between the life, social, and behavioral sciences often remains underappreciated and underutilized in addressing complex diseases and disorders and in developing effective remediation strategies. Using a case-study format, we present examples as to how the inclusion of genetic, environmental, and epigenetic data can augment social and behavioral health research by expanding the parameters of such studies, adding specificity to phenotypic assessments, and providing additional internal control in comparative studies. We highlight the important roles of gene–environment interactions and epigenetics as sources of phenotypic change and as a bridge between the life and social and behavioral sciences in the development of robust interdisciplinary analyses. PMID:23927503

  11. A Twin and Adoption Study of Reading Achievement: Exploration of Shared-Environmental and Gene-Environment-Interaction Effects.

    PubMed

    Kirkpatrick, Robert M; Legrand, Lisa N; Iacono, William G; McGue, Matt

    2011-08-01

    Existing behavior-genetic research implicates substantial influence of heredity and modest influence of shared environment on reading achievement and reading disability. Applying DeFries-Fulker analysis to a combined sample of twins and adoptees (N = 4,886, including 266 reading-disabled probands), the present study replicates prior findings of considerable heritability for both reading achievement and reading disability. A simple biometric model adequately described parent and offspring data (combined N = 9,430 parents and offspring) across differing types of families present in the sample Analyses yielded a high heritability estimate (around 0.70) and a negligible shared-environmentality estimate for both reading achievement and reading disability. No evidence of gene × environment interaction was found for parental reading ability and parental educational attainment, the two moderators analyzed. PMID:21743785

  12. A Twin and Adoption Study of Reading Achievement: Exploration of Shared-Environmental and Gene-Environment-Interaction Effects

    PubMed Central

    Kirkpatrick, Robert M.; Legrand, Lisa N.; Iacono, William G.; McGue, Matt

    2011-01-01

    Existing behavior-genetic research implicates substantial influence of heredity and modest influence of shared environment on reading achievement and reading disability. Applying DeFries-Fulker analysis to a combined sample of twins and adoptees (N = 4,886, including 266 reading-disabled probands), the present study replicates prior findings of considerable heritability for both reading achievement and reading disability. A simple biometric model adequately described parent and offspring data (combined N = 9,430 parents and offspring) across differing types of families present in the sample Analyses yielded a high heritability estimate (around 0.70) and a negligible shared-environmentality estimate for both reading achievement and reading disability. No evidence of gene × environment interaction was found for parental reading ability and parental educational attainment, the two moderators analyzed. PMID:21743785

  13. Have studies of the developmental regulation of behavioral phenotypes revealed the mechanisms of gene-environment interactions?

    PubMed Central

    Hall, F. Scott; Perona, Maria T. G.

    2012-01-01

    This review addresses the recent convergence of our long-standing knowledge of the regulation of behavioral phenotypes by developmental experience with recent advances in our understanding of mechanisms regulating gene expression. This review supports a particular perspective on the developmental regulation of behavioral phenotypes: That the role of common developmental experiences (e.g. maternal interactions, peer interactions, exposure to a complex environment, etc.) is to fit individuals to the circumstances of their lives within bounds determined by long-standing (evolutionary) mechanisms that have shaped responses to critical and fundamental types of experience via those aspects of gene structure that regulate gene expression. The phenotype of a given species is not absolute for a given genotype but rather variable within bounds that are determined by mechanisms regulated by experience (e.g. epigenetic mechanisms). This phenotypic variation is not necessarily random, or evenly distributed along a continuum of description or measurement, but often highly disjointed, producing distinct, even opposing, phenotypes. The potentiality for these varying phenotypes is itself the product of evolution, the potential for alternative phenotypes itself conveying evolutionary advantage. Examples of such phenotypic variation, resulting from environmental or experiential influences, have a long history of study in neurobiology, and a number of these will be discussed in this review: neurodevelopmental experiences that produce phenotypic variation in visual perception, cognitive function, and emotional behavior. Although other examples will be discussed, particular emphasis will be made on the role of social behavior on neurodevelopment and phenotypic determination. It will be argued that an important purpose of some aspects of social behavior is regulation of neurobehavioral phenotypes by experience via genetic regulatory mechanisms. PMID:22643448

  14. Gene--environment interactions influence feeding and anti-predator behavior in wild and transgenic coho salmon.

    PubMed

    Sundström, L F; Löhmus, M; Devlin, R H

    2016-01-01

    Environmental conditions are known to affect phenotypic development in many organisms, making the characteristics of an animal reared under one set of conditions not always representative of animals reared under a different set of conditions. Previous results show that such plasticity can also affect the phenotypes and ecological interactions of different genotypes, including animals anthropogenically generated by genetic modification. To understand how plastic development can affect behavior in animals of different genotypes, we examined the feeding and risk-taking behavior in growth-enhanced transgenic coho salmon (with two- to threefold enhanced daily growth rates compared to wild type) under a range of conditions. When compared to wild-type siblings, we found clear effects of the rearing environment on feeding and risk-taking in transgenic animals and noted that in some cases, this environmental effect was stronger than the effects of the genetic modification. Generally, transgenic fish, regardless of rearing conditions, behaved similar to wild-type fish reared under natural-like conditions. Instead, the more unusual phenotype was associated with wild-type fish reared under hatchery conditions, which possessed an extreme risk averse phenotype compared to the same strain reared in naturalized conditions. Thus, the relative performance of genotypes from one environment (e.g., laboratory) may not always accurately reflect ecological interactions as would occur in a different environment (e.g., nature). Further, when assessing risks of genetically modified organisms, it is important to understand how the environment affects phenotypic development, which in turn may variably influence consequences to ecosystem components across different conditions found in the complexity of nature. PMID:27039510

  15. Have studies of the developmental regulation of behavioral phenotypes revealed the mechanisms of gene-environment interactions?

    PubMed

    Hall, F Scott; Perona, Maria T G

    2012-12-01

    This review addresses the recent convergence of our long-standing knowledge of the regulation of behavioral phenotypes by developmental experience with recent advances in our understanding of mechanisms regulating gene expression. This review supports a particular perspective on the developmental regulation of behavioral phenotypes: That the role of common developmental experiences (e.g. maternal interactions, peer interactions, exposure to a complex environment, etc.) is to fit individuals to the circumstances of their lives within bounds determined by long-standing (evolutionary) mechanisms that have shaped responses to critical and fundamental types of experience via those aspects of gene structure that regulate gene expression. The phenotype of a given species is not absolute for a given genotype but rather variable within bounds that is determined by mechanisms regulated by experience (e.g. epigenetic mechanisms). This phenotypic variation is not necessarily random, or evenly distributed along a continuum of description or measurement, but often highly disjointed, producing distinct, even opposing, phenotypes. The potentiality for these varying phenotypes is itself the product of evolution, the potential for alternative phenotypes itself conveying evolutionary advantage. Examples of such phenotypic variation, resulting from environmental or experiential influences, have a long history of study in neurobiology, and a number of these will be discussed in this review: neurodevelopmental experiences that produce phenotypic variation in visual perception, cognitive function, and emotional behavior. Although other examples will be discussed, particular emphasis will be made on the role of social behavior on neurodevelopment and phenotypic determination. It will be argued that an important purpose of some aspects of social behavior is regulation of neurobehavioral phenotypes by experience via genetic regulatory mechanisms. PMID:22643448

  16. Neurobehavioral Integrity of Chimpanzee Newborns: Comparisons across groups and across species reveal gene-environment interaction effects

    PubMed Central

    Bard, Kim A.; Brent, Linda; Lester, Barry; Worobey, John; Suomi, Stephen J.

    2014-01-01

    The aims of this article are to describe the neurobehavioral integrity of chimpanzee newborns, to investigate how early experiences affect the neurobehavioral organization of chimpanzees, and to explore species differences by comparing chimpanzee newborns to a group of typically developing human newborns. Neurobehavioral integrity related to orientation, motor performance, arousal, and state regulation of 55 chimpanzee (raised in four different settings) and 42 human newborns was measured with the Neonatal Behavioral Assessment Scale (NBAS) a semi-structured 25-minute interactive assessment. Thirty-eight chimpanzees were tested every other day from birth, and analyses revealed significant developmental changes in 19 of 27 NBAS scores. The cross-group and cross-species comparisons were conducted at 2 and 30 days of age. Among the 4 chimpanzee groups, significant differences were found in 23 of 24 NBAS scores. Surprisingly, the cross-species comparisons revealed that the human group was distinct in only 1 of 25 NBAS scores (the human group had significantly less muscle tone than all the chimpanzee groups). The human group was indistinguishable from at least one of the chimpanzee groups in the remaining 24 of 25 NBAS scores. The results of this study support the conclusion that the interplay between genes and environment, rather than genes alone or environment alone, accounts for phenotypic expressions of newborn neurobehavioral integrity in hominids. PMID:25110465

  17. Gene-environment interactions in male reproductive health: Special reference to the aryl hydrocarbon receptor signaling pathway

    PubMed Central

    Brokken, Leon J S; Giwercman, Yvonne Lundberg

    2014-01-01

    Over the last few decades, there have been numerous reports of adverse effects on the reproductive health of wildlife and laboratory animals caused by exposure to endocrine disrupting chemicals (EDCs). The increasing trends in human male reproductive disorders and the mounting evidence for causative environmental factors have therefore sparked growing interest in the health threat posed to humans by EDCs, which are substances in our food, environment and consumer items that interfere with hormone action, biosynthesis or metabolism, resulting in disrupted tissue homeostasis or reproductive function. The mechanisms of EDCs involve a wide array of actions and pathways. Examples include the estrogenic, androgenic, thyroid and retinoid pathways, in which the EDCs may act directly as agonists or antagonists, or indirectly via other nuclear receptors. Dioxins and dioxin-like EDCs exert their biological and toxicological actions through activation of the aryl hydrocarbon-receptor, which besides inducing transcription of detoxifying enzymes also regulates transcriptional activity of other nuclear receptors. There is increasing evidence that genetic predispositions may modify the susceptibility to adverse effects of toxic chemicals. In this review, potential consequences of hereditary predisposition and EDCs are discussed, with a special focus on the currently available publications on interactions between dioxin and androgen signaling. PMID:24369137

  18. Environmental and genetic risk factors and gene-environment interactions in the pathogenesis of chronic obstructive lung disease.

    PubMed Central

    Walter, R; Gottlieb, D J; O'Connor, G T

    2000-01-01

    Current understanding of the pathogenesis of chronic obstructive pulmonary disease (COPD), a source of substantial morbidity and mortality in the United States, suggests that chronic inflammation leads to the airways obstruction and parenchymal destruction that characterize this condition. Environmental factors, especially tobacco smoke exposure, are known to accelerate longitudinal decline of lung function, and there is substantial evidence that upregulation of inflammatory pathways plays a vital role in this process. Genetic regulation of both inflammatory responses and anti-inflammatory protective mechanisms likely underlies the heritability of COPD observed in family studies. In alpha-1 protease inhibitor deficiency, the only genetic disorder known to cause COPD, lack of inhibition of elastase activity, results in the parenchymal destruction of emphysema. Other genetic polymorphisms have been hypothesized to alter the risk of COPD but have not been established as causes of this condition. It is likely that multiple genetic factors interacting with each other and with a number of environmental agents will be found to result in the development of COPD. PMID:10931792

  19. Depression and the serotonin transporter 5-HTTLPR polymorphism: a review and a hypothesis concerning gene-environment interaction.

    PubMed

    Brown, George W; Harris, Tirril O

    2008-11-01

    Studies of the interaction of the serotonin transporter genotype and environment upon adult depression (G x E) have suggested a role for both childhood maltreatment and stressful life events. This paper deals with two main issues. First, do both contribute? Evidence that G x E with childhood maltreatment plays a role is much stronger than that for G x E with life events occurring close to onset, although that for G x E with life events occurring over a 5-year period before the presence of the recorded depression is stronger. However, non-genetic research shows that life events occurring so long before onset as 5 years have little or no relationship with adult depression once childhood maltreatment is taken into account, suggesting they serve as a marker for childhood maltreatment rather than making a direct contribution to G x E. Second, genetic research has dealt only with the presence of depression and taking account of course may radically change ideas about the point at which G x E occurs. Two findings from non-genetic research concerning childhood maltreatment are relevant. Childhood maltreatment is associated with a particularly high risk of an adult onset of depression taking a chronic course (i.e. lasting 12 months or more). Moreover such maltreatment makes a substantial direct contribution - i.e. its link with course is independent of all other childhood and adult risk factors. This is consistent with early changes in brain function associated with the polymorphism in the context of childhood maltreatment explaining the link of such maltreatment with adult chronic episodes. It also follows that restricting analysis to such episodes would increase current estimates of G x E. PMID:18534686

  20. Arsenic metabolism efficiency has a causal role in arsenic toxicity: Mendelian randomization and gene-environment interaction

    PubMed Central

    Pierce, Brandon L; Tong, Lin; Argos, Maria; Gao, Jianjun; Jasmine, Farzana; Roy, Shantanu; Paul-Brutus, Rachelle; Rahaman, Ronald; Rakibuz-Zaman, Muhammad; Parvez, Faruque; Ahmed, Alauddin; Quasem, Iftekhar; Hore, Samar K; Alam, Shafiul; Islam, Tariqul; Harjes, Judith; Sarwar, Golam; Slavkovich, Vesna; Gamble, Mary V; Chen, Yu; Yunus, Mohammad; Rahman, Mahfuzar; Baron, John A; Graziano, Joseph H; Ahsan, Habibul

    2013-01-01

    Background Arsenic exposure through drinking water is a serious global health issue. Observational studies suggest that individuals who metabolize arsenic efficiently are at lower risk for toxicities such as arsenical skin lesions. Using two single nucleotide polymorphisms (SNPs) in the 10q24.32 region (near AS3MT) that show independent associations with metabolism efficiency, Mendelian randomization can be used to assess whether the association between metabolism efficiency and skin lesions is likely to be causal. Methods Using data on 2060 arsenic-exposed Bangladeshi individuals, we estimated associations for two 10q24.32 SNPs with relative concentrations of three urinary arsenic species (representing metabolism efficiency): inorganic arsenic (iAs), monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). SNP-based predictions of iAs%, MMA% and DMA% were tested for association with skin lesion status among 2483 cases and 2857 controls. Results Causal odds ratios for skin lesions were 0.90 (95% confidence interval [CI]: 0.87, 0.95), 1.19 (CI: 1.10, 1.28) and 1.23 (CI: 1.12, 1.36) for a one standard deviation increase in DMA%, MMA% and iAs%, respectively. We demonstrated genotype-arsenic interaction, with metabolism-related variants showing stronger associations with skin lesion risk among individuals with high arsenic exposure (synergy index: 1.37; CI: 1.11, 1.62). Conclusions We provide strong evidence for a causal relationship between arsenic metabolism efficiency and skin lesion risk. Mendelian randomization can be used to assess the causal role of arsenic exposure and metabolism in a wide array of health conditions. Developing interventions that increase arsenic metabolism efficiency are likely to reduce the impact of arsenic exposure on health. PMID:24536095

  1. Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium.

    PubMed

    Fan, Qiao; Guo, Xiaobo; Tideman, J Willem L; Williams, Katie M; Yazar, Seyhan; Hosseini, S Mohsen; Howe, Laura D; Pourcain, Beaté St; Evans, David M; Timpson, Nicholas J; McMahon, George; Hysi, Pirro G; Krapohl, Eva; Wang, Ya Xing; Jonas, Jost B; Baird, Paul Nigel; Wang, Jie Jin; Cheng, Ching-Yu; Teo, Yik-Ying; Wong, Tien-Yin; Ding, Xiaohu; Wojciechowski, Robert; Young, Terri L; Pärssinen, Olavi; Oexle, Konrad; Pfeiffer, Norbert; Bailey-Wilson, Joan E; Paterson, Andrew D; Klaver, Caroline C W; Plomin, Robert; Hammond, Christopher J; Mackey, David A; He, Mingguang; Saw, Seang-Mei; Williams, Cathy; Guggenheim, Jeremy A

    2016-01-01

    Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04). PMID:27174397

  2. Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium

    PubMed Central

    Fan, Qiao; Guo, Xiaobo; Tideman, J. Willem L.; Williams, Katie M.; Yazar, Seyhan; Hosseini, S. Mohsen; Howe, Laura D.; Pourcain, Beaté St; Evans, David M.; Timpson, Nicholas J.; McMahon, George; Hysi, Pirro G.; Krapohl, Eva; Wang, Ya Xing; Jonas, Jost B.; Baird, Paul Nigel; Wang, Jie Jin; Cheng, Ching-Yu; Teo, Yik-Ying; Wong, Tien-Yin; Ding, Xiaohu; Wojciechowski, Robert; Young, Terri L.; Pärssinen, Olavi; Oexle, Konrad; Pfeiffer, Norbert; Bailey-Wilson, Joan E.; Paterson, Andrew D.; Klaver, Caroline C. W.; Plomin, Robert; Hammond, Christopher J.; Mackey, David A.; He, Mingguang; Saw, Seang-Mei; Williams, Cathy; Guggenheim, Jeremy A.; Meguro, Akira; Wright, Alan F.; Hewitt, Alex W.; Young, Alvin L.; Veluchamy, Amutha Barathi; Metspalu, Andres; Paterson, Andrew D.; Döring, Angela; Khawaja, Anthony P.; Klein, Barbara E.; Pourcain, Beate St; Fleck, Brian; Klaver, Caroline C. W.; Hayward, Caroline; Williams, Cathy; Delcourt, Cécile; Pang, Chi Pui; Khor, Chiea-Chuen; Cheng, Ching-Yu; Gieger, Christian; Hammond, Christopher J.; Simpson, Claire L.; van Duijn, Cornelia M.; Mackey, David A.; Evans, David M.; Stambolian, Dwight; Chew, Emily; Tai, E-Shyong; Krapohl, Eva; Mihailov, Evelin; Smith, George Davey; McMahon, George; Biino, Ginevra; Campbell, Harry; Rudan, Igor; Seppälä, Ilkka; Kaprio, Jaakko; Wilson, James F.; Craig, Jamie E.; Tideman, J. Willem L.; Ried, Janina S.; Korobelnik, Jean-François; Guggenheim, Jeremy A.; Fondran, Jeremy R.; Wang, Jie Jin; Liao, Jiemin; Zhao, Jing Hua; Xie, Jing; Bailey-Wilson, Joan E.; Kemp, John P.; Lass, Jonathan H.; Jonas, Jost B.; Rahi, Jugnoo S.; Wedenoja, Juho; Mäkelä, Kari-Matti; Burdon, Kathryn P.; Williams, Katie M; Khaw, Kay-Tee; Yamashiro, Kenji; Oexle, Konrad; Howe, Laura D.; Chen, Li Jia; Xu, Liang; Farrer, Lindsay; Ikram, M. Kamran; Deangelis, Margaret M.; Morrison, Margaux; Schache, Maria; Pirastu, Mario; Miyake, Masahiro; Yap, Maurice K. H.; Fossarello, Maurizio; Kähönen, Mika; Tedja, Milly S.; He, Mingguang; Yoshimura, Nagahisa; Martin, Nicholas G.; Timpson, Nicholas J.; Wareham, Nick J.; Mizuki, Nobuhisa; Pfeiffer, Norbert; Pärssinen, Olavi; Raitakari, Olli; Polasek, Ozren; Tam, Pancy O.; Foster, Paul J.; Mitchell, Paul; Baird, Paul Nigel; Chen, Peng; Hysi, Pirro G.; Cumberland, Phillippa; Gharahkhani, Puya; Fan, Qiao; Höhn, René; Fogarty, Rhys D.; Luben, Robert N.; Igo Jr, Robert P.; Plomin, Robert; Wojciechowski, Robert; Klein, Ronald; Mohsen Hosseini, S.; Janmahasatian, Sarayut; Saw, Seang-Mei; Yazar, Seyhan; Ping Yip, Shea; Feng, Sheng; Vaccargiu, Simona; Panda-Jonas, Songhomitra; MacGregor, Stuart; Iyengar, Sudha K.; Rantanen, Taina; Lehtimäki, Terho; Young, Terri L.; Meitinger, Thomas; Wong, Tien-Yin; Aung, Tin; Haller, Toomas; Vitart, Veronique; Nangia, Vinay; Verhoeven, Virginie J. M.; Jhanji, Vishal; Zhao, Wanting; Chen, Wei; Zhou, Xiangtian; Guo, Xiaobo; Ding, Xiaohu; Wang, Ya Xing; Lu, Yi; Teo, Yik-Ying; Vatavuk, Zoran

    2016-01-01

    Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7–15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E–08) and 2.3% (P = 6.9E–21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E–04). PMID:27174397

  3. Gene-environment interaction: Introduction

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The execution and completion of the Human Genome Project was surrounded by great expectations and many overstated promises, and for the first time in history, the information revolution has made of the general public a first row spectator of the scientific advances in real time. Therefore, the publi...

  4. Nevoid basal cell carcinoma syndrome with medulloblastoma in an African-American boy: A rare case illustrating gene-environment interaction

    SciTech Connect

    Korczak, J.F.; Goldstein, A.M.; Kase, R.G.

    1997-03-31

    We present an 8-year-old African-American boy with medulloblastoma and nevoid basal cell carcinoma syndrome (NBCCS) who exhibited the radiosensitive response of basal cell carcinoma (BCC) formation in the area irradiated for medulloblastoma. Such a response is well-documented in Caucasian NBCCS patients with medulloblastoma. The propositus was diagnosed with medulloblastoma at the age of 2 years and underwent surgery, chemotherapy, and craniospinal irradiation. At the age of 6 years, he was diagnosed with NBCCS following his presentation with a large odontogenic keratocyst of the mandible, pits of the palms and soles and numerous BCCs in the area of the back and neck that had been irradiated previously for medulloblastoma. Examination of other relatives showed that the propositus mother also had NBCCS but was more mildly affected; in particular, she had no BCCs. This case illustrates complex gene-environment interaction, in that increased skin pigmentation in African-Americans is presumably protective against ultraviolet, but not ionizing, radiation. This case and other similar cases in the literature show the importance of considering NBCCS in the differential diagnosis of any patient who presents with a medulloblastoma, especially before the age of 5 years, and of examining other close relatives for signs of NBCCS to determine the patient`s at-risk status. Finally, for individuals who are radiosensitive, protocols that utilize chemotherapy in lieu of radiotherapy should be considered. 27 refs., 4 figs.

  5. Influence of 5-HTT variation, childhood trauma and self-efficacy on anxiety traits: a gene-environment-coping interaction study.

    PubMed

    Schiele, Miriam A; Ziegler, Christiane; Holitschke, Karoline; Schartner, Christoph; Schmidt, Brigitte; Weber, Heike; Reif, Andreas; Romanos, Marcel; Pauli, Paul; Zwanzger, Peter; Deckert, Jürgen; Domschke, Katharina

    2016-08-01

    Environmental vulnerability factors such as adverse childhood experiences in interaction with genetic risk variants, e.g., the serotonin transporter gene linked polymorphic region (5-HTTLPR), are assumed to play a role in the development of anxiety and affective disorders. However, positive influences such as general self-efficacy (GSE) may exert a compensatory effect on genetic disposition, environmental adversity, and anxiety traits. We, thus, assessed childhood trauma (Childhood Trauma Questionnaire, CTQ) and GSE in 678 adults genotyped for 5-HTTLPR/rs25531 and their interaction on agoraphobic cognitions (Agoraphobic Cognitions Questionnaire, ACQ), social anxiety (Liebowitz Social Anxiety Scale, LSAS), and trait anxiety (State-Trait Anxiety Inventory, STAI-T). The relationship between anxiety traits and childhood trauma was moderated by self-efficacy in 5-HTTLPR/rs25531 LALA genotype carriers: LALA probands maltreated as children showed high anxiety scores when self-efficacy was low, but low anxiety scores in the presence of high self-efficacy despite childhood maltreatment. Our results extend previous findings regarding anxiety-related traits showing an interactive relationship between 5-HTT genotype and adverse childhood experiences by suggesting coping-related measures to function as an additional dimension buffering the effects of a gene-environment risk constellation. Given that anxiety disorders manifest already early in childhood, this insight could contribute to the improvement of psychotherapeutic interventions by including measures strengthening self-efficacy and inform early targeted preventive interventions in at-risk populations, particularly within the crucial time window of childhood and adolescence. PMID:27145764

  6. Gene-environment interactions affect long-term depression (LTD) through changes in dopamine receptor affinity in Snap25 deficient mice

    PubMed Central

    Baca, Michael; Allan, Andrea M.; Partridge, L. Donald; Wilson, Michael C.

    2013-01-01

    Genes and environmental conditions interact in the development of cognitive capacities and each plays an important role in neuropsychiatric disorders such as attention deficit/hyperactivity disorder (ADHD) and schizophrenia. Multiple studies have indicated that the gene for the SNARE protein SNAP-25 is a candidate susceptibility gene for ADHD, as well as schizophrenia, while maternal smoking is a candidate environmental risk factor for ADHD. We utilized mice heterozygous for a Snap25 null allele and deficient in SNAP-25 expression to model genetic effects in combination with prenatal exposure to nicotine to explore genetic and environmental interactions in synaptic plasticity and behavior. We show that SNAP-25 deficient mice exposed to prenatal nicotine exhibit hyperactivity and deficits in social interaction. Using a high frequency stimulus electrophysiological paradigm for long-term depression (LTD) induction, we examined the roles of dopaminergic D2 receptors (D2Rs) and cannabinoid CB1 receptors (CB1Rs), both critical for LTD induction in the striatum. We found that prenatal exposure to nicotine in Snap25 heterozygote null mice produced a deficit in the D2R-dependent induction of LTD, although CB1R regulation of plasticity was not impaired. We also show that prenatal nicotine exposure altered the affinity and/or receptor coupling of D2Rs, but not the number of these receptors in heterozygote null Snap25 mutants. These results refine the observations made in the coloboma mouse mutant, a proposed mouse model of ADHD, and illustrate how gene × environmental influences can interact to perturb neural functions that regulate behavior. PMID:23939223

  7. Q -Ball Candidates for Self-Interacting Dark Matter

    SciTech Connect

    Kusenko, Alexander; Steinhardt, Paul J.

    2001-10-01

    We show that nontopological solitons, known as Q-balls, are promising candidates for self-interacting dark matter. They can satisfy the cross-section requirements for a broad range of masses. Unlike previously considered examples, Q-balls can stick together after collision, reducing the effective self-interaction rate to a negligible value after a few collisions per particle. This feature modifies predictions for halo formation. We also discuss the possibility that Q-balls have large interaction cross sections with ordinary matter.

  8. Genes, Environment, and Human Behavior.

    ERIC Educational Resources Information Center

    Bloom, Mark V.; Cutter, Mary Ann; Davidson, Ronald; Dougherty, Michael J.; Drexler, Edward; Gelernter, Joel; McCullough, Laurence B.; McInerney, Joseph D.; Murray, Jeffrey C.; Vogler, George P.; Zola, John

    This curriculum module explores genes, environment, and human behavior. This book provides materials to teach about the nature and methods of studying human behavior, raise some of the ethical and public policy dilemmas emerging from the Human Genome Project, and provide professional development for teachers. An extensive Teacher Background…

  9. Breast cancer risk, fungicide exposure and CYP1A1*2A gene-environment interactions in a province-wide case control study in Prince Edward Island, Canada.

    PubMed

    Ashley-Martin, Jillian; VanLeeuwen, John; Cribb, Alastair; Andreou, Pantelis; Guernsey, Judith Read

    2012-05-01

    Scientific certainty regarding environmental toxin-related etiologies of breast cancer, particularly among women with genetic polymorphisms in estrogen metabolizing enzymes, is lacking. Fungicides have been recognized for their carcinogenic potential, yet there is a paucity of epidemiological studies examining the health risks of these agents. The association between agricultural fungicide exposure and breast cancer risk was examined in a secondary analysis of a province-wide breast cancer case-control study in Prince Edward Island (PEI) Canada. Specific objectives were: (1) to derive and examine the level of association between estimated fungicide exposures, and breast cancer risk among women in PEI; and (2) to assess the potential for gene-environment interactions between fungicide exposure and a CYP1A1 polymorphism in cases versus controls. After 1:3 matching of 207 cases to 621 controls by age, family history of breast cancer and menopausal status, fungicide exposure was not significantly associated with an increased risk of breast cancer (OR = 0.74; 95% CI: 0.46-1.17). Moreover, no statistically significant interactions between fungicide exposure and CYP1A1*2A were observed. Gene-environment interactions were identified. Though interpretations of findings are challenged by uncertainty of exposure assignment and small sample sizes, this study does provide grounds for further research. PMID:22754477

  10. Gene-Environment Interplay in Twin Models.

    PubMed

    Verhulst, Brad; Hatemi, Peter K

    2013-07-01

    In this article, we respond to Shultziner's critique that argues that identical twins are more alike not because of genetic similarity, but because they select into more similar environments and respond to stimuli in comparable ways, and that these effects bias twin model estimates to such an extent that they are invalid. The essay further argues that the theory and methods that undergird twin models, as well as the empirical studies which rely upon them, are unaware of these potential biases. We correct this and other misunderstandings in the essay and find that gene-environment (GE) interplay is a well-articulated concept in behavior genetics and political science, operationalized as gene-environment correlation and gene-environment interaction. Both are incorporated into interpretations of the classical twin design (CTD) and estimated in numerous empirical studies through extensions of the CTD. We then conduct simulations to quantify the influence of GE interplay on estimates from the CTD. Due to the criticism's mischaracterization of the CTD and GE interplay, combined with the absence of any empirical evidence to counter what is presented in the extant literature and this article, we conclude that the critique does not enhance our understanding of the processes that drive political traits, genetic or otherwise. PMID:24808718

  11. Gene-Environment Interplay in Twin Models

    PubMed Central

    Hatemi, Peter K.

    2013-01-01

    In this article, we respond to Shultziner’s critique that argues that identical twins are more alike not because of genetic similarity, but because they select into more similar environments and respond to stimuli in comparable ways, and that these effects bias twin model estimates to such an extent that they are invalid. The essay further argues that the theory and methods that undergird twin models, as well as the empirical studies which rely upon them, are unaware of these potential biases. We correct this and other misunderstandings in the essay and find that gene-environment (GE) interplay is a well-articulated concept in behavior genetics and political science, operationalized as gene-environment correlation and gene-environment interaction. Both are incorporated into interpretations of the classical twin design (CTD) and estimated in numerous empirical studies through extensions of the CTD. We then conduct simulations to quantify the influence of GE interplay on estimates from the CTD. Due to the criticism’s mischaracterization of the CTD and GE interplay, combined with the absence of any empirical evidence to counter what is presented in the extant literature and this article, we conclude that the critique does not enhance our understanding of the processes that drive political traits, genetic or otherwise. PMID:24808718

  12. Association between polymorphisms in the dopamine transporter gene and depression: evidence for a gene-environment interaction in a sample of juvenile detainees.

    PubMed

    Haeffel, Gerald J; Getchell, Marya; Koposov, Roman A; Yrigollen, Carolyn M; Deyoung, Colin G; Klinteberg, Britt Af; Oreland, Lars; Ruchkin, Vladislav V; Grigorenko, Elena L

    2008-01-01

    Previous research has generated examples of how genetic and environmental factors can interact to create risk for psychopathology. Using a gene-by-environment (G x E) interaction design, we tested whether three polymorphisms in the dopamine transporter gene (DAT1, also referred to as SLC6A3, located at 5p15.33) interacted with maternal parenting style to predict first-onset episodes of depression. Participants were male adolescents (N= 176) recruited from a juvenile detention center in northern Russia. As hypothesized, one of the polymorphisms (rs40184) moderated the effect of perceived maternal rejection on the onset of major depressive disorder, as well as on suicidal ideation. Further, this G x E interaction was specific to depression; it did not predict clinically significant anxiety. These results highlight the need for further research investigating the moderating effects of dopaminergic genes on depression. PMID:18181793

  13. Identification of gene-gene and gene-environment interactions within the fibrinogen gene cluster for fibrinogen levels in three ethnically diverse populations.

    PubMed

    Jeff, Janina M; Brown-Gentry, Kristin; Crawford, Dana C

    2015-01-01

    Elevated levels of plasma fibrinogen are associated with clot formation in the absence of inflammation or injury and is a biomarker for arterial clotting, the leading cause of cardiovascular disease. Fibrinogen levels are heritable with >50% attributed to genetic factors, however little is known about possible genetic modifiers that might explain the missing heritability. The fibrinogen gene cluster is comprised of three genes (FGA, FGB, and FGG) that make up the fibrinogen polypeptide essential for fibrinogen production in the blood. Given the known interaction with these genes, we tested 25 variants in the fibrinogen gene cluster for gene x gene and gene x environment interactions in 620 non-Hispanic blacks, 1,385 non-Hispanic whites, and 664 Mexican Americans from a cross-sectional dataset enriched with environmental data, the Third National Health and Nutrition Examination Survey (NHANES III). Using a multiplicative approach, we added cross product terms (gene x gene or gene x environment) to a linear regression model and declared significance at p < 0.05. We identified 19 unique gene x gene and 13 unique gene x environment interactions that impact fibrinogen levels in at least one population at p < 0.05. Over 90% of the gene x gene interactions identified include a variant in the rate-limiting gene, FGB that is essential for the formation of the fibrinogen polypeptide. We also detected gene x environment interactions with fibrinogen variants and sex, smoking, and body mass index. These findings highlight the potential for the discovery of genetic modifiers for complex phenotypes in multiple populations and give a better understanding of the interaction between genes and/or the environment for fibrinogen levels. The need for more powerful and robust methods to identify genetic modifiers is still warranted. PMID:25592583

  14. IDENTIFICATION OF GENE-GENE AND GENE-ENVIRONMENT INTERACTIONS WITHIN THE FIBRINOGEN GENE CLUSTER FOR FIBRINOGEN LEVELS IN THREE ETHNICALLY DIVERSE POPULATIONS

    PubMed Central

    Jeff, Janina M.; Brown-Gentry, Kristin; Crawford, Dana C.

    2014-01-01

    Elevated levels of plasma fibrinogen are associated with clot formation in the absence of inflammation or injury and is a biomarker for arterial clotting, the leading cause of cardiovascular disease. Fibrinogen levels are heritable with >50% attributed to genetic factors, however little is known about possible genetic modifiers that might explain the missing heritability. The fibrinogen gene cluster is comprised of three genes (FGA, FGB, and FGG) that make up the fibrinogen polypeptide essential for fibrinogen production in the blood. Given the known interaction with these genes, we tested 25 variants in the fibrinogen gene cluster for gene × gene and gene × environment interactions in 620 non-Hispanic blacks, 1,385 non-Hispanic whites, and 664 Mexican Americans from a cross-sectional dataset enriched with environmental data, the Third National Health and Nutrition Examination Survey (NHANES III). Using a multiplicative approach, we added cross product terms (gene × gene or gene × environment) to a linear regression model and declared significance at p < 0.05. We identified 19 unique gene × gene and 13 unique gene × environment interactions that impact fibrinogen levels in at least one population at p <0.05. Over 90% of the gene × gene interactions identified include a variant in the rate-limiting gene, FGB that is essential for the formation of the fibrinogen polypeptide. We also detected gene × environment interactions with fibrinogen variants and sex, smoking, and body mass index. These findings highlight the potential for the discovery of genetic modifiers for complex phenotypes in multiple populations and give a better understanding of the interaction between genes and/or the environment for fibrinogen levels. The need for more powerful and robust methods to identify genetic modifiers is still warranted. PMID:25592583

  15. The Dopamine Receptor D4 7-Repeat Allele and Prenatal Smoking in ADHD-Affected Children and Their Unaffected Siblings: No Gene-Environment Interaction

    ERIC Educational Resources Information Center

    Altink, Marieke E.; Arias-Vasquez, Alejandro; Franke, Barbara; Slaats-Willemse, Dorine I. E.; Buschgens, Cathelijne J. M.; Rommelse, Nanda N. J.; Fliers, Ellen A.; Anney, Richard; Brookes, Keeley-Joanne; Chen, Wai; Gill, Michael; Mulligan, Aisling; Sonuga-Barke, Edmund; Thompson, Margaret; Sergeant, Joseph A.; Faraone, Stephen V.; Asherson, Philip; Buitelaar, Jan K.

    2008-01-01

    Background: The dopamine receptor D4 ("DRD4") 7-repeat allele and maternal smoking during pregnancy are both considered as risk factors in the aetiology of attention deficit hyperactivity disorder (ADHD), but few studies have been conducted on their interactive effects in causing ADHD. The purpose of this study is to examine the gene by…

  16. Confluence of Genes, Environment, Development, and Behavior in a Post-GWAS World

    PubMed Central

    Vrieze, Scott I.; Iacono, William G.; McGue, Matt

    2012-01-01

    This article serves to outline a research paradigm to investigate main effects and interactions of genes, environment, and development on behavior and psychiatric illness. We provide a historical context for candidate gene studies and genome-wide association studies, including benefits, limitations, and expected payoff. Using substance use and abuse as our driving example, we then turn to the importance of etiological psychological theory in guiding genetic, environmental, and developmental research, as well as the utility of refined phenotypic measures, such as endophenotypes, in the pursuit of etiological understanding and focused tests of genetic and environmental associations. Phenotypic measurement has received considerable attention and is informed by psychometrics, while the environment remains relatively poorly measured and is often confounded with genetic effects (i.e., gene-environment correlation). Genetically-informed designs which—thanks to ever cheaper genotyping—are no longer are limited to twin and adoption studies, are required to understand environmental influences. Finally, we outline the vast amount of individual differences in structural genomic variation, most of which remains to be leveraged in genetic association tests. While the genetic data can be burdensomely massive (tens of millions of variants per person), we argue that improved understanding of genomic structure and function will provide investigators with new tools to test specific a priori hypotheses derived from etiological psychological theory, much like current candidate gene research, but with less confusion and more payoff than candidate gene research has to date. PMID:23062291

  17. Confluence of genes, environment, development, and behavior in a post Genome-Wide Association Study world.

    PubMed

    Vrieze, Scott I; Iacono, William G; McGue, Matt

    2012-11-01

    This article serves to outline a research paradigm to investigate main effects and interactions of genes, environment, and development on behavior and psychiatric illness. We provide a historical context for candidate gene studies and genome-wide association studies, including benefits, limitations, and expected payoffs. Using substance use and abuse as our driving example, we then turn to the importance of etiological psychological theory in guiding genetic, environmental, and developmental research, as well as the utility of refined phenotypic measures, such as endophenotypes, in the pursuit of etiological understanding and focused tests of genetic and environmental associations. Phenotypic measurement has received considerable attention in the history of psychology and is informed by psychometrics, whereas the environment remains relatively poorly measured and is often confounded with genetic effects (i.e., gene-environment correlation). Genetically informed designs, which are no longer limited to twin and adoption studies thanks to ever-cheaper genotyping, are required to understand environmental influences. Finally, we outline the vast amount of individual difference in structural genomic variation, most of which remains to be leveraged in genetic association tests. Although the genetic data can be massive and burdensome (tens of millions of variants per person), we argue that improved understanding of genomic structure and function will provide investigators with new tools to test specific a priori hypotheses derived from etiological psychological theory, much like current candidate gene research but with less confusion and more payoff than candidate gene research has to date. PMID:23062291

  18. Gene-gene-environment interactions between drugs, transporters, receptors, and metabolizing enzymes: Statins, SLCO1B1, and CYP3A4 as an example.

    PubMed

    Sadee, Wolfgang

    2013-09-01

    Pharmacogenetic biomarker tests include mostly specific single gene-drug pairs, capable of accounting for a portion of interindividual variability in drug response and toxicity. However, multiple genes are likely to contribute, either acting independently or epistatically, with the CYP2C9-VKORC1-warfarin test panel, an example of a clinically used gene-gene-dug interaction. I discuss here further instances of gene-gene-drug interactions, including a proposed dynamic effect on statin therapy by genetic variants in both a transporter (SLCO1B1) and a metabolizing enzyme (CYP3A4) in liver cells, the main target site where statins block cholesterol synthesis. These examples set a conceptual framework for developing diagnostic panels involving multiple gene-drug combinations. PMID:23436703

  19. Gene-environment interaction between DRD4 7-repeat VNTR and early child-care experiences predicts self-regulation abilities in prekindergarten.

    PubMed

    Berry, Daniel; McCartney, Kathleen; Petrill, Stephen; Deater-Deckard, Kirby; Blair, Clancy

    2014-04-01

    Intervention studies indicate that children's early child-care experiences can be leveraged to foster their development of effective self-regulation skills. It is less clear whether typical child-care experiences play a similar role. In addition, evidence suggests that children with a common variant of the DRD4 gene (48-bp VNTR, 7-repeat) may be more sensitive to their experiences than those without this variant. Using data from the NICHD Study of Early Child Care and Youth Development, we considered the degree to which children's early child-care experiences-quantity, quality, and type-were associated with their attention and self-regulation abilities in prekindergarten, and, in particular, whether these relations were conditional on DRD4 genotype. G × E interactions were evident across multiple neuropsychological and observational measures of children's attention and self-regulation abilities. Across most outcome measures, DRD4 7+ children spending fewer hours in child care showed more effective attention/self-regulation abilities. For those without a copy of the DRD4 7-repeat allele, such associations were typically null. The results for child-care quality and type indicated no interactions with genotype; the main-effect associations were somewhat inconsistent. PMID:23460366

  20. Nature, nurture and neurology: gene-environment interactions in neurodegenerative disease. FEBS Anniversary Prize Lecture delivered on 27 June 2004 at the 29th FEBS Congress in Warsaw.

    PubMed

    Spires, Tara L; Hannan, Anthony J

    2005-05-01

    Neurodegenerative disorders, such as Huntington's, Alzheimer's, and Parkinson's diseases, affect millions of people worldwide and currently there are few effective treatments and no cures for these diseases. Transgenic mice expressing human transgenes for huntingtin, amyloid precursor protein, and other genes associated with familial forms of neurodegenerative disease in humans provide remarkable tools for studying neurodegeneration because they mimic many of the pathological and behavioural features of the human conditions. One of the recurring themes revealed by these various transgenic models is that different diseases may share similar molecular and cellular mechanisms of pathogenesis. Cellular mechanisms known to be disrupted at early stages in multiple neurodegenerative disorders include gene expression, protein interactions (manifesting as pathological protein aggregation and disrupted signaling), synaptic function and plasticity. Recent work in mouse models of Huntington's disease has shown that enriching the environment of transgenic animals delays the onset and slows the progression of Huntington's disease-associated motor and cognitive symptoms. Environmental enrichment is known to induce various molecular and cellular changes in specific brain regions of wild-type animals, including altered gene expression profiles, enhanced neurogenesis and synaptic plasticity. The promising effects of environmental stimulation, demonstrated recently in models of neurodegenerative disease, suggest that therapy based on the principles of environmental enrichment might benefit disease sufferers and provide insight into possible mechanisms of neurodegeneration and subsequent identification of novel therapeutic targets. Here, we review the studies of environmental enrichment relevant to some major neurodegenerative diseases and discuss their research and clinical implications. PMID:15885086

  1. Research designs for the study of gene-environment interactions in psychiatric disorders. Report of a Foundations Fund for Research in Psychiatry Panel.

    PubMed

    Kidd, K K; Matthysee, S

    1978-08-01

    Understanding the genetic and environmental contributions (and their interactions, which are likely to be complex) to the etiology of psychiatric disorders requires research designs incorporating many basic principles of genetics. Genetic variation is likely to contribute to psychiatric disorders and genetic heterogeneity is likely to exist for any single disorder, ie, completely different genetic variants may each be capable of increasing an individual's susceptibility to the disorder. Thus, it is important to define phenotypes that may more closely reflect each individual genetic variant rather than to rely solely on the psychiatric diagnosis. Research should be undertaken with the goal of testing specific hypotheses that can be excluded. Research designs can include studies of unrelated individuals, twins, separated relatives, nuclear families, or extended pedigrees. Not all hypotheses can be tested on one type of data, and appropriate analytic methods vary. Because genetic hypotheses cannot be tested on studies of unrelated individuals, it is important that data be collected on families instead of unrelated individual patients and/or controls. Studies should include traits that bridge the gap between the genotype and the diagnostic phenotype. Such studies should be multidisciplinary, and the best statistical-genetics methodology should be used for data analysis. PMID:678045

  2. Can genes play a role in explaining frequent job changes? An examination of gene-environment interaction from human capital theory.

    PubMed

    Chi, Wei; Li, Wen-Dong; Wang, Nan; Song, Zhaoli

    2016-07-01

    This study examined how a dopamine genetic marker, DRD4 7 Repeat allele, interacted with early life environmental factors (i.e., family socioeconomic status, and neighborhood poverty) to influence job change frequency in adulthood using a national representative sample from the United States. The dopamine gene played a moderating role in the relationship between early life environments and later job change behaviors, which was meditated through educational achievement. In particular, higher family socioeconomic status was associated with higher educational achievement, and thereafter higher frequency of voluntary job changes and lower frequency of involuntary job changes; such relationships were stronger (i.e., more positive or negative) for individuals with more DRD4 7R alleles. In contrast, higher neighborhood poverty was associated with lower educational achievement, and thereafter lower frequency of voluntary job change and higher frequency of involuntary job change; such relationships were again stronger (i.e., more positive or negative) for individuals with more DRD4 7R alleles. The results demonstrated that molecular genetics using DNA information, along with early life environmental factors, can bring new insights to enhance our understanding of job change frequency in individuals' early career development. (PsycINFO Database Record PMID:27077527

  3. Gene-Environment Interplay between Number of Friends and Prosocial Leadership Behavior in Children

    ERIC Educational Resources Information Center

    Rivizzigno, Alessandra S.; Brendgen, Mara; Feng, Bei; Vitaro, Frank; Dionne, Ginette; Tremblay, Richard E.; Boivin, Michel

    2014-01-01

    Enriched environments may moderate the effect of genetic factors on prosocial leadership (gene-environment interaction, G × E). However, positive environmental experiences may also themselves be influenced by a genetic disposition for prosocial leadership (gene-environment correlation, rGE). Relating these processes to friendships, the present…

  4. Gene-Environment Processes Linking Aggression, Peer Victimization, and the Teacher-Child Relationship

    ERIC Educational Resources Information Center

    Brendgen, Mara; Boivin, Michel; Dionne, Ginette; Barker, Edward D.; Vitaro, Frank; Girard, Alain; Tremblay, Richard; Perusse, Daniel

    2011-01-01

    Aggressive behavior in middle childhood is at least partly explained by genetic factors. Nevertheless, estimations of simple effects ignore possible gene-environment interactions (G x E) or gene-environment correlations (rGE) in the etiology of aggression. The present study aimed to simultaneously test for G x E and rGE processes between…

  5. Gene-Environment Interplay between Peer Rejection and Depressive Behavior in Children

    ERIC Educational Resources Information Center

    Brendgen, Mara; Vitaro, Frank; Boivin, Michel; Girard, Alain; Bukowski, William M.; Dionne, Ginette; Tremblay, Richard E.; Perusse, Daniel

    2009-01-01

    Background: Genetic risk for depressive behavior may increase the likelihood of exposure to environmental stressors (gene-environment correlation, rGE). By the same token, exposure to environmental stressors may moderate the effect of genes on depressive behavior (gene-environment interaction, GxE). Relating these processes to a peer-related…

  6. Community-Based Participatory Research and Gene-Environment Interaction Methodologies Addressing Environmental Justice among Migrant and Seasonal Farmworker Women and Children in Texas: "From Mother to Child Project"

    PubMed

    Hernández-Valero, María A; Herrera, Angelica P; Zahm, Sheila H; Jones, Lovell A

    2007-05-01

    The "From Mother to Child Project" is a molecular epidemiological study that employs a community- based participatory research (CBPR) approach and gene-environment interaction research to address environmental justice in migrant and seasonal farmworker (MSF) women and children of Mexican origin home-based in Baytown and La Joya, Texas. This paper presents the background and rationale for the study and describes the study design and methodology. Preliminary data showed that MSF women and children in Texas have measurable levels of pesticides in their blood and urine, some of which were banned in the United States decades ago and are possible human carcinogens. Polymorphisms in genes involved in chemical detoxification and DNA repair have been associated with susceptibility to genetic damage and cancer development in populations exposed to environmental toxins. The "From Mother to Child Project" is testing three hypotheses: (1) MSF women and children who are occupationally exposed to pesticides are at higher risk for DNA damage than are non-exposed women and children. (2) Both, the extent of pesticide exposure and type of polymorphisms in chemical detoxification and DNA repair genes contribute to the extent of DNA damage observed in study participants. (3) The mutagenic potency levels measured in the organic compounds extracted from the urine and serum of study participants will correlate with the total concentrations of pesticides and with the measured DNA damage in study participants. The study will enroll 800 participants: 200 MSF mother-child pairs; 200 children (one per family) whose parents have never worked in agriculture, matched with the MSF children by ethnicity, age ± 2 years, gender, and city of residence; and these children's mothers. Personal interviews with the mothers are used to gather data for both mothers and children on sociodemographic characteristics; pesticide exposure at work and home; medical and reproductive history; dietary assessment, and

  7. Exome Analyses of Long QT Syndrome Reveal Candidate Pathogenic Mutations in Calmodulin-Interacting Genes.

    PubMed

    Shigemizu, Daichi; Aiba, Takeshi; Nakagawa, Hidewaki; Ozaki, Kouichi; Miya, Fuyuki; Satake, Wataru; Toda, Tatsushi; Miyamoto, Yoshihiro; Fujimoto, Akihiro; Suzuki, Yutaka; Kubo, Michiaki; Tsunoda, Tatsuhiko; Shimizu, Wataru; Tanaka, Toshihiro

    2015-01-01

    Long QT syndrome (LQTS) is an arrhythmogenic disorder that can lead to sudden death. To date, mutations in 15 LQTS-susceptibility genes have been implicated. However, the genetic cause for approximately 20% of LQTS patients remains elusive. Here, we performed whole-exome sequencing analyses on 59 LQTS and 61 unaffected individuals in 35 families and 138 unrelated LQTS cases, after genetic screening of known LQTS genes. Our systematic analysis of familial cases and subsequent verification by Sanger sequencing identified 92 candidate mutations in 88 genes for 23 of the 35 families (65.7%): these included eleven de novo, five recessive (two homozygous and three compound heterozygous) and seventy-three dominant mutations. Although no novel commonly mutated gene was identified other than known LQTS genes, protein-protein interaction (PPI) network analyses revealed ten new pathogenic candidates that directly or indirectly interact with proteins encoded by known LQTS genes. Furthermore, candidate gene based association studies using an independent set of 138 unrelated LQTS cases and 587 controls identified an additional novel candidate. Together, mutations in these new candidates and known genes explained 37.1% of the LQTS families (13 in 35). Moreover, half of the newly identified candidates directly interact with calmodulin (5 in 11; comparison with all genes; p=0.042). Subsequent variant analysis in the independent set of 138 cases identified 16 variants in the 11 genes, of which 14 were in calmodulin-interacting genes (87.5%). These results suggest an important role of calmodulin and its interacting proteins in the pathogenesis of LQTS. PMID:26132555

  8. A Multiple Interaction Analysis Reveals ADRB3 as a Potential Candidate for Gallbladder Cancer Predisposition via a Complex Interaction with Other Candidate Gene Variations

    PubMed Central

    Rai, Rajani; Kim, Jong Joo; Misra, Sanjeev; Kumar, Ashok; Mittal, Balraj

    2015-01-01

    Gallbladder cancer is the most common and a highly aggressive biliary tract malignancy with a dismal outcome. The pathogenesis of the disease is multifactorial, comprising the combined effect of multiple genetic variations of mild consequence along with numerous dietary and environmental risk factors. Previously, we demonstrated the association of several candidate gene variations with GBC risk. In this study, we aimed to identify the combination of gene variants and their possible interactions contributing towards genetic susceptibility of GBC. Here, we performed Multifactor-Dimensionality Reduction (MDR) and Classification and Regression Tree Analysis (CRT) to investigate the gene–gene interactions and the combined effect of 14 SNPs in nine genes (DR4 (rs20576, rs6557634); FAS (rs2234767); FASL (rs763110); DCC (rs2229080, rs4078288, rs7504990, rs714); PSCA (rs2294008, rs2978974); ADRA2A (rs1801253); ADRB1 (rs1800544); ADRB3 (rs4994); CYP17 (rs2486758)) involved in various signaling pathways. Genotyping was accomplished by PCR-RFLP or Taqman allelic discrimination assays. SPSS software version 16.0 and MDR software version 2.0 were used for all the statistical analysis. Single locus investigation demonstrated significant association of DR4 (rs20576, rs6557634), DCC (rs714, rs2229080, rs4078288) and ADRB3 (rs4994) polymorphisms with GBC risk. MDR analysis revealed ADRB3 (rs4994) to be crucial candidate in GBC susceptibility that may act either alone (p < 0.0001, CVC = 10/10) or in combination with DCC (rs714 and rs2229080, p < 0.0001, CVC = 9/10). Our CRT results are in agreement with the above findings. Further, in-silico results of studied SNPs advocated their role in splicing, transcriptional and/or protein coding regulation. Overall, our result suggested complex interactions amongst the studied SNPs and ADRB3 rs4994 as candidate influencing GBC susceptibility. PMID:26602921

  9. A Multiple Interaction Analysis Reveals ADRB3 as a Potential Candidate for Gallbladder Cancer Predisposition via a Complex Interaction with Other Candidate Gene Variations.

    PubMed

    Rai, Rajani; Kim, Jong Joo; Misra, Sanjeev; Kumar, Ashok; Mittal, Balraj

    2015-01-01

    Gallbladder cancer is the most common and a highly aggressive biliary tract malignancy with a dismal outcome. The pathogenesis of the disease is multifactorial, comprising the combined effect of multiple genetic variations of mild consequence along with numerous dietary and environmental risk factors. Previously, we demonstrated the association of several candidate gene variations with GBC risk. In this study, we aimed to identify the combination of gene variants and their possible interactions contributing towards genetic susceptibility of GBC. Here, we performed Multifactor-Dimensionality Reduction (MDR) and Classification and Regression Tree Analysis (CRT) to investigate the gene-gene interactions and the combined effect of 14 SNPs in nine genes (DR4 (rs20576, rs6557634); FAS (rs2234767); FASL (rs763110); DCC (rs2229080, rs4078288, rs7504990, rs714); PSCA (rs2294008, rs2978974); ADRA2A (rs1801253); ADRB1 (rs1800544); ADRB3 (rs4994); CYP17 (rs2486758)) involved in various signaling pathways. Genotyping was accomplished by PCR-RFLP or Taqman allelic discrimination assays. SPSS software version 16.0 and MDR software version 2.0 were used for all the statistical analysis. Single locus investigation demonstrated significant association of DR4 (rs20576, rs6557634), DCC (rs714, rs2229080, rs4078288) and ADRB3 (rs4994) polymorphisms with GBC risk. MDR analysis revealed ADRB3 (rs4994) to be crucial candidate in GBC susceptibility that may act either alone (p < 0.0001, CVC = 10/10) or in combination with DCC (rs714 and rs2229080, p < 0.0001, CVC = 9/10). Our CRT results are in agreement with the above findings. Further, in-silico results of studied SNPs advocated their role in splicing, transcriptional and/or protein coding regulation. Overall, our result suggested complex interactions amongst the studied SNPs and ADRB3 rs4994 as candidate influencing GBC susceptibility. PMID:26602921

  10. Gene-environment interplay and psychopathology: multiple varieties but real effects.

    PubMed

    Rutter, Michael; Moffitt, Terrie E; Caspi, Avshalom

    2006-01-01

    Gene-environment interplay is a general term that covers several divergent concepts with different meanings and different implications. In this review, we evaluate research evidence on four varieties of gene-environment interplay. First, we consider epigenetic mechanisms by which environmental influences alter the effects of genes. Second, we focus on variations in heritability according to environmental circumstances. Third, we discuss what is known about gene-environment correlations. Finally, we assess concepts and findings on the interaction between specific identified genes and specific measured environmental risks. In order to provide an understanding of what may be involved in gene-environment interplay, we begin our presentation with a brief historical review of prevailing views about the role of genetic and environmental factors in the causation of mental disorders, and we provide a simplified account of some of the key features of how genes 'work'. PMID:16492258

  11. A Tendon Cell Specific RNAi Screen Reveals Novel Candidates Essential for Muscle Tendon Interaction.

    PubMed

    Tiwari, Prabhat; Kumar, Arun; Das, Rudra Nayan; Malhotra, Vivek; VijayRaghavan, K

    2015-01-01

    Tendons are fibrous connective tissue which connect muscles to the skeletal elements thus acting as passive transmitters of force during locomotion and provide appropriate body posture. Tendon-derived cues, albeit poorly understood, are necessary for proper muscle guidance and attachment during development. In the present study, we used dorsal longitudinal muscles of Drosophila and their tendon attachment sites to unravel the molecular nature of interactions between muscles and tendons. We performed a genetic screen using RNAi-mediated knockdown in tendon cells to find out molecular players involved in the formation and maintenance of myotendinous junction and found 21 candidates out of 2507 RNAi lines screened. Of these, 19 were novel molecules in context of myotendinous system. Integrin-βPS and Talin, picked as candidates in this screen, are known to play important role in the cell-cell interaction and myotendinous junction formation validating our screen. We have found candidates with enzymatic function, transcription activity, cell adhesion, protein folding and intracellular transport function. Tango1, an ER exit protein involved in collagen secretion was identified as a candidate molecule involved in the formation of myotendinous junction. Tango1 knockdown was found to affect development of muscle attachment sites and formation of myotendinous junction. Tango1 was also found to be involved in secretion of Viking (Collagen type IV) and BM-40 from hemocytes and fat cells. PMID:26488612

  12. A Tendon Cell Specific RNAi Screen Reveals Novel Candidates Essential for Muscle Tendon Interaction

    PubMed Central

    Tiwari, Prabhat; Malhotra, Vivek; VijayRaghavan, K.

    2015-01-01

    Tendons are fibrous connective tissue which connect muscles to the skeletal elements thus acting as passive transmitters of force during locomotion and provide appropriate body posture. Tendon-derived cues, albeit poorly understood, are necessary for proper muscle guidance and attachment during development. In the present study, we used dorsal longitudinal muscles of Drosophila and their tendon attachment sites to unravel the molecular nature of interactions between muscles and tendons. We performed a genetic screen using RNAi-mediated knockdown in tendon cells to find out molecular players involved in the formation and maintenance of myotendinous junction and found 21 candidates out of 2507 RNAi lines screened. Of these, 19 were novel molecules in context of myotendinous system. Integrin-βPS and Talin, picked as candidates in this screen, are known to play important role in the cell-cell interaction and myotendinous junction formation validating our screen. We have found candidates with enzymatic function, transcription activity, cell adhesion, protein folding and intracellular transport function. Tango1, an ER exit protein involved in collagen secretion was identified as a candidate molecule involved in the formation of myotendinous junction. Tango1 knockdown was found to affect development of muscle attachment sites and formation of myotendinous junction. Tango1 was also found to be involved in secretion of Viking (Collagen type IV) and BM-40 from hemocytes and fat cells. PMID:26488612

  13. The First Pilot Genome-Wide Gene-Environment Study of Depression in the Japanese Population.

    PubMed

    Otowa, Takeshi; Kawamura, Yoshiya; Tsutsumi, Akizumi; Kawakami, Norito; Kan, Chiemi; Shimada, Takafumi; Umekage, Tadashi; Kasai, Kiyoto; Tokunaga, Katsushi; Sasaki, Tsukasa

    2016-01-01

    Stressful events have been identified as a risk factor for depression. Although gene-environment (G × E) interaction in a limited number of candidate genes has been explored, no genome-wide search has been reported. The aim of the present study is to identify genes that influence the association of stressful events with depression. Therefore, we performed a genome-wide G × E interaction analysis in the Japanese population. A genome-wide screen with 320 subjects was performed using the Affymetrix Genome-Wide Human Array 6.0. Stressful life events were assessed using the Social Readjustment Rating Scale (SRRS) and depression symptoms were assessed with self-rating questionnaires using the Center for Epidemiologic Studies Depression (CES-D) scale. The p values for interactions between single nucleotide polymorphisms (SNPs) and stressful events were calculated using the linear regression model adjusted for sex and age. After quality control of genotype data, a total of 534,848 SNPs on autosomal chromosomes were further analyzed. Although none surpassed the level of the genome-wide significance, a marginal significant association of interaction between SRRS and rs10510057 with depression were found (p = 4.5 × 10-8). The SNP is located on 10q26 near Regulators of G-protein signaling 10 (RGS10), which encodes a regulatory molecule involved in stress response. When we investigated a similar G × E interaction between depression (K6 scale) and work-related stress in an independent sample (n = 439), a significant G × E effect on depression was observed (p = 0.015). Our findings suggest that rs10510057, interacting with stressors, may be involved in depression risk. Incorporating G × E interaction into GWAS can contribute to find susceptibility locus that are potentially missed by conventional GWAS. PMID:27529621

  14. Effects of the Family Environment: Gene-Environment Interaction and Passive Gene-Environment Correlation

    ERIC Educational Resources Information Center

    Price, Thomas S.; Jaffee, Sara R.

    2008-01-01

    The classical twin study provides a useful resource for testing hypotheses about how the family environment influences children's development, including how genes can influence sensitivity to environmental effects. However, existing statistical models do not account for the possibility that children can inherit exposure to family environments…

  15. Identifying Novel Candidate Genes Related to Apoptosis from a Protein-Protein Interaction Network

    PubMed Central

    Wang, Baoman; Yuan, Fei; Kong, Xiangyin; Hu, Lan-Dian; Cai, Yu-Dong

    2015-01-01

    Apoptosis is the process of programmed cell death (PCD) that occurs in multicellular organisms. This process of normal cell death is required to maintain the balance of homeostasis. In addition, some diseases, such as obesity, cancer, and neurodegenerative diseases, can be cured through apoptosis, which produces few side effects. An effective comprehension of the mechanisms underlying apoptosis will be helpful to prevent and treat some diseases. The identification of genes related to apoptosis is essential to uncover its underlying mechanisms. In this study, a computational method was proposed to identify novel candidate genes related to apoptosis. First, protein-protein interaction information was used to construct a weighted graph. Second, a shortest path algorithm was applied to the graph to search for new candidate genes. Finally, the obtained genes were filtered by a permutation test. As a result, 26 genes were obtained, and we discuss their likelihood of being novel apoptosis-related genes by collecting evidence from published literature. PMID:26543496

  16. Candidate genes and their interactions with other genetic / environmental risk factors in the etiology of schizophrenia

    PubMed Central

    Prasad, KM; Talkowski, MT; Chowdari, KV; McClain, L; Yolken, RH

    2016-01-01

    Identification of causative factors for common, chronic disorders is a major focus of current human health science research. These disorders are likely to be caused by multiple etiological agents. Available evidence also suggests that interactions between the risk factors may explain some of their pathogenic effects. While progress in genomics and allied biological research has brought forth powerful analytic techniques, the predicted complexity poses daunting analytic challenges. The search for pathogenesis of schizophrenia shares most of these challenges. We have reviewed the analytic and logistic problems associated with the search for pathogenesis. Evidence for pathogenic interactions is presented for selected diseases and for schizophrenia. We end by suggesting ‘recursive analyses’ as a potential design to address these challenges. This scheme involves initial focused searches for interactions motivated by available evidence, typically involving identified individual risk factors, such as candidate gene variants. Putative interactions are tested rigorously for replication and for biological plausibility. Support for the interactions from statistical and functional analyses motivates a progressively larger array of interactants that are evaluated recursively. The risk explained by the interactions is assessed concurrently and further elaborate searches may be guided by the results of such analyses. By way of example, we summarize our ongoing analyses of dopaminergic polymorphisms, as well as infectious etiological factors in schizophrenia genesis to exemplify this approach. PMID:19729054

  17. Interaction of Sr-90 with site candidate soil for demonstration disposal facility at Serpong

    NASA Astrophysics Data System (ADS)

    Setiawan, Budi; Mila, Oktri; Safni

    2014-03-01

    Interaction of radiostrontium (Sr-90) with site candidate soil for demonstration disposal facility to be constructed in the near future at Serpong has been done. This activity is to anticipate the interim storage facility at Serpong nuclear area becomes full off condition, and show to the public how radioactive waste can be well managed with the existing technology. To ensure that the location is save, a reliability study of site candidate soil becomes very importance to be conducted through some experiments consisted some affected parameters such as contact time, effect of ionic strength, and effect of Sr+ ion in solution. Radiostrontium was used as a tracer on the experiments and has role as radionuclide reference in low-level radioactive waste due to its long half-live and it's easy to associate with organism in nature. So, interaction of radiostrontium and soil samples from site becomes important to be studied. Experiment was performed in batch method, and soil sample-solution containing radionuclide was mixed in a 20 ml of PE vial. Ratio of solid: liquid was 10-2 g/ml. Objective of the experiment is to collect the specific characteristics data of radionuclide sorption onto soil from site candidate. Distribution coefficient value was used as indicator where the amount of initial and final activities of radiostrontium in solution was compared. Result showed that equilibrium condition was reached after contact time 10 days with Kd values ranged from 1600-2350 ml/g. Increased in ionic strength in solution made decreased of Kd value into soil sample due to competition of background salt and radiostrontium into soil samples, and increased in Sr ion in solution caused decreased of Kd value in soil sample due to limitation of sorption capacity in soil samples. Fast condition in saturated of metal ion into soil samples was reached due to a simple reaction was occurred.

  18. Interaction of Sr-90 with site candidate soil for demonstration disposal facility at Serpong

    SciTech Connect

    Setiawan, Budi; Mila, Oktri; Safni

    2014-03-24

    Interaction of radiostrontium (Sr-90) with site candidate soil for demonstration disposal facility to be constructed in the near future at Serpong has been done. This activity is to anticipate the interim storage facility at Serpong nuclear area becomes full off condition, and show to the public how radioactive waste can be well managed with the existing technology. To ensure that the location is save, a reliability study of site candidate soil becomes very importance to be conducted through some experiments consisted some affected parameters such as contact time, effect of ionic strength, and effect of Sr{sup +} ion in solution. Radiostrontium was used as a tracer on the experiments and has role as radionuclide reference in low-level radioactive waste due to its long half-live and it's easy to associate with organism in nature. So, interaction of radiostrontium and soil samples from site becomes important to be studied. Experiment was performed in batch method, and soil sample-solution containing radionuclide was mixed in a 20 ml of PE vial. Ratio of solid: liquid was 10{sup −2} g/ml. Objective of the experiment is to collect the specific characteristics data of radionuclide sorption onto soil from site candidate. Distribution coefficient value was used as indicator where the amount of initial and final activities of radiostrontium in solution was compared. Result showed that equilibrium condition was reached after contact time 10 days with Kd values ranged from 1600-2350 ml/g. Increased in ionic strength in solution made decreased of Kd value into soil sample due to competition of background salt and radiostrontium into soil samples, and increased in Sr ion in solution caused decreased of Kd value in soil sample due to limitation of sorption capacity in soil samples. Fast condition in saturated of metal ion into soil samples was reached due to a simple reaction was occurred.

  19. Commentary: Gene-Environment Interplay in the Context of Genetics, Epigenetics, and Gene Expression.

    ERIC Educational Resources Information Center

    Kramer, Douglas A.

    2005-01-01

    Objective: To comment on the article in this issue of the Journal by Professor Michael Rutter, "Environmentally Mediated Risks for Psychopathology: Research Strategies and Findings," in the context of current research findings on gene-environment interaction, epigenetics, and gene expression. Method: Animal and human studies are reviewed that…

  20. Interactions between the Powdery Mildew Effector BEC1054 and Barley Proteins Identify Candidate Host Targets.

    PubMed

    Pennington, Helen G; Gheorghe, Dana M; Damerum, Annabelle; Pliego, Clara; Spanu, Pietro D; Cramer, Rainer; Bindschedler, Laurence V

    2016-03-01

    There are over 500 candidate secreted effector proteins (CSEPs) or Blumeria effector candidates (BECs) specific to the barley powdery mildew pathogen Blumeria graminis f.sp. hordei. The CSEP/BEC proteins are expressed and predicted to be secreted by biotrophic feeding structures called haustoria. Eight BECs are required for the formation of functional haustoria. These include the RNase-like effector BEC1054 (synonym CSEP0064). In order to identify host proteins targeted by BEC1054, recombinant BEC1054 was expressed in E. coli, solubilized, and used in pull-down assays from barley protein extracts. Many putative interactors were identified by LC-MS/MS after subtraction of unspecific binders in negative controls. Therefore, a directed yeast-2-hybrid assay, developed to measure the effectiveness of the interactions in yeast, was used to validate putative interactors. We conclude that BEC1054 may target several host proteins, including a glutathione-S-transferase, a malate dehydrogenase, and a pathogen-related-5 protein isoform, indicating a possible role for BEC1054 in compromising well-known key players of defense and response to pathogens. In addition, BEC1054 interacts with an elongation factor 1 gamma. This study already suggests that BEC1054 plays a central role in barley powdery mildew virulence by acting at several levels. PMID:26813582

  1. Saccharomyces cerevisiae Genetics Predicts Candidate Therapeutic Genetic Interactions at the Mammalian Replication Fork

    PubMed Central

    van Pel, Derek M.; Stirling, Peter C.; Minaker, Sean W.; Sipahimalani, Payal; Hieter, Philip

    2013-01-01

    The concept of synthetic lethality has gained popularity as a rational guide for predicting chemotherapeutic targets based on negative genetic interactions between tumor-specific somatic mutations and a second-site target gene. One hallmark of most cancers that can be exploited by chemotherapies is chromosome instability (CIN). Because chromosome replication, maintenance, and segregation represent conserved and cell-essential processes, they can be modeled effectively in simpler eukaryotes such as Saccharomyces cerevisiae. Here we analyze and extend genetic networks of CIN cancer gene orthologs in yeast, focusing on essential genes. This identifies hub genes and processes that are candidate targets for synthetic lethal killing of cancer cells with defined somatic mutations. One hub process in these networks is DNA replication. A nonessential, fork-associated scaffold, CTF4, is among the most highly connected genes. As Ctf4 lacks enzymatic activity, potentially limiting its development as a therapeutic target, we exploited its function as a physical interaction hub to rationally predict synthetic lethal interactions between essential Ctf4-binding proteins and CIN cancer gene orthologs. We then validated a subset of predicted genetic interactions in a human colorectal cancer cell line, showing that siRNA-mediated knockdown of MRE11A sensitizes cells to depletion of various replication fork-associated proteins. Overall, this work describes methods to identify, predict, and validate in cancer cells candidate therapeutic targets for tumors with known somatic mutations in CIN genes using data from yeast. We affirm not only replication stress but also the targeting of DNA replication fork proteins themselves as potential targets for anticancer therapeutic development. PMID:23390603

  2. When Chocolate Seeking Becomes Compulsion: Gene-Environment Interplay

    PubMed Central

    Patella, Loris; Andolina, Diego; Valzania, Alessandro; Latagliata, Emanuele Claudio; Felsani, Armando; Pompili, Assunta; Gasbarri, Antonella; Puglisi-Allegra, Stefano; Ventura, Rossella

    2015-01-01

    Background Eating disorders appear to be caused by a complex interaction between environmental and genetic factors, and compulsive eating in response to adverse circumstances characterizes many eating disorders. Materials and Methods We compared compulsion-like eating in the form of conditioned suppression of palatable food-seeking in adverse situations in stressed C57BL/6J and DBA/2J mice, two well-characterized inbred strains, to determine the influence of gene-environment interplay on this behavioral phenotype. Moreover, we tested the hypothesis that low accumbal D2 receptor (R) availability is a genetic risk factor of food compulsion-like behavior and that environmental conditions that induce compulsive eating alter D2R expression in the striatum. To this end, we measured D1R and D2R expression in the striatum and D1R, D2R and α1R levels in the medial prefrontal cortex, respectively, by western blot. Results Exposure to environmental conditions induces compulsion-like eating behavior, depending on genetic background. This behavioral pattern is linked to decreased availability of accumbal D2R. Moreover, exposure to certain environmental conditions upregulates D2R and downregulates α1R in the striatum and medial prefrontal cortex, respectively, of compulsive animals. These findings confirm the function of gene-environment interplay in the manifestation of compulsive eating and support the hypothesis that low accumbal D2R availability is a “constitutive” genetic risk factor for compulsion-like eating behavior. Finally, D2R upregulation and α1R downregulation in the striatum and medial prefrontal cortex, respectively, are potential neuroadaptive responses that parallel the shift from motivated to compulsive eating. PMID:25781028

  3. Genotypes Do Not Confer Risk For Delinquency ut Rather Alter Susceptibility to Positive and Negative Environmental Factors: Gene-Environment Interactions of BDNF Val66Met, 5-HTTLPR, and MAOA-uVNTR

    PubMed Central

    Comasco, Erika; Hodgins, Sheilagh; Oreland, Lars; Åslund, Cecilia

    2015-01-01

    Background: Previous evidence of gene-by-environment interactions associated with emotional and behavioral disorders is contradictory. Differences in findings may result from variation in valence and dose of the environmental factor, and/or failure to take account of gene-by-gene interactions. The present study investigated interactions between the brain-derived neurotrophic factor gene (BDNF Val66Met), the serotonin transporter gene-linked polymorphic region (5-HTTLPR), the monoamine oxidase A (MAOA-uVNTR) polymorphisms, family conflict, sexual abuse, the quality of the child-parent relationship, and teenage delinquency. Methods: In 2006, as part of the Survey of Adolescent Life in Västmanland, Sweden, 1 337 high-school students, aged 17–18 years, anonymously completed questionnaires and provided saliva samples for DNA analyses. Results: Teenage delinquency was associated with two-, three-, and four-way interactions of each of the genotypes and the three environmental factors. Significant four-way interactions were found for BDNF Val66Met × 5-HTTLPR×MAOA-uVNTR × family conflicts and for BDNF Val66Met × 5-HTTLPR×MAOA-uVNTR × sexual abuse. Further, the two genotype combinations that differed the most in expression levels (BDNF Val66Met Val, 5-HTTLPR LL, MAOA-uVNTR LL [girls] and L [boys] vs BDNF Val66Met Val/Met, 5-HTTLPR S/LS, MAOA-uVNTR S/SS/LS) in interaction with family conflict and sexual abuse were associated with the highest delinquency scores. The genetic variants previously shown to confer vulnerability for delinquency (BDNF Val66Met Val/Met × 5-HTTLPR S × MAOA-uVNTR S) were associated with the lowest delinquency scores in interaction with a positive child-parent relationship. Conclusions: Functional variants of the MAOA-uVNTR, 5-HTTLPR, and BDNF Val66Met, either alone or in interaction with each other, may be best conceptualized as modifying sensitivity to environmental factors that confer either risk or protection for teenage delinquency. PMID

  4. In Vitro Assessment of CYP-Mediated Drug Interactions for Kinsenoside, an Antihyperlipidemic Candidate.

    PubMed

    Rehman, Shaheed Ur; Choi, Min Sun; Kim, In Sook; Luo, Zengwei; Xue, Yongbo; Yao, Guangming; Zhang, Yonghui; Yoo, Hye Hyun

    2016-01-01

    Kinsenoside, the herb-derived medicine isolated from the plant Anoect chilus, has diverse pharmacological actions, and it is considered to be a promising antihyperlipidemic drug candidate. This study evaluates the effects of kinsenoside on CYP enzyme-mediated drug metabolism in order to predict the potential for kinsenoside-drug interactions. Kinsenoside was tested at different concentrations of 0.1, 0.3, 1, 3, 10, 30, and 100 µM in human liver microsomes. The c Cktail probe assay based on liquid chromatography-tandem mass spectrometry was conducted to measure the CYP inhibitory effect of kinsenoside. Subsequently, the metabolism profiles of amlodipine and lovastatin in human liver microsomes were analyzed following co-incubation with kinsenoside. The concentration levels of the parent drug and the major metabolites were compared with the kinsenoside-cotreated samples. The effect of kinsenoside was negligible on the enzyme activity of all the CYP isozymes tested even though CYP2A6 was slightly inhibited at higher concentrations. The drug-drug interaction assay also showed that the concomitant use of kinsenoside has a non-significant effect on the concentration of lovastatin or amlodipine, and their major metabolites. So, it was concluded that there is almost no risk of drug interaction between kinsenoside and CYP drug substrates via CYP inhibition. PMID:27322236

  5. Chromatin interactions and candidate genes at ten prostate cancer risk loci.

    PubMed

    Du, Meijun; Tillmans, Lori; Gao, Jianzhong; Gao, Ping; Yuan, Tiezheng; Dittmar, Rachel L; Song, Wei; Yang, Yuehong; Sahr, Natasha; Wang, Tao; Wei, Gong-Hong; Thibodeau, Stephen N; Wang, Liang

    2016-01-01

    Genome-wide association studies have identified more than 100 common single nucleotide polymorphisms (SNPs) that are associated with prostate cancer risk. However, the vast majority of these SNPs lie in noncoding regions of the genome. To test whether these risk SNPs regulate their target genes through long-range chromatin interactions, we applied capture-based 3C sequencing technology to investigate possible cis-interactions at ten prostate cancer risk loci in six cell lines. We identified significant physical interactions between risk regions and their potential target genes including CAPG at 2p11.2, C2orf43 at 2p24.1, RFX6 at 6q22.1, NFASC at 1q32.1, MYC at 8q24.1 and AGAP7P at 10q11.23. Most of the interaction peaks were co-localized to regions of active histone modification and transcription factor binding sites. Expression quantitative trait locus (eQTL) analysis showed suggestive eQTL signals at rs1446669, rs699664 and rs1078004 for CAPG (p < 0.004), rs13394027 for C2orf43 (p = 2.25E-27), rs10993994 and rs4631830 for AGAP7P (p < 8.02E-5). Further analysis revealed an enhancer activity at genomic region surrounding rs4631830 which was expected to disrupt HOXB-like DNA binding affinity. This study identifies a set of candidate genes and their potential regulatory variants, and provides additional evidence showing the role of long-range chromatin interactions in prostate cancer etiology. PMID:26979803

  6. Chromatin interactions and candidate genes at ten prostate cancer risk loci

    PubMed Central

    Du, Meijun; Tillmans, Lori; Gao, Jianzhong; Gao, Ping; Yuan, Tiezheng; Dittmar, Rachel L; Song, Wei; Yang, Yuehong; Sahr, Natasha; Wang, Tao; Wei, Gong-Hong; Thibodeau, Stephen N.; Wang, Liang

    2016-01-01

    Genome-wide association studies have identified more than 100 common single nucleotide polymorphisms (SNPs) that are associated with prostate cancer risk. However, the vast majority of these SNPs lie in noncoding regions of the genome. To test whether these risk SNPs regulate their target genes through long-range chromatin interactions, we applied capture-based 3C sequencing technology to investigate possible cis-interactions at ten prostate cancer risk loci in six cell lines. We identified significant physical interactions between risk regions and their potential target genes including CAPG at 2p11.2, C2orf43 at 2p24.1, RFX6 at 6q22.1, NFASC at 1q32.1, MYC at 8q24.1 and AGAP7P at 10q11.23. Most of the interaction peaks were co-localized to regions of active histone modification and transcription factor binding sites. Expression quantitative trait locus (eQTL) analysis showed suggestive eQTL signals at rs1446669, rs699664 and rs1078004 for CAPG (p < 0.004), rs13394027 for C2orf43 (p = 2.25E-27), rs10993994 and rs4631830 for AGAP7P (p < 8.02E-5). Further analysis revealed an enhancer activity at genomic region surrounding rs4631830 which was expected to disrupt HOXB-like DNA binding affinity. This study identifies a set of candidate genes and their potential regulatory variants, and provides additional evidence showing the role of long-range chromatin interactions in prostate cancer etiology. PMID:26979803

  7. Gene-Environment Interplay in the Link of Friends' and Nonfriends' Behaviors with Children's Social Reticence in a Competitive Situation

    ERIC Educational Resources Information Center

    Guimond, Fanny-Alexandra; Brendgen, Mara; Vitaro, Frank; Forget-Dubois, Nadine; Dionne, Ginette; Tremblay, Richard E.; Boivin, Michel

    2014-01-01

    This study used a genetically informed design to assess the effects of friends' and nonfriends' reticent and dominant behaviors on children's observed social reticence in a competitive situation. Potential gene-environment correlations (rGE) and gene-environment interactions (GxE) in the link between (a) friends' and…

  8. Distilling a Visual Network of Retinitis Pigmentosa Gene-Protein Interactions to Uncover New Disease Candidates

    PubMed Central

    Boloc, Daniel; Castillo-Lara, Sergio; Marfany, Gemma; Gonzàlez-Duarte, Roser; Abril, Josep F.

    2015-01-01

    Background Retinitis pigmentosa (RP) is a highly heterogeneous genetic visual disorder with more than 70 known causative genes, some of them shared with other non-syndromic retinal dystrophies (e.g. Leber congenital amaurosis, LCA). The identification of RP genes has increased steadily during the last decade, and the 30% of the cases that still remain unassigned will soon decrease after the advent of exome/genome sequencing. A considerable amount of genetic and functional data on single RD genes and mutations has been gathered, but a comprehensive view of the RP genes and their interacting partners is still very fragmentary. This is the main gap that needs to be filled in order to understand how mutations relate to progressive blinding disorders and devise effective therapies. Methodology We have built an RP-specific network (RPGeNet) by merging data from different sources: high-throughput data from BioGRID and STRING databases, manually curated data for interactions retrieved from iHOP, as well as interactions filtered out by syntactical parsing from up-to-date abstracts and full-text papers related to the RP research field. The paths emerging when known RP genes were used as baits over the whole interactome have been analysed, and the minimal number of connections among the RP genes and their close neighbors were distilled in order to simplify the search space. Conclusions In contrast to the analysis of single isolated genes, finding the networks linking disease genes renders powerful etiopathological insights. We here provide an interactive interface, RPGeNet, for the molecular biologist to explore the network centered on the non-syndromic and syndromic RP and LCA causative genes. By integrating tissue-specific expression levels and phenotypic data on top of that network, a more comprehensive biological view will highlight key molecular players of retinal degeneration and unveil new RP disease candidates. PMID:26267445

  9. BPD'S INTERPERSONAL HYPERSENSITIVITY PHENOTYPE: A GENE-ENVIRONMENT-DEVELOPMENTAL MODEL

    PubMed Central

    Gunderson, John G.; Lyons-Ruth, Karlen

    2008-01-01

    This paper explores the development of BPD as it might emerge in the child's early interpersonal reactions and how such reactions might evolve into the interpersonal pattern that typifies BPD. It begins to bridge the relevant bodies of clinical literature on the borderline's prototypic interpersonal problems with the concurrently expanding relevant literature on early child development. We will start by considering how a psychobiological disposition to BPD is likely to include a constitutional diathesis for relational reactivity, that is, for hypersensitivity to interpersonal stressors. Data relevant to this disposition's manifestations in adult clinical samples and to its heritability and neurobiology will be reviewed. We then consider how such a psychobiological disposition for interpersonal reactivity might contribute to the development of a disorganized-ambivalent form of attachment, noting especially the likely contributions of both the predisposed child and of parents who are themselves predisposed to maladaptive responses, leading to an escalation of problematic transactions. Evidence concerning both the genetics and the developmental pathways associated with disorganized attachments will be considered. Emerging links between such developmental pathways and adult BPD will be described, in particular the potential appearance by early- to middle-childhood of controlling-caregiving or controlling-punitive interpersonal strategies. Some implications from this gene-environment interactional theory for a better developmental understanding of BPD's etiology are discussed. PMID:18312121

  10. Gene-environment contributions to young adult sexual partnering.

    PubMed

    Halpern, Carolyn T; Kaestle, Christine E; Guo, Guang; Hallfors, Denise D

    2007-08-01

    To date, there has been relatively little work on gene-environment contributions to human sexuality, especially molecular analyses examining the potential contributions of specific polymorphisms in conjunction with life experiences. Using Wave III data from 717 heterozygous young adult sibling pairs included in the National Longitudinal Study of Adolescent Health, this article examined the combined contributions of attendance at religious services and three genetic polymorphisms (in the dopamine D4 receptor [DRD4]), dopamine D2 receptor [DRD2]), and the serotonin transporter promoter [5HTT]) to sensation seeking, a personality construct related to sexual behavior, and the number of vaginal sex partners participants had in the year before interview. Data analyses used an Allison mixed model approach to account for population stratification and correlated observations. DRD4 was unrelated to sensation seeking and to the number of sex partners in tests of both main effects and in interaction with religious attendance. Contrary to hypothesis, presence of the A1 DRD2 allele was associated with having had fewer sex partners in the past year. Associations between the 5HTT allele and sex partners varied by religious attendance, but again the patterns of associations were contrary to hypothesized relationships and were small in magnitude. These findings underscore the necessity of using more comprehensive multiple gene-multiple life experience approaches to investigations of complex behaviors such as sexual patterns. PMID:17186131

  11. Mining for Candidate Genes Related to Pancreatic Cancer Using Protein-Protein Interactions and a Shortest Path Approach

    PubMed Central

    Yuan, Fei; Zhang, Yu-Hang; Wan, Sibao; Wang, ShaoPeng; Kong, Xiang-Yin

    2015-01-01

    Pancreatic cancer (PC) is a highly malignant tumor derived from pancreas tissue and is one of the leading causes of death from cancer. Its molecular mechanism has been partially revealed by validating its oncogenes and tumor suppressor genes; however, the available data remain insufficient for medical workers to design effective treatments. Large-scale identification of PC-related genes can promote studies on PC. In this study, we propose a computational method for mining new candidate PC-related genes. A large network was constructed using protein-protein interaction information, and a shortest path approach was applied to mine new candidate genes based on validated PC-related genes. In addition, a permutation test was adopted to further select key candidate genes. Finally, for all discovered candidate genes, the likelihood that the genes are novel PC-related genes is discussed based on their currently known functions. PMID:26613085

  12. An integrative in silico approach for discovering candidates for drug-targetable protein-protein interactions in interactome data

    PubMed Central

    Sugaya, Nobuyoshi; Ikeda, Kazuyoshi; Tashiro, Toshiyuki; Takeda, Shizu; Otomo, Jun; Ishida, Yoshiko; Shiratori, Akiko; Toyoda, Atsushi; Noguchi, Hideki; Takeda, Tadayuki; Kuhara, Satoru; Sakaki, Yoshiyuki; Iwayanagi, Takao

    2007-01-01

    Background Protein-protein interactions (PPIs) are challenging but attractive targets for small chemical drugs. Whole PPIs, called the 'interactome', have been emerged in several organisms, including human, based on the recent development of high-throughput screening (HTS) technologies. Individual PPIs have been targeted by small drug-like chemicals (SDCs), however, interactome data have not been fully utilized for exploring drug targets due to the lack of comprehensive methodology for utilizing these data. Here we propose an integrative in silico approach for discovering candidates for drug-targetable PPIs in interactome data. Results Our novel in silico screening system comprises three independent assessment procedures: i) detection of protein domains responsible for PPIs, ii) finding SDC-binding pockets on protein surfaces, and iii) evaluating similarities in the assignment of Gene Ontology (GO) terms between specific partner proteins. We discovered six candidates for drug-targetable PPIs by applying our in silico approach to original human PPI data composed of 770 binary interactions produced by our HTS yeast two-hybrid (HTS-Y2H) assays. Among them, we further examined two candidates, RXRA/NRIP1 and CDK2/CDKN1A, with respect to their biological roles, PPI network around each candidate, and tertiary structures of the interacting domains. Conclusion An integrative in silico approach for discovering candidates for drug-targetable PPIs was applied to original human PPIs data. The system excludes false positive interactions and selects reliable PPIs as drug targets. Its effectiveness was demonstrated by the discovery of the six promising candidate target PPIs. Inhibition or stabilization of the two interactions may have potential therapeutic effects against human diseases. PMID:17705877

  13. Gene-environment interaction and biological monitoring of occupational exposures

    SciTech Connect

    Hirvonen, Ari . E-mail: Ari.Hirvonen@ttl.fi

    2005-09-01

    Biological monitoring methods and biological limit values applied in occupational and environmental medicine have been traditionally developed on the assumption that individuals do not differ significantly in their biotransformation capacities. It has become clear, however, that this is not the case, but wide inter-individual differences exist in the metabolism of chemicals. Integration of the data on individual metabolic capacity in biological monitoring studies is therefore anticipated to represent a significant refinement of the currently used methods. We have recently conducted several biological monitoring studies on occupationally exposed subjects, which have included the determination of the workers' genotypes for the metabolic genes of potential importance for a given chemical exposure. The exposure levels have been measured by urine metabolites, adducts in blood macromolecules, and cytogenetic alterations in lymphocytes. Our studies indicate that genetic polymorphisms in metabolic genes may indeed be important modifiers of individual biological monitoring results of, e.g., carbon disulphide and styrene. The information is anticipated to be useful in insuring that the workplace is safe for everyone, including the most sensitive individuals. This knowledge could also be useful to occupational physicians, industrial hygienists, and regulatory bodies in charge of defining acceptable exposure limits for environmental and/or occupational pollutants.

  14. Integrating nutrigenomics data to identify cardiometabolic gene-environment interactions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Nutrition is a key factor in health and in many age-related diseases. This is particularly the case for cardiometabolic diseases such as cardiovascular disease, type 2 diabetes and hypertension, and is often precluded by obesity, glucose impairment and metabolic syndrome. Our research objectives are...

  15. Dopaminergic, Serotonergic, and Oxytonergic Candidate Genes Associated with Infant Attachment Security and Disorganization? In Search of Main and Interaction Effects

    ERIC Educational Resources Information Center

    Luijk, Maartje P. C. M.; Roisman, Glenn I.; Haltigan, John D.; Tiemeier, Henning; Booth-LaForce, Cathryn; van IJzendoorn, Marinus H.; Belsky, Jay; Uitterlinden, Andre G.; Jaddoe, Vincent W. V.; Hofman, Albert; Verhulst, Frank C.; Tharner, Anne; Bakermans-Kranenburg, Marian J.

    2011-01-01

    Background and methods: In two birth cohort studies with genetic, sensitive parenting, and attachment data of more than 1,000 infants in total, we tested main and interaction effects of candidate genes involved in the dopamine, serotonin, and oxytocin systems ("DRD4", "DRD2", "COMT", "5-HTT", "OXTR") on attachment security and disorganization.…

  16. Gene-Environment Interplay, Family Relationships, and Child Adjustment

    ERIC Educational Resources Information Center

    Horwitz, Briana N.; Neiderhiser, Jenae M.

    2011-01-01

    This paper reviews behavioral genetic research from the past decade that has moved beyond simply studying the independent influences of genes and environments. The studies considered in this review have instead focused on understanding gene-environment interplay, including genotype-environment correlation (rGE) and genotype x environment…

  17. Placental Genome and Maternal-Placental Genetic Interactions: A Genome-Wide and Candidate Gene Association Study of Placental Abruption

    PubMed Central

    Denis, Marie; Enquobahrie, Daniel A.; Tadesse, Mahlet G.; Gelaye, Bizu; Sanchez, Sixto E.; Salazar, Manuel; Ananth, Cande V.; Williams, Michelle A.

    2014-01-01

    While available evidence supports the role of genetics in the pathogenesis of placental abruption (PA), PA-related placental genome variations and maternal-placental genetic interactions have not been investigated. Maternal blood and placental samples collected from participants in the Peruvian Abruptio Placentae Epidemiology study were genotyped using Illumina’s Cardio-Metabochip platform. We examined 118,782 genome-wide SNPs and 333 SNPs in 32 candidate genes from mitochondrial biogenesis and oxidative phosphorylation pathways in placental DNA from 280 PA cases and 244 controls. We assessed maternal-placental interactions in the candidate gene SNPS and two imprinted regions (IGF2/H19 and C19MC). Univariate and penalized logistic regression models were fit to estimate odds ratios. We examined the combined effect of multiple SNPs on PA risk using weighted genetic risk scores (WGRS) with repeated ten-fold cross-validations. A multinomial model was used to investigate maternal-placental genetic interactions. In placental genome-wide and candidate gene analyses, no SNP was significant after false discovery rate correction. The top genome-wide association study (GWAS) hits were rs544201, rs1484464 (CTNNA2), rs4149570 (TNFRSF1A) and rs13055470 (ZNRF3) (p-values: 1.11e-05 to 3.54e-05). The top 200 SNPs of the GWAS overrepresented genes involved in cell cycle, growth and proliferation. The top candidate gene hits were rs16949118 (COX10) and rs7609948 (THRB) (p-values: 6.00e-03 and 8.19e-03). Participants in the highest quartile of WGRS based on cross-validations using SNPs selected from the GWAS and candidate gene analyses had a 8.40-fold (95% CI: 5.8–12.56) and a 4.46-fold (95% CI: 2.94–6.72) higher odds of PA compared to participants in the lowest quartile. We found maternal-placental genetic interactions on PA risk for two SNPs in PPARG (chr3∶12313450 and chr3∶12412978) and maternal imprinting effects for multiple SNPs in the C19MC and IGF2/H19 regions

  18. Candidate gene–environment interactions and their relationships with timing of breeding in a wild bird population

    PubMed Central

    Bourret, Audrey; Garant, Dany

    2015-01-01

    Monitoring and predicting evolutionary changes underlying current environmental modifications are complex challenges. Recent approaches to achieve these objectives include assessing the genetic variation and effects of candidate genes on traits indicating adaptive potential. In birds, for example, short tandem repeat polymorphism at four candidate genes (CLOCK, NPAS2, ADCYAP1, and CREB1) has been linked to variation in phenological traits such as laying date and timing of migration. However, our understanding of their importance as evolutionary predictors is still limited, mainly because the extent of genotype–environment interactions (GxE) related to these genes has yet to be assessed. Here, we studied a population of Tree swallow (Tachycineta bicolor) over 4 years in southern Québec (Canada) to assess the relationships between those four candidate genes and two phenological traits related to reproduction (laying date and incubation duration) and also determine the importance of GxE in this system. Our results showed that NPAS2 female genotypes were nonrandomly distributed across the study system and formed a longitudinal cline with longer genotypes located to the east. We observed relationships between length polymorphism at all candidate genes and laying date and/or incubation duration, and most of these relationships were affected by environmental variables (breeding density, latitude, or temperature). In particular, the positive relationships detected between laying date and both CLOCK and NPAS2 female genotypes were variable depending on breeding density. Our results suggest that all four candidate genes potentially affect timing of breeding in birds and that GxE are more prevalent and important than previously reported in this context. PMID:26380692

  19. Gγ recruitment systems specifically select PPI and affinity-enhanced candidate proteins that interact with membrane protein targets

    PubMed Central

    Kaishima, Misato; Ishii, Jun; Fukuda, Nobuo; Kondo, Akihiko

    2015-01-01

    Protein-protein interactions (PPIs) are crucial for the vast majority of biological processes. We previously constructed a Gγ recruitment system to screen PPI candidate proteins and desirable affinity-altered (affinity-enhanced and affinity-attenuated) protein variants. The methods utilized a target protein fused to a mutated G-protein γ subunit (Gγcyto) lacking the ability to localize to the inner leaflet of the plasma membrane. However, the previous systems were adapted to use only soluble cytosolic proteins as targets. Recently, membrane proteins have been found to form the principal nodes of signaling involved in diseases and have attracted a great deal of interest as primary drug targets. Here, we describe new protocols for the Gγ recruitment systems that are specifically designed to use membrane proteins as targets to overcome previous limitations. These systems represent an attractive approach to exploring novel interacting candidates and affinity-altered protein variants and their interactions with proteins on the inner side of the plasma membrane, with high specificity and selectivity. PMID:26581329

  20. Gγ recruitment systems specifically select PPI and affinity-enhanced candidate proteins that interact with membrane protein targets.

    PubMed

    Kaishima, Misato; Ishii, Jun; Fukuda, Nobuo; Kondo, Akihiko

    2015-01-01

    Protein-protein interactions (PPIs) are crucial for the vast majority of biological processes. We previously constructed a Gγ recruitment system to screen PPI candidate proteins and desirable affinity-altered (affinity-enhanced and affinity-attenuated) protein variants. The methods utilized a target protein fused to a mutated G-protein γ subunit (Gγcyto) lacking the ability to localize to the inner leaflet of the plasma membrane. However, the previous systems were adapted to use only soluble cytosolic proteins as targets. Recently, membrane proteins have been found to form the principal nodes of signaling involved in diseases and have attracted a great deal of interest as primary drug targets. Here, we describe new protocols for the Gγ recruitment systems that are specifically designed to use membrane proteins as targets to overcome previous limitations. These systems represent an attractive approach to exploring novel interacting candidates and affinity-altered protein variants and their interactions with proteins on the inner side of the plasma membrane, with high specificity and selectivity. PMID:26581329

  1. Gene-gene interaction between tuberculosis candidate genes in a South African population.

    PubMed

    de Wit, Erika; van der Merwe, Lize; van Helden, Paul D; Hoal, Eileen G

    2011-02-01

    In a complex disease such as tuberculosis (TB) it is increasingly evident that gene-gene interactions play a far more important role in an individual's susceptibility to develop the disease than single polymorphisms on their own, as one gene can enhance or hinder the expression of another gene. Gene-gene interaction analysis is a new approach to elucidate susceptibility to TB. The possibility of gene-gene interactions was assessed, focusing on 11 polymorphisms in nine genes (DC-SIGN, IFN-γ, IFNGR1, IL-8, IL-1Ra, MBL, NRAMP1, RANTES, and SP-D) that have been associated with TB, some repeatedly. An optimal model, which best describes and predicts TB case-control status, was constructed. Significant interactions were detected between eight pairs of variants. The models fitted the observed data extremely well, with p < 0.0001 for all eight models. A highly significant interaction was detected between INFGR1 and NRAMP1, which is not surprising because macrophage activation is greatly enhanced by IFN-γ and IFN-γ response elements that are present in the human NRAMP1 promoter region, providing further evidence for their interaction. This study enabled us to test the theory that disease outcome may be due to interaction of several gene effects. With eight instances of statistically significant gene-gene interactions, the importance of epistasis is clearly identifiable in this study. Methods for studying gene-gene interactions are based on a multilocus and multigene approach, consistent with the nature of complex-trait diseases, and may provide the paradigm for future genetic studies of TB. PMID:20799037

  2. Capture Hi-C reveals novel candidate genes and complex long-range interactions with related autoimmune risk loci

    PubMed Central

    Martin, Paul; McGovern, Amanda; Orozco, Gisela; Duffus, Kate; Yarwood, Annie; Schoenfelder, Stefan; Cooper, Nicholas J.; Barton, Anne; Wallace, Chris; Fraser, Peter; Worthington, Jane; Eyre, Steve

    2015-01-01

    Genome-wide association studies have been tremendously successful in identifying genetic variants associated with complex diseases. The majority of association signals are intergenic and evidence is accumulating that a high proportion of signals lie in enhancer regions. We use Capture Hi-C to investigate, for the first time, the interactions between associated variants for four autoimmune diseases and their functional targets in B- and T-cell lines. Here we report numerous looping interactions and provide evidence that only a minority of interactions are common to both B- and T-cell lines, suggesting interactions may be highly cell-type specific; some disease-associated SNPs do not interact with the nearest gene but with more compelling candidate genes (for example, FOXO1, AZI2) often situated several megabases away; and finally, regions associated with different autoimmune diseases interact with each other and the same promoter suggesting common autoimmune gene targets (for example, PTPRC, DEXI and ZFP36L1). PMID:26616563

  3. Gene-gene interactions among genetic variants from obesity candidate genes for nonobese and obese populations in type 2 diabetes.

    PubMed

    Lin, Eugene; Pei, Dee; Huang, Yi-Jen; Hsieh, Chang-Hsun; Wu, Lawrence Shih-Hsin

    2009-08-01

    Recent studies indicate that obesity may play a key role in modulating genetic predispositions to type 2 diabetes (T2D). This study examines the main effects of both single-locus and multilocus interactions among genetic variants in Taiwanese obese and nonobese individuals to test the hypothesis that obesity-related genes may contribute to the etiology of T2D independently and/or through such complex interactions. We genotyped 11 single nucleotide polymorphisms for 10 obesity candidate genes including adrenergic beta-2-receptor surface, adrenergic beta-3-receptor surface, angiotensinogen, fat mass and obesity associated gene, guanine nucleotide binding protein beta polypeptide 3 (GNB3), interleukin 6 receptor, proprotein convertase subtilisin/kexin type 1 (PCSK1), uncoupling protein 1, uncoupling protein 2, and uncoupling protein 3. There were 389 patients diagnosed with T2D and 186 age- and sex-matched controls. Single-locus analyses showed significant main effects of the GNB3 and PCSK1 genes on the risk of T2D among the nonobese group (p = 0.002 and 0.047, respectively). Further, interactions involving GNB3 and PCSK1 were suggested among the nonobese population using the generalized multifactor dimensionality reduction method (p = 0.001). In addition, interactions among angiotensinogen, fat mass and obesity associated gene, GNB3, and uncoupling protein 3 genes were found in a significant four-locus generalized multifactor dimensionality reduction model among the obese population (p = 0.001). The results suggest that the single nucleotide polymorphisms from the obesity candidate genes may contribute to the risk of T2D independently and/or in an interactive manner according to the presence or absence of obesity. PMID:19594364

  4. Microbial interactions in crude oils: Possible impact on biochemical versatility on the choice of microbial candidates

    SciTech Connect

    Premuzic, E.T.; Lin, M.S.; Lian, H.

    1995-10-01

    Experimental data gathered over the past several years show that the interactions of microorganisms with crude oils are variable and depend on the microbial species and the chemical composition of crude oils. The variations can be observed in terms of the extent of emulsification, changes in the hydrocarbon composition of crude oils, and duration of biotreatment. All of these factors indicate that the interaction of microbes with crude oils involves multiple chemical reactions resulting from the biochemical interactions between microbes and oils. Different interactions may influence the efficiency of processes in which single or mixed microbial species are used for the oil treatment and may also suggest possible combinations of biological and chemical technologies. Some of these concepts will be discussed in this paper.

  5. Pathway Analysis Incorporating Protein-Protein Interaction Networks Identified Candidate Pathways for the Seven Common Diseases.

    PubMed

    Lin, Peng-Lin; Yu, Ya-Wen; Chung, Ren-Hua

    2016-01-01

    Pathway analysis has become popular as a secondary analysis strategy for genome-wide association studies (GWAS). Most of the current pathway analysis methods aggregate signals from the main effects of single nucleotide polymorphisms (SNPs) in genes within a pathway without considering the effects of gene-gene interactions. However, gene-gene interactions can also have critical effects on complex diseases. Protein-protein interaction (PPI) networks have been used to define gene pairs for the gene-gene interaction tests. Incorporating the PPI information to define gene pairs for interaction tests within pathways can increase the power for pathway-based association tests. We propose a pathway association test, which aggregates the interaction signals in PPI networks within a pathway, for GWAS with case-control samples. Gene size is properly considered in the test so that genes do not contribute more to the test statistic simply due to their size. Simulation studies were performed to verify that the method is a valid test and can have more power than other pathway association tests in the presence of gene-gene interactions within a pathway under different scenarios. We applied the test to the Wellcome Trust Case Control Consortium GWAS datasets for seven common diseases. The most significant pathway is the chaperones modulate interferon signaling pathway for Crohn's disease (p-value = 0.0003). The pathway modulates interferon gamma, which induces the JAK/STAT pathway that is involved in Crohn's disease. Several other pathways that have functional implications for the seven diseases were also identified. The proposed test based on gene-gene interaction signals in PPI networks can be used as a complementary tool to the current existing pathway analysis methods focusing on main effects of genes. An efficient software implementing the method is freely available at http://puppi.sourceforge.net. PMID:27622767

  6. Stochastic Dynamics of the Multi-State Voter Model Over a Network Based on Interacting Cliques and Zealot Candidates

    NASA Astrophysics Data System (ADS)

    Palombi, Filippo; Toti, Simona

    2014-07-01

    The stochastic dynamics of the multi-state voter model is investigated on a class of complex networks made of non-overlapping cliques, each hosting a political candidate and interacting with the others via Erdős-Rényi links. Numerical simulations of the model are interpreted in terms of an ad-hoc mean field theory, specifically tuned to resolve the inter/intra-clique interactions. Under a proper definition of the thermodynamic limit (with the average degree of the agents kept fixed while increasing the network size), the model is found to display the empirical scaling discovered by Fortunato and Castellano (Phys Rev Lett 99(13):138701, 2007) , while the vote distribution resembles roughly that observed in Brazilian elections.

  7. Small molecule inhibitors of the Dishevelled-CXXC5 interaction are new drug candidates for bone anabolic osteoporosis therapy.

    PubMed

    Kim, Hyun-Yi; Choi, Sehee; Yoon, Ji-Hye; Lim, Hwan Jung; Lee, Hyuk; Choi, Jiwon; Ro, Eun Ji; Heo, Jung-Nyoung; Lee, Weontae; No, Kyoung Tai; Choi, Kang-Yell

    2016-01-01

    Bone anabolic agents promoting bone formation and rebuilding damaged bones would ideally overcome the limitations of anti-resorptive therapy, the current standard prescription for osteoporosis. However, the currently prescribed parathyroid hormone (PTH)-based anabolic drugs present limitations and adverse effects including osteosarcoma during long-term use. Also, the antibody-based anabolic drugs that are currently being developed present the potential limits in clinical application typical of macromolecule drugs. We previously identified that CXXC5 is a negative feedback regulator of the Wnt/β-catenin pathway via its interaction with Dishevelled (Dvl) and suggested the Dvl-CXXC5 interaction as a potential target for anabolic therapy of osteoporosis. Here, we screened small-molecule inhibitors of the Dvl-CXXC5 interaction via a newly established in vitro assay system. The screened compounds were found to activate the Wnt/β-catenin pathway and enhance osteoblast differentiation in primary osteoblasts. The bone anabolic effects of the compounds were shown using ex vivo-cultured calvaria. Nuclear magnetic resonance (NMR) titration analysis confirmed interaction between Dvl PDZ domain and KY-02061, a representative of the screened compounds. Oral administration of KY-02327, one of 55 newly synthesized KY-02061 analogs, successfully rescued bone loss in the ovariectomized (OVX) mouse model. In conclusion, small-molecule inhibitors of the Dvl-CXXC5 interaction that block negative feedback regulation of Wnt/β-catenin signaling are potential candidates for the development of bone anabolic anti-osteoporosis drugs. PMID:26941261

  8. Candidate Cell and Matrix Interaction Domains on the Collagen Fibril, the Predominant Protein of Vertebrates

    SciTech Connect

    Sweeney, Shawn M.; Orgel, Joseph P.; Fertala, Andrzej; McAuliffe, Jon D.; Turner, Kevin R.; Di Lullo, Gloria A.; Chen, Steven; Antipova, Olga; Perumal, Shiamalee; Ala-Kokko, Leena; Forlinoi, Antonella; Cabral, Wayne A.; Barnes, Aileen M.; Marini, Joan C.; San Antonio, James D.

    2008-07-18

    Type I collagen, the predominant protein of vertebrates, polymerizes with type III and V collagens and non-collagenous molecules into large cable-like fibrils, yet how the fibril interacts with cells and other binding partners remains poorly understood. To help reveal insights into the collagen structure-function relationship, a data base was assembled including hundreds of type I collagen ligand binding sites and mutations on a two-dimensional model of the fibril. Visual examination of the distribution of functional sites, and statistical analysis of mutation distributions on the fibril suggest it is organized into two domains. The 'cell interaction domain' is proposed to regulate dynamic aspects of collagen biology, including integrin-mediated cell interactions and fibril remodeling. The 'matrix interaction domain' may assume a structural role, mediating collagen cross-linking, proteoglycan interactions, and tissue mineralization. Molecular modeling was used to superimpose the positions of functional sites and mutations from the two-dimensional fibril map onto a three-dimensional x-ray diffraction structure of the collagen microfibril in situ, indicating the existence of domains in the native fibril. Sequence searches revealed that major fibril domain elements are conserved in type I collagens through evolution and in the type II/XI collagen fibril predominant in cartilage. Moreover, the fibril domain model provides potential insights into the genotype-phenotype relationship for several classes of human connective tissue diseases, mechanisms of integrin clustering by fibrils, the polarity of fibril assembly, heterotypic fibril function, and connective tissue pathology in diabetes and aging.

  9. A Library of Plasmodium vivax Recombinant Merozoite Proteins Reveals New Vaccine Candidates and Protein-Protein Interactions

    PubMed Central

    Hostetler, Jessica B.; Sharma, Sumana; Bartholdson, S. Josefin; Wright, Gavin J.; Fairhurst, Rick M.; Rayner, Julian C.

    2015-01-01

    Background A vaccine targeting Plasmodium vivax will be an essential component of any comprehensive malaria elimination program, but major gaps in our understanding of P. vivax biology, including the protein-protein interactions that mediate merozoite invasion of reticulocytes, hinder the search for candidate antigens. Only one ligand-receptor interaction has been identified, that between P. vivax Duffy Binding Protein (PvDBP) and the erythrocyte Duffy Antigen Receptor for Chemokines (DARC), and strain-specific immune responses to PvDBP make it a complex vaccine target. To broaden the repertoire of potential P. vivax merozoite-stage vaccine targets, we exploited a recent breakthrough in expressing full-length ectodomains of Plasmodium proteins in a functionally-active form in mammalian cells and initiated a large-scale study of P. vivax merozoite proteins that are potentially involved in reticulocyte binding and invasion. Methodology/Principal Findings We selected 39 P. vivax proteins that are predicted to localize to the merozoite surface or invasive secretory organelles, some of which show homology to P. falciparum vaccine candidates. Of these, we were able to express 37 full-length protein ectodomains in a mammalian expression system, which has been previously used to express P. falciparum invasion ligands such as PfRH5. To establish whether the expressed proteins were correctly folded, we assessed whether they were recognized by antibodies from Cambodian patients with acute vivax malaria. IgG from these samples showed at least a two-fold change in reactivity over naïve controls in 27 of 34 antigens tested, and the majority showed heat-labile IgG immunoreactivity, suggesting the presence of conformation-sensitive epitopes and native tertiary protein structures. Using a method specifically designed to detect low-affinity, extracellular protein-protein interactions, we confirmed a predicted interaction between P. vivax 6-cysteine proteins P12 and P41, further

  10. The developmental origins of externalizing behavioral problems: parental disengagement and the role of gene-environment interplay.

    PubMed

    Boutwell, Brian B; Beaver, Kevin M; Barnes, James C; Vaske, Jamie

    2012-05-30

    A line of research has revealed that the influence of genes on behavioral development is closely tied to environmental experiences. Known as gene-environment interaction, research in this area is beginning to reveal that variation in parenting behaviors may moderate genetic influences on antisocial behaviors in children. Despite growing interest in gene-environment interaction research, little evidence exists concerning the role of maternal disengagement in the conditioning of genetic influences on childhood behavioral problems. The current study is intended to address this gap in the literature by analyzing a sample of twin pairs drawn from the Early Childhood Longitudinal Study, Birth Cohort (ECLS-B). Analysis of the ECLS-B provided evidence that maternal disengagement moderates genetic influences on the development of externalizing problems. PMID:22421070

  11. Telomere-telomere interactions and candidate telomere binding protein(s) in mammalian sperm cells.

    PubMed

    Zalensky, A O; Tomilin, N V; Zalenskaya, I A; Teplitz, R L; Bradbury, E M

    1997-04-10

    We have used fluorescent in situ hybridization to localize telomeres within the nuclei of sperm from six mammals (human, rat, mouse, stallion, boar, and bull). In minimally swollen sperm of mouse and rat, most of the telomeres are clustered within a limited area in the posterior part of nuclei. In sperm of other species, telomeres associate into tetrameres and dimers. On swelling of sperm cells with heparin/dithiotriethol, telomere associations disperse, and hybridization signals become smaller in size and their numbers approach or correspond to the number of chromosome ends in a haploid genome. Quantitation of telomere loci indicates that dimeric associations are prominent features of mammalian sperm nuclear architecture. Higher order telomere-telomere interactions and organization develop during meiotic stages of human spermatogenesis. At this stage, telomeres also become associated with the nuclear membrane. In an attempt to elucidate the molecular mechanisms underlying telomere interactions in sperm, we have identified a novel protein activity that binds to the double-stranded telomeric repeat (TTAGGG)n. Sperm telomere binding protein(s) (STBP) was extracted from human and bull sperm by 0.5 M NaCl. STBP does not bind single-stranded telomeric DNA and is highly specific for single base substitutions in a duplex DNA sequence. Depending on the conditions of binding, we observed the formation of several nucleoprotein complexes. We have shown that there is a transition between complexes, which indicates that the slower migrating complex is a multimer of the higher mobility one. We propose that STBP participates in association between the telomere domains which were microscopically observed in mammalian spermatozoa. PMID:9141618

  12. Gene-Environment Interplay between Parent-Child Relationship Problems and Externalizing Disorders in Adolescence and Young Adulthood

    PubMed Central

    Samek, Diana R.; Hicks, Brian M.; Keyes, Margaret A.; Bailey, Jennifer; McGue, Matt; Iacono, William G.

    2014-01-01

    Background Previous studies have shown that genetic risk for externalizing (EXT) disorders is greater in the context of adverse family environments during adolescence, but it is unclear whether these effects are long-lasting. The current study evaluated developmental changes in gene-environment interplay in the concurrent and prospective associations between parent-child relationship problems and EXT at ages 18 and 25. Method The sample included 1,382 twin pairs (48% male) from the Minnesota Twin Family Study, participating in assessments at ages 18 (M = 17.8 years, SD = 0.69) and 25 (M = 25.0 years, SD = 0.90). Perceptions of parent-child relationship problems were assessed using questionnaires. Structured interviews were used to assess symptoms of adult antisocial behavior and nicotine, alcohol, and illicit drug dependence. Results We detected a gene-environment interaction at age 18, such that the genetic influence on EXT was greater in the context of more parent-child relationship problems. This moderation effect was not present at age 25, nor did parent-relationship problems at age 18 moderate genetic influence on EXT at age 25. Rather, common genetic influences accounted for this longitudinal association. Conclusions Gene-environment interaction evident in the relationship between adolescent parent-child relationship problems and EXT is both proximal and developmentally limited. Common genetic influence, rather than a gene-environment interaction, accounts for the long-term association between parent-child relationship problems at age 18 and EXT at age 25. These results are consistent with a relatively pervasive importance of gene-environmental correlation in the transition from late adolescence to young adulthood. PMID:25066478

  13. Jenner-predict server: prediction of protein vaccine candidates (PVCs) in bacteria based on host-pathogen interactions

    PubMed Central

    2013-01-01

    Background Subunit vaccines based on recombinant proteins have been effective in preventing infectious diseases and are expected to meet the demands of future vaccine development. Computational approach, especially reverse vaccinology (RV) method has enormous potential for identification of protein vaccine candidates (PVCs) from a proteome. The existing protective antigen prediction software and web servers have low prediction accuracy leading to limited applications for vaccine development. Besides machine learning techniques, those software and web servers have considered only protein’s adhesin-likeliness as criterion for identification of PVCs. Several non-adhesin functional classes of proteins involved in host-pathogen interactions and pathogenesis are known to provide protection against bacterial infections. Therefore, knowledge of bacterial pathogenesis has potential to identify PVCs. Results A web server, Jenner-Predict, has been developed for prediction of PVCs from proteomes of bacterial pathogens. The web server targets host-pathogen interactions and pathogenesis by considering known functional domains from protein classes such as adhesin, virulence, invasin, porin, flagellin, colonization, toxin, choline-binding, penicillin-binding, transferring-binding, fibronectin-binding and solute-binding. It predicts non-cytosolic proteins containing above domains as PVCs. It also provides vaccine potential of PVCs in terms of their possible immunogenicity by comparing with experimentally known IEDB epitopes, absence of autoimmunity and conservation in different strains. Predicted PVCs are prioritized so that only few prospective PVCs could be validated experimentally. The performance of web server was evaluated against known protective antigens from diverse classes of bacteria reported in Protegen database and datasets used for VaxiJen server development. The web server efficiently predicted known vaccine candidates reported from Streptococcus pneumoniae and

  14. Evidence of reactive gene-environment correlation in preschoolers' prosocial play with unfamiliar peers.

    PubMed

    DiLalla, Lisabeth Fisher; Bersted, Kyle; John, Sufna Gheyara

    2015-10-01

    The development of prosocial behaviors during the preschool years is essential for children's positive interactions with peers in school and other social situations. Although there is some evidence of genetic influences on prosocial behaviors, very little is known about how genes and environment, independently and in concert, affect prosocial behaviors in young children. This study of 126 twin and sibling pairs examined 5-year-old preschool children's positive behaviors (prosocial and easy-going) while playing freely with an unfamiliar, same-age, same-sex peer. Children were randomly paired, allowing us to rule out passive (parent-influenced environment) and active (child-driven peer choices) gene-environment correlations as potential influences on the results. We found evidence of reactive gene-environment correlation, demonstrating that children who are genetically more likely to act prosocially and to be temperamentally outgoing appear to evoke more prosocial and easy-going behaviors from an unfamiliar peer. We also found that both dominant genetic and nonshared environmental factors were significant influences on preschoolers' prosocial play behaviors, but that neither genetic nor shared environmental factors were significant for easy-going play behaviors. These findings shed important light on influences of prosocial behaviors in preschoolers. Via inherited tendencies, preschool children's positive behaviors evoke similar positive behaviors from their play peers. Given that prosocial behaviors are preludes to a large range of important socially appropriate behaviors, prosocial children should be encouraged to interact with their peers to potentially create a more positive atmosphere within social contexts. PMID:26372295

  15. Multilocus analyses of seven candidate genes suggest interacting pathways for obesity-related traits in Brazilian populations.

    PubMed

    Angeli, Cláudia B; Kimura, Lilian; Auricchio, Maria T; Vicente, João P; Mattevi, Vanessa S; Zembrzuski, Verônica M; Hutz, Mara H; Pereira, Alexandre C; Pereira, Tiago V; Mingroni-Netto, Regina C

    2011-06-01

    We investigated whether variants in major candidate genes for food intake and body weight regulation contribute to obesity-related traits under a multilocus perspective. We studied 375 Brazilian subjects from partially isolated African-derived populations (quilombos). Seven variants displaying conflicting results in previous reports and supposedly implicated in the susceptibility of obesity-related phenotypes were investigated: β2-adrenergic receptor (ADRB2) (Arg16Gly), insulin induced gene 2 (INSIG2) (rs7566605), leptin (LEP) (A19G), LEP receptor (LEPR) (Gln223Arg), perilipin (PLIN) (6209T > C), peroxisome proliferator-activated receptor-γ (PPARG) (Pro12Ala), and resistin (RETN) (-420 C > G). Regression models as well as generalized multifactor dimensionality reduction (GMDR) were employed to test the contribution of individual effects and higher-order interactions to BMI and waist-hip ratio (WHR) variation and risk of overweight/obesity. The best multilocus association signal identified in the quilombos was further examined in an independent sample of 334 Brazilian subjects of European ancestry. In quilombos, only the PPARG polymorphism displayed significant individual effects (WHR variation, P = 0.028). No association was observed either with the risk of overweight/obesity (BMI ≥ 25 kg/m2), risk of obesity alone (BMI ≥ 30 kg/m2) or BMI variation. However, GMDR analyses revealed an interaction between the LEPR and ADRB2 polymorphisms (P = 0.009) as well as a third-order effect involving the latter two variants plus INSIG2 (P = 0.034) with overweight/obesity. Assessment of the LEPR-ADRB2 interaction in the second sample indicated a marginally significant association (P = 0.0724), which was further verified to be limited to men (P = 0.0118). Together, our findings suggest evidence for a two-locus interaction between the LEPR Gln223Arg and ADRB2 Arg16Gly variants in the risk of overweight/obesity, and highlight further the importance of multilocus effects in

  16. Gene-Environment Interplay and Psychopathology: Multiple Varieties but Real Effects

    ERIC Educational Resources Information Center

    Rutter, Michael; Moffitt, Terrie E.; Caspi, Avshalom

    2006-01-01

    Gene-environment interplay is a general term that covers several divergent concepts with different meanings and different implications. In this review, we evaluate research evidence on four varieties of gene-environment interplay. First, we consider epigenetic mechanisms by which environmental influences alter the effects of genes. Second, we…

  17. Identification and Characterization of a Candidate Wolbachia pipientis Type IV Effector That Interacts with the Actin Cytoskeleton

    PubMed Central

    Sheehan, Kathy B.; Martin, MaryAnn; Lesser, Cammie F.; Isberg, Ralph R.

    2016-01-01

    ABSTRACT Many bacteria live as intracellular symbionts, causing persistent infections within insects. One extraordinarily common infection is that of Wolbachia pipientis, which infects 40% of insect species and induces reproductive effects. The bacteria are passed from generation to generation both vertically (through the oocyte) and horizontally (by environmental transmission). Maintenance of the infection within Drosophila melanogaster is sensitive to the regulation of actin, as Wolbachia inefficiently colonizes strains hemizygous for the profilin or villin genes. Therefore, we hypothesized that Wolbachia must depend on the host actin cytoskeleton. In this study, we identify and characterize a Wolbachia protein (WD0830) that is predicted to be secreted by the bacterial parasite. Expression of WD0830 in a model eukaryote (the yeast Saccharomyces cerevisiae) induces a growth defect associated with the appearance of aberrant, filamentous structures which colocalize with rhodamine-phalloidin-stained actin. Purified WD0830 bundles actin in vitro and cosediments with actin filaments, suggesting a direct interaction of the two proteins. We characterized the expression of WD0830 throughout Drosophila development and found it to be upregulated in third-instar larvae, peaking in early pupation, during the critical formation of adult tissues, including the reproductive system. In transgenic flies, heterologously expressed WD0830 localizes to the developing oocyte. Additionally, overexpression of WD0830 results in increased Wolbachia titers in whole flies, in stage 9 and 10 oocytes, and in embryos, compared to controls, suggesting that the protein may facilitate Wolbachia’s replication or transmission. Therefore, this candidate secreted effector may play a role in Wolbachia’s infection of and persistence within host niches. PMID:27381293

  18. Dual RNA-seq reveals Meloidogyne graminicola transcriptome and candidate effectors during the interaction with rice plants.

    PubMed

    Petitot, Anne-Sophie; Dereeper, Alexis; Agbessi, Mawusse; Da Silva, Corinne; Guy, Julie; Ardisson, Morgane; Fernandez, Diana

    2016-08-01

    Root-knot nematodes secrete proteinaceous effectors into plant tissues to facilitate infection by suppressing host defences and reprogramming the host metabolism to their benefit. Meloidogyne graminicola is a major pest of rice (Oryza sativa) in Asia and Latin America, causing important crop losses. The goal of this study was to identify M. graminicola pathogenicity genes expressed during the plant-nematode interaction. Using the dual RNA-sequencing (RNA-seq) strategy, we generated transcriptomic data of M. graminicola samples covering the pre-parasitic J2 stage and five parasitic stages in rice plants, from the parasitic J2 to the adult female. In the absence of a reference genome, a de novo M. graminicola transcriptome of 66 396 contigs was obtained from those reads that were not mapped on the rice genome. Gene expression profiling across the M. graminicola life cycle revealed key genes involved in nematode development and provided insights into the genes putatively associated with parasitism. The development of a 'secreted protein prediction' pipeline revealed a typical set of proteins secreted by nematodes, as well as a large number of cysteine-rich proteins and putative nuclear proteins. Combined with expression data, this pipeline enabled the identification of 15 putative effector genes, including two homologues of well-characterized effectors from cyst nematodes (CLE-like and VAP1) and a metallothionein. The localization of gene expression was assessed by in situ hybridization for a subset of candidates. All of these data represent important molecular resources for the elucidation of M. graminicola biology and for the selection of potential targets for the development of novel control strategies for this nematode species. PMID:26610268

  19. Interactions between a Candidate Gene for Migration (ADCYAP1), Morphology and Sex Predict Spring Arrival in Blackcap Populations.

    PubMed

    Mettler, Raeann; Segelbacher, Gernot; Schaefer, H Martin

    2015-01-01

    Avian research has begun to reveal associations between candidate genes and migratory behaviors of captive birds, yet few studies utilize genotypic, morphometric, and phenological data from wild individuals. Previous studies have identified an association between ADCYAP1 polymorphism and autumn migratory behavior (restlessness, or zugunruhe), but little is known about the relationship between ADCYAP1 and spring migratory behavior. The timing of spring migration and arrival to the breeding ground are phenological traits which could be particularly favorable for establishing territories and acquiring mates, thus important to fitness and reproductive success. Here, we investigated how individual genotypic ADCYAP1 variation and phenotypic variation (wing length and shape) of blackcaps (Sylvia atricapilla) affect spring arrival date across nine natural populations in Europe. We hypothesized that longer alleles should be associated with earlier spring arrival dates and expected the effect on arrival date to be stronger for males as they arrive earlier. However, we found that longer wings were associated with earlier spring arrival to the breeding grounds for females, but not for males. Another female-specific effect indicated an interaction between ADCYAP1 allele size and wing pointedness on the response of spring arrival: greater allele size had a positive effect on spring arrival date for females with rounder wings, while a negative effect was apparent for females with more pointed wings. Also, female heterozygotes with pointed wing tips arrived significantly earlier than both homozygotes with pointed wings and heterozygotes with round wings. Stable isotope ratios (δ2H) of a subset of blackcaps captured in Freiburg in 2011 allowed us also to assign individuals to their main overwintering areas in northwest (NW) and southwest (SW) Europe. NW males arrived significantly earlier to the Freiburg breeding site than both SW males and females in 2011. NW females had more

  20. Interactions between a Candidate Gene for Migration (ADCYAP1), Morphology and Sex Predict Spring Arrival in Blackcap Populations

    PubMed Central

    2015-01-01

    Avian research has begun to reveal associations between candidate genes and migratory behaviors of captive birds, yet few studies utilize genotypic, morphometric, and phenological data from wild individuals. Previous studies have identified an association between ADCYAP1 polymorphism and autumn migratory behavior (restlessness, or zugunruhe), but little is known about the relationship between ADCYAP1 and spring migratory behavior. The timing of spring migration and arrival to the breeding ground are phenological traits which could be particularly favorable for establishing territories and acquiring mates, thus important to fitness and reproductive success. Here, we investigated how individual genotypic ADCYAP1 variation and phenotypic variation (wing length and shape) of blackcaps (Sylvia atricapilla) affect spring arrival date across nine natural populations in Europe. We hypothesized that longer alleles should be associated with earlier spring arrival dates and expected the effect on arrival date to be stronger for males as they arrive earlier. However, we found that longer wings were associated with earlier spring arrival to the breeding grounds for females, but not for males. Another female-specific effect indicated an interaction between ADCYAP1 allele size and wing pointedness on the response of spring arrival: greater allele size had a positive effect on spring arrival date for females with rounder wings, while a negative effect was apparent for females with more pointed wings. Also, female heterozygotes with pointed wing tips arrived significantly earlier than both homozygotes with pointed wings and heterozygotes with round wings. Stable isotope ratios (δ2H) of a subset of blackcaps captured in Freiburg in 2011 allowed us also to assign individuals to their main overwintering areas in northwest (NW) and southwest (SW) Europe. NW males arrived significantly earlier to the Freiburg breeding site than both SW males and females in 2011. NW females had more

  1. Gene-Environment Interplay in the Association between Pubertal Timing and Delinquency in Adolescent Girls

    PubMed Central

    Harden, K. Paige; Mendle, Jane

    2014-01-01

    Early pubertal timing places girls at elevated risk for a breadth of negative outcomes, including involvement in delinquent behavior. While previous developmental research has emphasized the unique social challenges faced by early maturing girls, this relation is complicated by genetic influences for both delinquent behavior and pubertal timing, which are seldom controlled for in existing research. The current study uses genetically informed data on 924 female-female twin and sibling pairs drawn from the National Longitudinal Study of Adolescent Health to (1) disentangle biological versus environmental mechanisms for the effects of early pubertal timing and (2) test for gene-environment interactions. Results indicate that early pubertal timing influences girls’ delinquency through a complex interplay between biological risk and environmental experiences. Genes related to earlier age at menarche and higher perceived development significantly predict increased involvement in both non-violent and violent delinquency. Moreover, after accounting for this genetic association between pubertal timing and delinquency, the impact of non-shared environmental influences on delinquency are significantly moderated by pubertal timing, such that the non-shared environment is most important among early maturing girls. This interaction effect is particularly evident for non-violent delinquency. Overall, results suggest early maturing girls are vulnerable to an interaction between genetic and environmental risks for delinquent behavior. PMID:21668078

  2. Life events in panic disorder-an update on "candidate stressors".

    PubMed

    Klauke, Benedikt; Deckert, Jürgen; Reif, Andreas; Pauli, Paul; Domschke, Katharina

    2010-08-01

    Studies on gene-environment interactions in mental disorders are characterized by powerful genetic techniques and well defined "candidate genes," whereas a definition of "candidate stressors," in most cases assessed in the form of life events (LEs), is inconsistent or not even provided. This review addresses this problem, with particular attention to the clinical phenotype of panic disorder (PD), by providing an overview and critical discussion for which life events are known to contribute to the etiology of the disease and how they may be conceptualized. There is converging evidence for a significant impact of cumulative as well as specific life events, such as threat, interpersonal and health-related events in adulthood, and abuse or loss/separation experiences in childhood, respectively, on the pathogenesis of panic disorder with some overlapping effect across the anxiety disorder spectrum as well as on comorbid major depression. Besides genetic vulnerability factors, personality and behavioral characteristics, such as anxiety sensitivity, neuroticism, and cognitive appraisal might moderate the influence of LEs on the development of panic disorder. The present state of knowledge regarding the specification and conceptualization of LEs in PD within a more complex multifactorial model, involving mediating and moderating factors in between genes and the clinical phenotype, is hoped to aid in informing future gene-environment interaction studies in panic disorder. PMID:20112245

  3. Interactive effect of two candidate genes in a disease: Extension of the marker-association-segregation {chi}{sup 2} method

    SciTech Connect

    Dizier, M.H.; Babron, M.C.; Clerget-Darpoux, F.

    1994-11-01

    For elucidating the genetic component of multifactorial diseases, it is important to investigate the effect of several factors and the possible interaction between them. In particular, for many diseases it is interesting to study the interactive effect of two genes. In this context, the marker-association-segregation {chi}{sup 2} method (MASC), initially proposed to detect the involvement of a candidate gene in multifactorial diseases, is developed here to investigate the involvement of two candidate genes and to model the joint effect of these two genes. In particular, it is possible to precisely determine whether the joint effect of both genes is multiplicative. This extension simultaneously uses information on two markers, one for each candidate gene, at both the population and the familial segregation level. We show here that there can be an important gain of power to detect the effect of a second gene in a disease when information is used simultaneously on two markers instead of studying each marker separately. This extension of MASC is then applied on a sample of insulin-dependent diabetes (IDD) families typed for the markers of two candidate regions: HLA and that of the insulin gene (INS). This analysis allows us to confirm the involvement of INS in IDD, and the best-fitting model is a multiplicative (noninteractive) effect of HLA and INS, with a biallelic locus for INS and a complementation model for HLA. 21 refs., 1 fig., 4 tabs.

  4. Genes, environment, and individual differences in responding to treatment for depression.

    PubMed

    Uher, Rudolf

    2011-01-01

    A principal weakness of evidence-based psychiatry is that it does not account for the individual variability in therapeutic response among individuals with the same diagnosis. The aim of personalized psychiatry is to remediate this shortcoming and to use predictors to select treatment that is most likely to be beneficial for an individual. This article reviews the evidence that genetic variation, environmental exposures, and gene-environment interactions shape mental illness and influence treatment outcomes, with a primary focus on depression. Several genetic polymorphisms have been identified that influence the outcome of specific treatments, but the strength and generalizability of such influences are not sufficient to justify personalized prescribing. Environmental exposures in early life, such as childhood maltreatment, exert long-lasting influences that are moderated by inherited genetic variation and mediated through stable epigenetic mechanisms such as tissue- and gene-specific DNA methylation. Pharmacological and psychological treatments act on and against the background of genetic disposition, with epigenetic annotation resulting from previous experiences. Research in animal models suggests the possibility that epigenetic interventions may modify the impact of environmental stressors on mental health. Gaps in evidence are identified that need to be bridged before knowledge about cause can inform cure in personalized psychiatry. PMID:21631158

  5. Identification of novel candidate drivers connecting different dysfunctional levels for lung adenocarcinoma using protein-protein interactions and a shortest path approach

    PubMed Central

    Chen, Lei; Huang, Tao; Zhang, Yu-Hang; Jiang, Yang; Zheng, Mingyue; Cai, Yu-Dong

    2016-01-01

    Tumors are formed by the abnormal proliferation of somatic cells with disordered growth regulation under the influence of tumorigenic factors. Recently, the theory of “cancer drivers” connects tumor initiation with several specific mutations in the so-called cancer driver genes. According to the differentiation of four basic levels between tumor and adjacent normal tissues, the cancer drivers can be divided into the following: (1) Methylation level, (2) microRNA level, (3) mutation level, and (4) mRNA level. In this study, a computational method is proposed to identify novel lung adenocarcinoma drivers based on dysfunctional genes on the methylation, microRNA, mutation and mRNA levels. First, a large network was constructed using protein-protein interactions. Next, we searched all of the shortest paths connecting dysfunctional genes on different levels and extracted new candidate genes lying on these paths. Finally, the obtained candidate genes were filtered by a permutation test and an additional strict selection procedure involving a betweenness ratio and an interaction score. Several candidate genes remained, which are deemed to be related to two different levels of cancer. The analyses confirmed our assertions that some have the potential to contribute to the tumorigenesis process on multiple levels. PMID:27412431

  6. Identification of novel candidate drivers connecting different dysfunctional levels for lung adenocarcinoma using protein-protein interactions and a shortest path approach.

    PubMed

    Chen, Lei; Huang, Tao; Zhang, Yu-Hang; Jiang, Yang; Zheng, Mingyue; Cai, Yu-Dong

    2016-01-01

    Tumors are formed by the abnormal proliferation of somatic cells with disordered growth regulation under the influence of tumorigenic factors. Recently, the theory of "cancer drivers" connects tumor initiation with several specific mutations in the so-called cancer driver genes. According to the differentiation of four basic levels between tumor and adjacent normal tissues, the cancer drivers can be divided into the following: (1) Methylation level, (2) microRNA level, (3) mutation level, and (4) mRNA level. In this study, a computational method is proposed to identify novel lung adenocarcinoma drivers based on dysfunctional genes on the methylation, microRNA, mutation and mRNA levels. First, a large network was constructed using protein-protein interactions. Next, we searched all of the shortest paths connecting dysfunctional genes on different levels and extracted new candidate genes lying on these paths. Finally, the obtained candidate genes were filtered by a permutation test and an additional strict selection procedure involving a betweenness ratio and an interaction score. Several candidate genes remained, which are deemed to be related to two different levels of cancer. The analyses confirmed our assertions that some have the potential to contribute to the tumorigenesis process on multiple levels. PMID:27412431

  7. Identification of New Candidate Genes and Chemicals Related to Esophageal Cancer Using a Hybrid Interaction Network of Chemicals and Proteins

    PubMed Central

    Liu, Junbao; Li, Li-Peng; He, Yi-Chun; Gao, Ru-Jian; Cai, Yu-Dong; Jiang, Yang

    2015-01-01

    Cancer is a serious disease responsible for many deaths every year in both developed and developing countries. One reason is that the mechanisms underlying most types of cancer are still mysterious, creating a great block for the design of effective treatments. In this study, we attempted to clarify the mechanism underlying esophageal cancer by searching for novel genes and chemicals. To this end, we constructed a hybrid network containing both proteins and chemicals, and generalized an existing computational method previously used to identify disease genes to identify new candidate genes and chemicals simultaneously. Based on jackknife test, our generalized method outperforms or at least performs at the same level as those obtained by a widely used method - the Random Walk with Restart (RWR). The analysis results of the final obtained genes and chemicals demonstrated that they highly shared gene ontology (GO) terms and KEGG pathways with direct and indirect associations with esophageal cancer. In addition, we also discussed the likelihood of selected candidate genes and chemicals being novel genes and chemicals related to esophageal cancer. PMID:26058041

  8. Topology assessment, G protein-coupled receptor (GPCR) prediction, and in vivo interaction assays to identify plant candidate GPCRs.

    PubMed

    Gookin, Timothy E; Bendtsen, Jannick D

    2013-01-01

    Genomic sequencing has provided a vast resource for identifying interesting genes, but often an exact "gene-of-interest" is unknown and is only described as putatively present in a genome by an observed phenotype, or by the known presence of a conserved signaling cascade, such as that facilitated by the heterotrimeric G-protein. The low sequence similarity of G protein-coupled receptors (GPCRs) and the absence of a known ligand with an associated high-throughput screening system in plants hampers their identification by simple BLAST queries or brute force experimental assays. Combinatorial bioinformatic analysis is useful in that it can reduce a large pool of possible candidates to a number manageable by medium or even low-throughput methods. Here we describe a method for the bioinformatic identification of candidate GPCRs from whole proteomes and their subsequent in vivo analysis for G-protein coupling using a membrane based yeast two-hybrid variant (Gookin et al., Genome Biol 9:R120, 2008). Rather than present the bioinformatic process in a format requiring scripts or computer programming knowledge, we describe procedures here in a simple, biologist-friendly outline that only utilizes the basic syntax of regular expressions. PMID:23913030

  9. ALS: A bucket of genes, environment, metabolism and unknown ingredients.

    PubMed

    Zufiría, Mónica; Gil-Bea, Francisco Javier; Fernández-Torrón, Roberto; Poza, Juan José; Muñoz-Blanco, Jose Luis; Rojas-García, Ricard; Riancho, Javier; de Munain, Adolfo López

    2016-07-01

    The scientific scenario of amyotrophic lateral sclerosis (ALS) has dramatically changed since TDP-43 aggregates were discovered in 2006 as the main component of the neuronal inclusions seen in the disease, and more recently, when the implication of C9ORF72 expansion in familial and sporadic cases of ALS and frontotemporal dementia was confirmed. These discoveries have enlarged an extense list of genes implicated in different cellular processes such as RNA processing or autophagia among others and have broaden the putative molecular targets of the disease. Some of ALS-related genes such as TARDBP or SOD1 among others have important roles in the regulation of glucose and fatty acids metabolism, so that an impairment of fatty acids (FA) consumption and ketogenic deficits during exercise in ALS patients would connect the physiopathology with some of the more intriguing epidemiological traits of the disease. The current understanding of ALS as part of a continuum with other neurodegenerative diseases and a crossroads between genetic, neurometabolic and environmental factors represent a fascinating model of interaction that could be translated to other neurodegenerative diseases. In this review we summarize the most relevant data obtained in the ten last years and the key lines for future research in ALS. PMID:27236050

  10. Satiety and the Self-Regulation of Food Take in Children: a Potential Role for Gene-Environment Interplay.

    PubMed

    Hughes, Sheryl O; Frazier-Wood, Alexis C

    2016-03-01

    Child eating self-regulation refers to behaviors that enable children to start and stop eating in a manner consistent with maintaining energy balance. Perturbations in these behaviors, manifesting as poorer child eating self-regulation, are associated with higher child weight status. Initial research into child eating self-regulation focused on the role of parent feeding styles and behaviors. However, we argue that child eating self-regulation is better understood as arising from a complex interplay between the child and their feeding environment, and highlight newer research into the heritable child characteristics, such as cognitive ability, that play an important role in this dynamic. Therefore, child eating self-regulation arises from gene-environment interactions. Identifying the genes and environmental influences contributing to these will help us tailor our parental feeding advice to the unique nature of the child. In this way, we will devise more effective advice for preventing childhood obesity. PMID:26847550