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

PubMed Central

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

2014-01-01

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

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

PubMed

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

2014-12-01

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

Gene-Environment Interactions in Schizophrenia: Review of Epidemiological Findings and Future Directions

PubMed Central

van Os, Jim; Rutten, Bart PF; Poulton, Richie

2008-01-01

Concern is building about high rates of schizophrenia in large cities, and among immigrants, cannabis users, and traumatized individuals, some of which likely reflects the causal influence of environmental exposures. This, in combination with very slow progress in the area of molecular genetics, has generated interest in more complicated models of schizophrenia etiology that explicitly posit gene-environment interactions (EU-GEI. European Network of Schizophrenia Networks for the Study of Gene Environment Interactions. Schizophrenia aetiology: do gene-environment interactions hold the key? [published online ahead of print April 25, 2008] Schizophr Res; S0920-9964(08) 00170–9). Although findings of epidemiological gene-environment interaction (G × E) studies are suggestive of widespread gene-environment interactions in the etiology of schizophrenia, numerous challenges remain. For example, attempts to identify gene-environment interactions cannot be equated with molecular genetic studies with a few putative environmental variables “thrown in”: G × E is a multidisciplinary exercise involving epidemiology, psychology, psychiatry, neuroscience, neuroimaging, pharmacology, biostatistics, and genetics. Epidemiological G × E studies using indirect measures of genetic risk in genetically sensitive designs have the advantage that they are able to model the net, albeit nonspecific, genetic load. In studies using direct molecular measures of genetic variation, a hypothesis-driven approach postulating synergistic effects between genes and environment impacting on a final common pathway, such as “sensitization” of mesolimbic dopamine neurotransmission, while simplistic, may provide initial focus and protection against the numerous false-positive and false-negative results that these investigations engender. Experimental ecogenetic approaches with randomized assignment may help to overcome some of the limitations of observational studies and allow for the additional elucidation of underlying mechanisms using a combination of functional enviromics and functional genomics. PMID:18791076

Nature versus nurture: death of a dogma, and the road ahead.

PubMed

Traynor, Bryan J; Singleton, Andrew B

2010-10-21

Interaction between the genome and the environment has been widely discussed in the literature, but has the importance ascribed to understanding these interactions been overstated? In this opinion piece, we critically discuss gene-environment interactions and attempt to answer three key questions. First, is it likely that gene-environment interactions actually exist? Second, what is the realistic value of trying to unravel these interactions, both in terms of understanding disease pathogenesis and as a means of ameliorating disease? Finally, and most importantly, do the technologies and methodologies exist to facilitate an unbiased search for gene-environment interactions? Addressing these questions highlights key areas of feasibility that must be considered in this area of research. Copyright © 2010 Elsevier Inc. All rights reserved.

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…

Does parental divorce moderate the heritability of body dissatisfaction? An extension of previous gene-environment interaction effects.

PubMed

O'Connor, Shannon M; Klump, Kelly L; VanHuysse, Jessica L; McGue, Matt; Iacono, William

2016-02-01

Previous research suggests that parental divorce moderates genetic influences on body dissatisfaction. Specifically, the heritability of body dissatisfaction is higher in children of divorced versus intact families, suggesting possible gene-environment interaction effects. However, prior research is limited to a single, self-reported measure of body dissatisfaction. The primary aim of this study was to examine whether these findings extend to a different dimension of body dissatisfaction: body image perceptions. Participants were 1,534 female twins from the Minnesota Twin Family Study, aged 16-20 years. The Body Rating Scale (BRS) was used to assess body image perceptions. Although BRS scores were heritable in twins from divorced and intact families, the heritability estimates in the divorced group were not significantly greater than estimates in the intact group. However, there were differences in nonshared environmental effects, where the magnitude of these environmental influences was larger in the divorced as compared with the intact families. Different dimensions of body dissatisfaction (i.e., negative self-evaluation versus body image perceptions) may interact with environmental risk, such as parental divorce, in discrete ways. Future research should examine this possibility and explore differential gene-environment interactions using diverse measures. © 2015 Wiley Periodicals, Inc.

Childhood temperament: passive gene-environment correlation, gene-environment interaction, and the hidden importance of the family environment.

PubMed

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

2013-02-01

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 (mean 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.

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…

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

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…

Peer Influence, Genetic Propensity, and Binge Drinking: A Natural Experiment and a Replication.

PubMed

Guo, Guang; Li, Yi; Wang, Hongyu; Cai, Tianji; Duncan, Greg J

2015-11-01

The authors draw data from the College Roommate Study (ROOM) and the National Longitudinal Study of Adolescent Health to investigate gene-environment interaction effects on youth binge drinking. In ROOM, the environmental influence was measured by the precollege drinking behavior of randomly assigned roommates. Random assignment safeguards against friend selection and removes the threat of gene-environment correlation that makes gene-environment interaction effects difficult to interpret. On average, being randomly assigned a drinking peer as opposed to a nondrinking peer increased college binge drinking by 0.5-1.0 episodes per month, or 20%-40% the average amount of binge drinking. However, this peer influence was found only among youths with a medium level of genetic propensity for alcohol use; those with either a low or high genetic propensity were not influenced by peer drinking. A replication of the findings is provided in data drawn from Add Health. The study shows that gene-environment interaction analysis can uncover social-contextual effects likely to be missed by traditional sociological approaches.

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…

The case-only test for gene-environment interaction is not uniformly powerful: an empirical example

PubMed Central

Wu, Chen; Chang, Jiang; Ma, Baoshan; Miao, Xiaoping; Zhou, Yifeng; Liu, Yu; Li, Yun; Wu, Tangchun; Hu, Zhibin; Shen, Hongbing; Jia, Weihua; Zeng, Yixin; Lin, Dongxin; Kraft, Peter

2016-01-01

The case-only test has been proposed as a more powerful approach to detect gene-environment (G×E) interactions. This approach assumes that the genetic and environmental factors are independent. While it is well known that Type I error rate will increase if this assumption is violated, it is less widely appreciated that gene-environment correlation can also lead to power loss. We illustrate this phenomenon by comparing the performance of the case-only test to other approaches to detect G×E interactions in a genome-wide association study of esophageal squamous carcinoma (ESCC) in Chinese populations. Some of these approaches do not use information on the correlation between exposure and genotype (standard logistic regression), while others seek to use this information in a robust fashion to boost power without increasing Type I error (two-step, empirical Bayes and cocktail methods). G×E interactions were identified involving drinking status and two regions containing genes in the alcohol metabolism pathway, 4q23 and 12q24. Although the case-only test yielded the most significant tests of G×E interaction in the 4q23 region, the case-only test failed to identify significant interactions in the 12q24 region which were readily identified using other approaches. The low power of the case-only test in the 12q24 region is likely due to the strong inverse association between the SNPs in this region and drinking status. This example underscores the need to consider multiple approaches to detect gene-environment interactions, as different tests are more or less sensitive to different alternative hypotheses and violations of the gene-environment independence assumption. PMID:23595356

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

USDA-ARS?s Scientific Manuscript database

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...

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

Mental and physical distress is modulated by a polymorphism in the 5-HT transporter gene interacting with social stressors and chronic disease burden.

PubMed

Grabe, H J; Lange, M; Wolff, B; Völzke, H; Lucht, M; Freyberger, H J; John, U; Cascorbi, I

2005-02-01

Previous studies have yielded conflicting results as to the putative role of the functional polymorphism of the promoter region of the serotonin transporter gene (SLC6A4) in the etiology of anxiety-related traits and depressive disorders. Recently, a significant gene-environment interaction was found between life stressors, the short allele of the SLC6A4 polymorphism and depression. The aim of the present study was to investigate if such a gene-environment interaction could be replicated within a different population with a different risk structure. A total of 1005 subjects from a general population sample (Study of Health in Pomerania) were genotyped. Mental and physical distress were assessed on 38 items of the modified complaint scale (BL-38). The interaction between the SLC6A4 genotype, social stressors and chronic diseases with regard to the BL-38 score was evaluated by ANOVA. There was no independent association of genotype with mental and physical distress. However, significant interactions between genotype, unemployment and chronic diseases (F = 6.6; df = 3, 671; P < 0.001) were found in females but not in males. The genotype explained 2% of the total variance of the BL-38 score and 9.1% of the explained variance. The results partly confirm previous findings of a significant gene-environment interaction of the short allele, indicating a higher mental vulnerability to social stressors and chronic diseases. The relevance of this finding is sustained by the fact that the sample characteristics and the risk structure were highly different from previous studies.

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…

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.…

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

PubMed

Ordovás, José M; Robertson, Ruairi; Cléirigh, Ellen Ní

2011-04-01

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 dyslipidemia. Many of these chronic illnesses can be partially blamed by altered lipid metabolism, combined with individual genetic components. Critical evaluation and comparison of these recent studies is essential in order to comprehend the results, conclusions and future prospects in the field of genomics as a whole. Recent literature elucidates significant gene--diet and gene--environment interactions resulting in altered lipid metabolism, inflammation and other metabolic imbalances leading to cardiovascular disease and obesity. Epigenetic and epistatic interactions are now becoming more significantly associated with such disorders, as genomic research digs deeper into the complex nature of genetic individuality and heritability. The vast array of data collected from genome-wide association studies must now be empowered and explored through more complex interaction studies, using standardized methods and larger sample sizes. In doing so the etiology of chronic disease progression will be further understood.

Predicting type 2 diabetes using genetic and environmental risk factors in a multi-ethnic Malaysian cohort.

PubMed

Abdullah, N; Abdul Murad, N A; Mohd Haniff, E A; Syafruddin, S E; Attia, J; Oldmeadow, C; Kamaruddin, M A; Abd Jalal, N; Ismail, N; Ishak, M; Jamal, R; Scott, R J; Holliday, E G

2017-08-01

Malaysia has a high and rising prevalence of type 2 diabetes (T2D). While environmental (non-genetic) risk factors for the disease are well established, the role of genetic variations and gene-environment interactions remain understudied in this population. This study aimed to estimate the relative contributions of environmental and genetic risk factors to T2D in Malaysia and also to assess evidence for gene-environment interactions that may explain additional risk variation. This was a case-control study including 1604 Malays, 1654 Chinese and 1728 Indians from the Malaysian Cohort Project. The proportion of T2D risk variance explained by known genetic and environmental factors was assessed by fitting multivariable logistic regression models and evaluating McFadden's pseudo R 2 and the area under the receiver-operating characteristic curve (AUC). Models with and without the genetic risk score (GRS) were compared using the log likelihood ratio Chi-squared test and AUCs. Multiplicative interaction between genetic and environmental risk factors was assessed via logistic regression within and across ancestral groups. Interactions were assessed for the GRS and its 62 constituent variants. The models including environmental risk factors only had pseudo R 2 values of 16.5-28.3% and AUC of 0.75-0.83. Incorporating a genetic score aggregating 62 T2D-associated risk variants significantly increased the model fit (likelihood ratio P-value of 2.50 × 10 -4 -4.83 × 10 -12 ) and increased the pseudo R 2 by about 1-2% and AUC by 1-3%. None of the gene-environment interactions reached significance after multiple testing adjustment, either for the GRS or individual variants. For individual variants, 33 out of 310 tested associations showed nominal statistical significance with 0.001 < P < 0.05. This study suggests that known genetic risk variants contribute a significant but small amount to overall T2D risk variation in Malaysian population groups. If gene-environment interactions involving common genetic variants exist, they are likely of small effect, requiring substantially larger samples for detection. Copyright © 2017 The Royal Society for Public Health. All rights reserved.

A Twin-Family Study of General IQ

ERIC Educational Resources Information Center

van Leeuwen, Marieke; van den Berg, Stephanie M.; Boomsma, Dorret I.

2008-01-01

In this paper we assess the presence of assortative mating, gene-environment interaction and the heritability of intelligence in childhood using a twin family design with twins, their siblings and parents from 112 families. We evaluate two competing hypotheses about the cause of assortative mating in intelligence: social homogamy and phenotypic…

Life events and borderline personality features: the influence of gene-environment interaction and gene-environment correlation.

PubMed

Distel, M A; Middeldorp, C M; Trull, T J; Derom, C A; Willemsen, G; Boomsma, D I

2011-04-01

Traumatic life events are generally more common in patients with borderline personality disorder (BPD) than in non-patients or patients with other personality disorders. This study investigates whether exposure to life events moderates the genetic architecture of BPD features. As the presence of genotype-environment correlation (rGE) can lead to spurious findings of genotype-environment interaction (G × E), we also test whether BPD features increase the likelihood of exposure to life events. The extent to which an individual is at risk to develop BPD was assessed with the Personality Assessment Inventory - Borderline features scale (PAI-BOR). Life events under study were a divorce/break-up, traffic accident, violent assault, sexual assault, robbery and job loss. Data were available for 5083 twins and 1285 non-twin siblings. Gene-environment interaction and correlation were assessed by using structural equation modelling (SEM) and the co-twin control design. There was evidence for both gene-environment interaction and correlation. Additive genetic influences on BPD features interacted with the exposure to sexual assault, with genetic variance being lower in exposed individuals. In individuals who had experienced a divorce/break-up, violent assault, sexual assault or job loss, environmental variance for BPD features was higher, leading to a lower heritability of BPD features in exposed individuals. Gene-environment correlation was present for some life events. The genes that influence BPD features thus also increased the likelihood of being exposed to certain life events. To our knowledge, this study is the first to test the joint effect of genetic and environmental influences and the exposure to life events on BPD features in the general population. Our results indicate the importance of both genetic vulnerability and life events.

Genetic Modification of the Relationship between Parental Rejection and Adolescent Alcohol Use.

PubMed

Stogner, John M; Gibson, Chris L

2016-07-01

Parenting practices are associated with adolescents' alcohol consumption, however not all youth respond similarly to challenging family situations and harsh environments. This study examines the relationship between perceived parental rejection and adolescent alcohol use, and specifically evaluates whether youth who possess greater genetic sensitivity to their environment are more susceptible to negative parental relationships. Analyzing data from the National Longitudinal Study of Adolescent Health, we estimated a series of regression models predicting alcohol use during adolescence. A multiplicative interaction term between parental rejection and a genetic index was constructed to evaluate this potential gene-environment interaction. Results from logistic regression analyses show a statistically significant gene-environment interaction predicting alcohol use. The relationship between parental rejection and alcohol use was moderated by the genetic index, indicating that adolescents possessing more 'risk alleles' for five candidate genes were affected more by stressful parental relationships. Feelings of parental rejection appear to influence the alcohol use decisions of youth, but they do not do so equally for all. Higher scores on the constructed genetic sensitivity measure are related to increased susceptibility to negative parental relationships. © The Author 2016. Medical Council on Alcohol and Oxford University Press. All rights reserved.

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…

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. Copyright © 2016 Elsevier Ltd. All rights reserved.

Gene-Environment Correlation and Interaction in Peer Effects on Adolescent Alcohol and Tobacco Use

PubMed Central

Harden, K. Paige; Hill, Jennifer E.; Turkheimer, Eric; Emery, Robert E.

2010-01-01

Peer relationships are commonly thought to be critical for adolescent socialization, including the development of negative health behaviors such as alcohol and tobacco use. The interplay between genetic liability and peer influences on the development of adolescent alcohol and tobacco use was examined using a nationally-representative sample of adolescent sibling pairs and their best friends. Genetic factors, some of them related to an adolescent's own substance use and some of them independent of use, were associated with increased exposure to best friends with heavy substance use—a gene-environment correlation. Moreover, adolescents who were genetically liable to substance use were more vulnerable to the adverse influences of their best friends—a gene-environment interaction. PMID:18368474

Design and analysis issues in gene and environment studies

PubMed Central

2012-01-01

Both nurture (environmental) and nature (genetic factors) play an important role in human disease etiology. Traditionally, these effects have been thought of as independent. This perspective is ill informed for non-mendelian complex disorders which result as an interaction between genetics and environment. To understand health and disease we must study how nature and nurture interact. Recent advances in human genomics and high-throughput biotechnology make it possible to study large numbers of genetic markers and gene products simultaneously to explore their interactions with environment. The purpose of this review is to discuss design and analytic issues for gene-environment interaction studies in the “-omics” era, with a focus on environmental and genetic epidemiological studies. We present an expanded environmental genomic disease paradigm. We discuss several study design issues for gene-environmental interaction studies, including confounding and selection bias, measurement of exposures and genotypes. We discuss statistical issues in studying gene-environment interactions in different study designs, such as choices of statistical models, assumptions regarding biological factors, and power and sample size considerations, especially in genome-wide gene-environment studies. Future research directions are also discussed. PMID:23253229

Design and analysis issues in gene and environment studies.

PubMed

Liu, Chen-yu; Maity, Arnab; Lin, Xihong; Wright, Robert O; Christiani, David C

2012-12-19

Both nurture (environmental) and nature (genetic factors) play an important role in human disease etiology. Traditionally, these effects have been thought of as independent. This perspective is ill informed for non-mendelian complex disorders which result as an interaction between genetics and environment. To understand health and disease we must study how nature and nurture interact. Recent advances in human genomics and high-throughput biotechnology make it possible to study large numbers of genetic markers and gene products simultaneously to explore their interactions with environment. The purpose of this review is to discuss design and analytic issues for gene-environment interaction studies in the "-omics" era, with a focus on environmental and genetic epidemiological studies. We present an expanded environmental genomic disease paradigm. We discuss several study design issues for gene-environmental interaction studies, including confounding and selection bias, measurement of exposures and genotypes. We discuss statistical issues in studying gene-environment interactions in different study designs, such as choices of statistical models, assumptions regarding biological factors, and power and sample size considerations, especially in genome-wide gene-environment studies. Future research directions are also discussed.

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

PubMed Central

Karlsson, Torgny; Ek, Weronica E.

2017-01-01

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

Using imputed genotype data in the joint score tests for genetic association and gene-environment interactions in case-control studies.

PubMed

Song, Minsun; Wheeler, William; Caporaso, Neil E; Landi, Maria Teresa; Chatterjee, Nilanjan

2018-03-01

Genome-wide association studies (GWAS) are now routinely imputed for untyped single nucleotide polymorphisms (SNPs) based on various powerful statistical algorithms for imputation trained on reference datasets. The use of predicted allele counts for imputed SNPs as the dosage variable is known to produce valid score test for genetic association. In this paper, we investigate how to best handle imputed SNPs in various modern complex tests for genetic associations incorporating gene-environment interactions. We focus on case-control association studies where inference for an underlying logistic regression model can be performed using alternative methods that rely on varying degree on an assumption of gene-environment independence in the underlying population. As increasingly large-scale GWAS are being performed through consortia effort where it is preferable to share only summary-level information across studies, we also describe simple mechanisms for implementing score tests based on standard meta-analysis of "one-step" maximum-likelihood estimates across studies. Applications of the methods in simulation studies and a dataset from GWAS of lung cancer illustrate ability of the proposed methods to maintain type-I error rates for the underlying testing procedures. For analysis of imputed SNPs, similar to typed SNPs, the retrospective methods can lead to considerable efficiency gain for modeling of gene-environment interactions under the assumption of gene-environment independence. Methods are made available for public use through CGEN R software package. © 2017 WILEY PERIODICALS, INC.

The psychiatric phenotype in triple X syndrome: New hypotheses illustrated in two cases

PubMed Central

Otter, Maarten; Schrander-Stumpel, Constance T. R. M.; Didden, Robert; Curfs, Leopold M. G.

2012-01-01

Background: Triple X syndrome (47,XXX or trisomy X) is a relatively frequent cytogenetic condition with a large variety of physical and behavioural phenotypes. Method: Two adult patients with a triple X karyotype are described. Results: Their karyotype was unknown until some years ago. What these patients have in common is that they were diagnosed with a broader autism phenotype, they were sexually abused, they suffer from psychotic illness and they show challenging behaviour, suicidality and a decline in occupational capacity. Discussion: These gene-environment interactions are discussed. Gene-environment interactions may explain the variety of behavioural and psychiatric phenotypes in triple X syndrome. Ongoing atypical development in adults is hypothesized. Conclusions: Gene-environment interactions and ongoing atypical development in adults should be taken into account in research concerning the psychiatric phenotype of developmental disorders, especially those involving triple X syndrome. PMID:22582855

Gene-Environment Interactions in Cardiovascular Disease

PubMed Central

Flowers, Elena; Froelicher, Erika Sivarajan; Aouizerat, Bradley E.

2011-01-01

Background Historically, models to describe disease were exclusively nature-based or nurture-based. Current theoretical models for complex conditions such as cardiovascular disease acknowledge the importance of both biologic and non-biologic contributors to disease. A critical feature is the occurrence of interactions between numerous risk factors for disease. The interaction between genetic (i.e. biologic, nature) and environmental (i.e. non-biologic, nurture) causes of disease is an important mechanism for understanding both the etiology and public health impact of cardiovascular disease. Objectives The purpose of this paper is to describe theoretical underpinnings of gene-environment interactions, models of interaction, methods for studying gene-environment interactions, and the related concept of interactions between epigenetic mechanisms and the environment. Discussion Advances in methods for measurement of genetic predictors of disease have enabled an increasingly comprehensive understanding of the causes of disease. In order to fully describe the effects of genetic predictors of disease, it is necessary to place genetic predictors within the context of known environmental risk factors. The additive or multiplicative effect of the interaction between genetic and environmental risk factors is often greater than the contribution of either risk factor alone. PMID:21684212

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.

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…

Genetics and Peer Relations: A Review

ERIC Educational Resources Information Center

Brendgen, Mara

2012-01-01

Researchers have become increasingly interested in uncovering how genetic factors work together with the peer environment in influencing development. This article offers an overview of the state of knowledge. It first describes the different types of gene-environment correlations (rGE) and gene-environment interactions (GxE) that are of relevance…

Study design options in evaluating gene-environment interactions: practical considerations for a planned case-control study of pediatric leukemia.

PubMed

Goodman, Michael; Dana Flanders, W

2007-04-01

We compare methodological approaches for evaluating gene-environment interaction using a planned study of pediatric leukemia as a practical example. We considered three design options: a full case-control study (Option I), a case-only study (Option II), and a partial case-control study (Option III), in which information on controls is limited to environmental exposure only. For each design option we determined its ability to measure the main effects of environmental factor E and genetic factor G, and the interaction between E and G. Using the leukemia study example, we calculated sample sizes required to detect and odds ratio (OR) of 2.0 for E alone, an OR of 10 for G alone and an interaction G x E of 3. Option I allows measuring both main effects and interaction, but requires a total sample size of 1,500 cases and 1,500 controls. Option II allows measuring only interaction, but requires just 121 cases. Option III allows calculating the main effect of E, and interaction, but not the main effect of G, and requires a total of 156 cases and 133 controls. In this case, the partial case-control study (Option III) appears to be more efficient with respect to its ability to answer the research questions for the amount of resources required. The design options considered in this example are not limited to observational epidemiology and may be applicable in studies of pharmacogenomics, survivorship, and other areas of pediatric ALL research.

A Penalized Robust Method for Identifying Gene-Environment Interactions

PubMed Central

Shi, Xingjie; Liu, Jin; Huang, Jian; Zhou, Yong; Xie, Yang; Ma, Shuangge

2015-01-01

In high-throughput studies, an important objective is to identify gene-environment interactions associated with disease outcomes and phenotypes. Many commonly adopted methods assume specific parametric or semiparametric models, which may be subject to model mis-specification. In addition, they usually use significance level as the criterion for selecting important interactions. In this study, we adopt the rank-based estimation, which is much less sensitive to model specification than some of the existing methods and includes several commonly encountered data and models as special cases. Penalization is adopted for the identification of gene-environment interactions. It achieves simultaneous estimation and identification and does not rely on significance level. For computation feasibility, a smoothed rank estimation is further proposed. Simulation shows that under certain scenarios, for example with contaminated or heavy-tailed data, the proposed method can significantly outperform the existing alternatives with more accurate identification. We analyze a lung cancer prognosis study with gene expression measurements under the AFT (accelerated failure time) model. The proposed method identifies interactions different from those using the alternatives. Some of the identified genes have important implications. PMID:24616063

Testing for gene-environment interaction under exposure misspecification.

PubMed

Sun, Ryan; Carroll, Raymond J; Christiani, David C; Lin, Xihong

2017-11-09

Complex interplay between genetic and environmental factors characterizes the etiology of many diseases. Modeling gene-environment (GxE) interactions is often challenged by the unknown functional form of the environment term in the true data-generating mechanism. We study the impact of misspecification of the environmental exposure effect on inference for the GxE interaction term in linear and logistic regression models. We first examine the asymptotic bias of the GxE interaction regression coefficient, allowing for confounders as well as arbitrary misspecification of the exposure and confounder effects. For linear regression, we show that under gene-environment independence and some confounder-dependent conditions, when the environment effect is misspecified, the regression coefficient of the GxE interaction can be unbiased. However, inference on the GxE interaction is still often incorrect. In logistic regression, we show that the regression coefficient is generally biased if the genetic factor is associated with the outcome directly or indirectly. Further, we show that the standard robust sandwich variance estimator for the GxE interaction does not perform well in practical GxE studies, and we provide an alternative testing procedure that has better finite sample properties. © 2017, The International Biometric Society.

Gene-Environment Interplay in Physical, Psychological, and Cognitive Domains in Mid to Late Adulthood: Is APOE a Variability Gene?

PubMed

Reynolds, Chandra A; Gatz, Margaret; Christensen, Kaare; Christiansen, Lene; Dahl Aslan, Anna K; Kaprio, Jaakko; Korhonen, Tellervo; Kremen, William S; Krueger, Robert; McGue, Matt; Neiderhiser, Jenae M; Pedersen, Nancy L

2016-01-01

Despite emerging interest in gene-environment interaction (GxE) effects, there is a dearth of studies evaluating its potential relevance apart from specific hypothesized environments and biometrical variance trends. Using a monozygotic within-pair approach, we evaluated evidence of G×E for body mass index (BMI), depressive symptoms, and cognition (verbal, spatial, attention, working memory, perceptual speed) in twin studies from four countries. We also evaluated whether APOE is a 'variability gene' across these measures and whether it partly represents the 'G' in G×E effects. In all three domains, G×E effects were pervasive across country and gender, with small-to-moderate effects. Age-cohort trends were generally stable for BMI and depressive symptoms; however, they were variable-with both increasing and decreasing age-cohort trends-for different cognitive measures. Results also suggested that APOE may represent a 'variability gene' for depressive symptoms and spatial reasoning, but not for BMI or other cognitive measures. Hence, additional genes are salient beyond APOE.

The challenge of causal inference in gene-environment interaction research: leveraging research designs from the social sciences.

PubMed

Fletcher, Jason M; Conley, Dalton

2013-10-01

The integration of genetics and the social sciences will lead to a more complex understanding of the articulation between social and biological processes, although the empirical difficulties inherent in this integration are large. One key challenge is the implications of moving "outside the lab" and away from the experimental tools available for research with model organisms. Social science research methods used to examine human behavior in nonexperimental, real-world settings to date have not been fully taken advantage of during this disciplinary integration, especially in the form of gene-environment interaction research. This article outlines and provides examples of several prominent research designs that should be used in gene-environment research and highlights a key benefit to geneticists of working with social scientists.

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

PubMed

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

2015-01-01

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

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…

Interactive Effects of in Utero Nutrition and Genetic Inheritance on Cognition: New Evidence Using Sibling Comparisons1

PubMed Central

Cook, C. Justin; Fletcher, Jason M.

2013-01-01

A large literature links early environments and later outcomes, such as cognition; however, little is known about the mechanisms. One potential mechanism is sensitivity to early environments that is moderated or amplified by the genotype. With this mechanism in mind, a complementary literature outside economics examines the interaction between genes and environments, but often problems of endogeneity and bias in estimation are uncorrected. A key issue in the literature is exploring environmental variation that is not exogenous, which is potentially problematic if there are gene-environment correlation or gene-gene interactions. Using sibling pairs with genetic data in the Wisconsin Longitudinal Study we extend a previous, and widely cited, gene-environment study that explores an interaction between the FADS2 gene, which is associated with the processing of essential fatty acids related to cognitive development, and early life nutrition in explaining later-life IQ. Our base OLS findings suggest that individuals with specific FADS2 variants gain roughly 0.15 standard deviations in IQ for each standard deviation increase in birth weight, our measure of the early nutrition environment; while, individuals with other variants of FADS2 do not have a statistically significant association with early nutrition, implying the genotype is influencing the effects of environmental exposure. When including family-level fixed effects, however, the magnitude of the gene-environment interaction is reduced by half and statistical significance dissipates, implying the interaction between FADS2 and early nutrition in explaining later life IQ may in part be due to unobserved, family-level factors. The example has wider implications for the practice of investigating gene-environment interactions when the environmental exposure is not exogenous and robustness to unobserved variation in the genome is not controlled for in the analysis. PMID:24172871

The BDNF Val66Met Polymorphism Interacts with Maternal Parenting Influencing Adolescent Depressive Symptoms: Evidence of Differential Susceptibility Model.

PubMed

Zhang, Leilei; Li, Zhi; Chen, Jie; Li, Xinying; Zhang, Jianxin; Belsky, Jay

2016-03-01

Although depressive symptoms are common during adolescence, little research has examined gene-environment interaction on youth depression. This study chose the brain-derived neurotrophic factor (BDNF) gene, tested the interaction between a functional polymorphism resulting amino acid substitution of valine (Val) to methionine (Met) in the proBDNF protein at codon 66 (Val66Met), and maternal parenting on youth depressive symptoms in a sample of 780 community adolescents of Chinese Han ethnicity (aged 11-17, M = 13.6, 51.3 % females). Participants reported their depressive symptoms and perceived maternal parenting. Results indicated the BDNF Val66Met polymorphism significantly moderated the influence of maternal warmth-reasoning, but not harshness-hostility, on youth depressive symptoms. Confirmatory model evaluation indicated that the interaction effect involving warmth-reasoning conformed to the differential-susceptibility rather than diathesis-stress model of person-X-environment interaction. Thus, Val carriers experienced less depressive symptoms than Met homozygotes when mothering was more positive but more symptoms when mothering was less positive. The findings provided evidence in support of the differential susceptibility hypothesis of youth depressive symptoms and shed light on the importance of examining the gene-environment interaction from a developmental perspective.

Genetic Predictors for Cardiovascular Disease in Hispanics

PubMed Central

Qi, Lu; Campos, Hannia

2012-01-01

A less favorable cardiovascular risk factor profile, but paradoxically lower cardiovascular morbidity and mortality have been observed in Hispanics, a pattern often referred to as the Hispanic Paradox. It was proposed the specific genetic susceptibility of this admixed population and gene-environment interactions may partly explain the paradox. The past few years have seen great advances in discovering genetic risk factors using genome-wide association studies (GWAS) for cardiovascular disease especially in Caucasians. However, there is no GWAS of cardiovascular disease that have been reported in Hispanics. In the Costa Rican Heart Study we reported both the consistency and disparity of genetic effects on risk of coronary heart disease (CHD) between Hispanics and other ethnic groups. We demonstrated the improvement in the identified genetic markers on discrimination of CHD in Hispanics was modest. Future genetic research in Hispanics would consider the diversities in genetic structure, lifestyle and socioeconomics among various sub-populations, and comprehensively evaluate potential gene-environment interactions in relation to cardiovascular risk. PMID:22498015

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. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

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

PubMed

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

2016-06-04

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.

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…

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.

Unconditional analyses can increase efficiency in assessing gene-environment interaction of the case-combined-control design.

PubMed

Goldstein, Alisa M; Dondon, Marie-Gabrielle; Andrieu, Nadine

2006-08-01

A design combining both related and unrelated controls, named the case-combined-control design, was recently proposed to increase the power for detecting gene-environment (GxE) interaction. Under a conditional analytic approach, the case-combined-control design appeared to be more efficient and feasible than a classical case-control study for detecting interaction involving rare events. We now propose an unconditional analytic strategy to further increase the power for detecting gene-environment (GxE) interactions. This strategy allows the estimation of GxE interaction and exposure (E) main effects under certain assumptions (e.g. no correlation in E between siblings and the same exposure frequency in both control groups). Only the genetic (G) main effect cannot be estimated because it is biased. Using simulations, we show that unconditional logistic regression analysis is often more efficient than conditional analysis for detecting GxE interaction, particularly for a rare gene and strong effects. The unconditional analysis is also at least as efficient as the conditional analysis when the gene is common and the main and joint effects of E and G are small. Under the required assumptions, the unconditional analysis retains more information than does the conditional analysis for which only discordant case-control pairs are informative leading to more precise estimates of the odds ratios.

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 (0.01

Does Parental Divorce Moderate the Heritability of Body Dissatisfaction? An Extension of Previous Gene-Environment Interaction Effects

PubMed Central

O’Connor, Shannon M.; Klump, Kelly L.; VanHuysse, Jessica L.; McGue, Matt; Iacono, William

2015-01-01

Objective Previous research suggests that parental divorce moderates genetic influences on body dissatisfaction. Specifically, the heritability of body dissatisfaction is higher in children of divorced versus intact families, suggesting possible gene-environment interaction effects. However, prior research is limited to a single, self-report measure of body dissatisfaction. The primary aim of the present study was to examine whether these findings extend to a different dimension of body dissatisfaction, body image perceptions. Method Participants were 1,534 female twins from the Minnesota Twin Family Study, ages 16–20 years. The Body Rating Scale (BRS) was used to assess body image perceptions. Results Although BRS scores were heritable in twins from divorced and intact families, the heritability estimates in the divorced group were not significantly greater than estimates in the intact group. However, there were differences in nonshared environmental effects, where the magnitude of these environmental influences was larger in the divorced as compared to the intact families. Discussion Different dimensions of body dissatisfaction (i.e., negative self-evaluation versus body image perceptions) may interact with environmental risk, such as parental divorce, in discrete ways. Future research should examine this possibility and explore differential gene x environment interactions using diverse measures. PMID:26314278

An Efficient Test for Gene-Environment Interaction in Generalized Linear Mixed Models with Family Data.

PubMed

Mazo Lopera, Mauricio A; Coombes, Brandon J; de Andrade, Mariza

2017-09-27

Gene-environment (GE) interaction has important implications in the etiology of complex diseases that are caused by a combination of genetic factors and environment variables. Several authors have developed GE analysis in the context of independent subjects or longitudinal data using a gene-set. In this paper, we propose to analyze GE interaction for discrete and continuous phenotypes in family studies by incorporating the relatedness among the relatives for each family into a generalized linear mixed model (GLMM) and by using a gene-based variance component test. In addition, we deal with collinearity problems arising from linkage disequilibrium among single nucleotide polymorphisms (SNPs) by considering their coefficients as random effects under the null model estimation. We show that the best linear unbiased predictor (BLUP) of such random effects in the GLMM is equivalent to the ridge regression estimator. This equivalence provides a simple method to estimate the ridge penalty parameter in comparison to other computationally-demanding estimation approaches based on cross-validation schemes. We evaluated the proposed test using simulation studies and applied it to real data from the Baependi Heart Study consisting of 76 families. Using our approach, we identified an interaction between BMI and the Peroxisome Proliferator Activated Receptor Gamma ( PPARG ) gene associated with diabetes.

Social defeat interacts with Disc1 mutations in the mouse to affect behavior.

PubMed

Haque, F Nipa; Lipina, Tatiana V; Roder, John C; Wong, Albert H C

2012-08-01

DISC1 (Disrupted-in-schizophrenia 1) is a strong candidate susceptibility gene for psychiatric disease that was originally discovered in a family with a chromosomal translocation severing this gene. Although the family members with the translocation had an identical genetic mutation, their clinical diagnosis and presentation varied significantly. Gene-environment interactions have been proposed as a mechanism underlying the complex heritability and variable phenotype of psychiatric disorders such as major depressive disorder and schizophrenia. We hypothesized that gene-environment interactions would affect behavior in a mutant Disc1 mouse model. We examined the effect of chronic social defeat (CSD) as an environmental stressor in two lines of mice carrying different Disc1 point mutations, on behaviors relevant to psychiatric illness: locomotion in a novel open field (OF), pre-pulse inhibition (PPI) of the acoustic startle response, latent inhibition (LI), elevated plus maze (EPM), forced swim test (FST), sucrose consumption (SC), and the social interaction task for sociability and social novelty (SSN). We found that Disc1-L100P +/- and wild-type mice have similar anxiety responses to CSD, while Q31L +/- mice had a very different response. We also found evidence of significant gene-environment interactions in the OF, EPM and SSN. Copyright © 2012 Elsevier B.V. All rights reserved.

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

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.

Gene-Environment Studies and Borderline Personality Disorder: A Review

PubMed Central

Carpenter, Ryan W.; Tomko, Rachel L.; Boomsma, Dorret I.

2014-01-01

We review recent gene-environment studies relevant to borderline personality disorder, including those focusing on impulsivity, emotion sensitivity, suicidal behavior, aggression and anger, and the borderline personality phenotype itself. Almost all the studies reviewed suffered from a number of methodological and statistical problems, limiting the conclusions that currently can be drawn. The best evidence to date supports a gene-environment correlation (rGE) model for borderline personality traits and a range of adverse life events, indicating that those at risk for BPD are also at increased risk for exposure to environments that may trigger BPD. We provide suggestions regarding future research on GxE interaction and rGE effects in borderline personality. PMID:23250817

Finding gene-environment interactions for phobias.

PubMed

Gregory, Alice M; Lau, Jennifer Y F; Eley, Thalia C

2008-03-01

Phobias are common disorders causing a great deal of suffering. Studies of gene-environment interaction (G x E) have revealed much about the complex processes underlying the development of various psychiatric disorders but have told us little about phobias. This article describes what is already known about genetic and environmental influences upon phobias and suggests how this information can be used to optimise the chances of discovering G x Es for phobias. In addition to the careful conceptualisation of new studies, it is suggested that data already collected should be re-analysed in light of increased understanding of processes influencing phobias.

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 and gene-environment interactions beyond GWAS, and that the EHR based approach provides an additional source of data for seeking these advanced explanatory models of the etiology of complex disease/outcome such as cataracts.

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

Latent variable models for gene-environment interactions in longitudinal studies with multiple correlated exposures.

PubMed

Tao, Yebin; Sánchez, Brisa N; Mukherjee, Bhramar

2015-03-30

Many existing cohort studies designed to investigate health effects of environmental exposures also collect data on genetic markers. The Early Life Exposures in Mexico to Environmental Toxicants project, for instance, has been genotyping single nucleotide polymorphisms on candidate genes involved in mental and nutrient metabolism and also in potentially shared metabolic pathways with the environmental exposures. Given the longitudinal nature of these cohort studies, rich exposure and outcome data are available to address novel questions regarding gene-environment interaction (G × E). Latent variable (LV) models have been effectively used for dimension reduction, helping with multiple testing and multicollinearity issues in the presence of correlated multivariate exposures and outcomes. In this paper, we first propose a modeling strategy, based on LV models, to examine the association between repeated outcome measures (e.g., child weight) and a set of correlated exposure biomarkers (e.g., prenatal lead exposure). We then construct novel tests for G × E effects within the LV framework to examine effect modification of outcome-exposure association by genetic factors (e.g., the hemochromatosis gene). We consider two scenarios: one allowing dependence of the LV models on genes and the other assuming independence between the LV models and genes. We combine the two sets of estimates by shrinkage estimation to trade off bias and efficiency in a data-adaptive way. Using simulations, we evaluate the properties of the shrinkage estimates, and in particular, we demonstrate the need for this data-adaptive shrinkage given repeated outcome measures, exposure measures possibly repeated and time-varying gene-environment association. Copyright © 2014 John Wiley & Sons, Ltd.

Gene-Environment Interactions in Asthma: Genetic and Epigenetic Effects.

PubMed

Lee, Jong-Uk; Kim, Jeong Dong; Park, Choon-Sik

2015-07-01

Over the past three decades, a large number of genetic studies have been aimed at finding genetic variants associated with the risk of asthma, applying various genetic and genomic approaches including linkage analysis, candidate gene polymorphism studies, and genome-wide association studies (GWAS). However, contrary to general expectation, even single nucleotide polymorphisms (SNPs) discovered by GWAS failed to fully explain the heritability of asthma. Thus, application of rare allele polymorphisms in well defined phenotypes and clarification of environmental factors have been suggested to overcome the problem of 'missing' heritability. Such factors include allergens, cigarette smoke, air pollutants, and infectious agents during pre- and post-natal periods. The first and simplest interaction between a gene and the environment is a candidate interaction of both a well known gene and environmental factor in a direct physical or chemical interaction such as between CD14 and endotoxin or between HLA and allergens. Several GWAS have found environmental interactions with occupational asthma, aspirin exacerbated respiratory disease, tobacco smoke-related airway dysfunction, and farm-related atopic diseases. As one of the mechanisms behind gene-environment interaction is epigenetics, a few studies on DNA CpG methylation have been reported on subphenotypes of asthma, pitching the exciting idea that it may be possible to intervene at the junction between the genome and the environment. Epigenetic studies are starting to include data from clinical samples, which will make them another powerful tool for re-search on gene-environment interactions in asthma.

The influence of urban/rural residency on depressive symptoms is moderated by the serotonin receptor 2A gene.

PubMed

Jokela, Markus; Lehtimäki, Terho; Keltikangas-Järvinen, Liisa

2007-10-05

Gene-environment interactions are thought to be involved in the development of depression. Here we examined the interaction effect between urban/rural residency and the serotonin receptor 2A (HTR2A) gene on subclinical depressive symptoms. The participants were 1,224 Finnish men and women being followed in the on-going population-based study of "Cardiovascular Risk in Young Finns". Urban/rural residency was determined on the basis of a (1) subjective report and (2) the population density of the residential area. Depressive symptoms were measured in two test settings four years apart. There was a significant gene-environment interaction, such that the urban residency was associated with low depressive symptoms in individuals carrying the T/T or T/C genotype of the T102C polymorphism, but not in those carrying the C/C genotype. The T allele was associated with high depressive symptoms in remote rural areas, but with low depressive symptoms in urban or suburban areas. The gene-environment interaction was not accounted by level of education, social support, unemployment, or partnership status. The HTR2A gene may be involved in the development of depression by influencing how individuals respond to environmental conditions. (c) 2007 Wiley-Liss, Inc.

Biomarkers of susceptibility to chemical carcinogens: the example of non-Hodgkin lymphomas.

PubMed

Kelly, Rachel S; Vineis, Paolo

2014-09-01

Genetic susceptibly to suspected chemical and environmental carcinogens may modify the response to exposure. The aim of this review was to explore the issues involved in the study of gene-environment interactions, and to consider the use of susceptibility biomarkers in cancer epidemiology, using non-Hodgkin lymphoma (NHL) as an example. PubMed, EMBASE and Web of Science were searched for peer-reviewed articles considering biomarkers of susceptibility to chemical, agricultural and industrial carcinogens in the aetiology of NHL. The results suggest a modifying role for genetic susceptibility to a number of occupational and environmental exposures including organochlorines, chlorinated solvents, chlordanes and benzene in the aetiology of NHL. The potential importance of these gene-environment interactions in NHL may help to explain the lack of definitive carcinogens identified to date for this malignancy. Although a large number of genetic variants and gene-environment interactions have been explored for NHL, to date replication is lacking and therefore the findings remain to be validated. These findings highlight the need for novel standardized methodologies in the study of genetic susceptibility to chemical carcinogens. © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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

The oxytocin receptor gene (OXTR) in relation to state levels of loneliness in adolescence: evidence for micro-level gene-environment interactions.

PubMed

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.

Boosting for detection of gene-environment interactions.

PubMed

Pashova, H; LeBlanc, M; Kooperberg, C

2013-01-30

In genetic association studies, it is typically thought that genetic variants and environmental variables jointly will explain more of the inheritance of a phenotype than either of these two components separately. Traditional methods to identify gene-environment interactions typically consider only one measured environmental variable at a time. However, in practice, multiple environmental factors may each be imprecise surrogates for the underlying physiological process that actually interacts with the genetic factors. In this paper, we develop a variant of L(2) boosting that is specifically designed to identify combinations of environmental variables that jointly modify the effect of a gene on a phenotype. Because the effect modifiers might have a small signal compared with the main effects, working in a space that is orthogonal to the main predictors allows us to focus on the interaction space. In a simulation study that investigates some plausible underlying model assumptions, our method outperforms the least absolute shrinkage and selection and Akaike Information Criterion and Bayesian Information Criterion model selection procedures as having the lowest test error. In an example for the Women's Health Initiative-Population Architecture using Genomics and Epidemiology study, the dedicated boosting method was able to pick out two single-nucleotide polymorphisms for which effect modification appears present. The performance was evaluated on an independent test set, and the results are promising. Copyright © 2012 John Wiley & Sons, Ltd.

Genome-Wide Analysis of Gene-Gene and Gene-Environment Interactions Using Closed-Form Wald Tests.

PubMed

Yu, Zhaoxia; Demetriou, Michael; Gillen, Daniel L

2015-09-01

Despite the successful discovery of hundreds of variants for complex human traits using genome-wide association studies, the degree to which genes and environmental risk factors jointly affect disease risk is largely unknown. One obstacle toward this goal is that the computational effort required for testing gene-gene and gene-environment interactions is enormous. As a result, numerous computationally efficient tests were recently proposed. However, the validity of these methods often relies on unrealistic assumptions such as additive main effects, main effects at only one variable, no linkage disequilibrium between the two single-nucleotide polymorphisms (SNPs) in a pair or gene-environment independence. Here, we derive closed-form and consistent estimates for interaction parameters and propose to use Wald tests for testing interactions. The Wald tests are asymptotically equivalent to the likelihood ratio tests (LRTs), largely considered to be the gold standard tests but generally too computationally demanding for genome-wide interaction analysis. Simulation studies show that the proposed Wald tests have very similar performances with the LRTs but are much more computationally efficient. Applying the proposed tests to a genome-wide study of multiple sclerosis, we identify interactions within the major histocompatibility complex region. In this application, we find that (1) focusing on pairs where both SNPs are marginally significant leads to more significant interactions when compared to focusing on pairs where at least one SNP is marginally significant; and (2) parsimonious parameterization of interaction effects might decrease, rather than increase, statistical power. © 2015 WILEY PERIODICALS, INC.

Testing in semiparametric models with interaction, with applications to gene-environment interactions.

PubMed

Maity, Arnab; Carroll, Raymond J; Mammen, Enno; Chatterjee, Nilanjan

2009-01-01

Motivated from the problem of testing for genetic effects on complex traits in the presence of gene-environment interaction, we develop score tests in general semiparametric regression problems that involves Tukey style 1 degree-of-freedom form of interaction between parametrically and non-parametrically modelled covariates. We find that the score test in this type of model, as recently developed by Chatterjee and co-workers in the fully parametric setting, is biased and requires undersmoothing to be valid in the presence of non-parametric components. Moreover, in the presence of repeated outcomes, the asymptotic distribution of the score test depends on the estimation of functions which are defined as solutions of integral equations, making implementation difficult and computationally taxing. We develop profiled score statistics which are unbiased and asymptotically efficient and can be performed by using standard bandwidth selection methods. In addition, to overcome the difficulty of solving functional equations, we give easy interpretations of the target functions, which in turn allow us to develop estimation procedures that can be easily implemented by using standard computational methods. We present simulation studies to evaluate type I error and power of the method proposed compared with a naive test that does not consider interaction. Finally, we illustrate our methodology by analysing data from a case-control study of colorectal adenoma that was designed to investigate the association between colorectal adenoma and the candidate gene NAT2 in relation to smoking history.

Child Dopamine Transporter Genotype and Parenting: Evidence for Evocative Gene-Environment Correlations

PubMed Central

Hayden, Elizabeth P.; Hanna, Brigitte; Sheikh, Haroon I.; Laptook, Rebecca S.; Kim, Jiyon; Singh, Shiva M.; Klein, Daniel N.

2017-01-01

The dopamine transporter (DAT1) gene is implicated in psychopathology risk. While the processes by which this gene exerts its effects on risk are poorly understood, a small body of research suggests that DAT1 influences early emerging negative emotionality (NE), a marker of children’s psychopathology risk. As child NE evokes negative parenting practices, the DAT1 may also play a role in gene-environment correlations. To test this model, children (N = 365) were genotyped for DAT1 and participated in standardized parent-child interaction tasks with their primary caregiver. The DAT1 9-repeat variant was associated with child negative affect expressed toward the parent during parent-child interactions, and parents of children with a 9-repeat allele exhibited more hostility and lower guidance/engagement than parents of children without a 9-repeat allele. These gene-environment associations were partially mediated by child negative affect toward the parent. Findings implicate a specific polymorphism in eliciting negative parenting, suggesting that evocative associations play a role in elevating children’s risk for emotional trajectories toward psychopathology risk. PMID:23398760

The relationship between glucocorticoid receptor polymorphisms, stressful life events, social support, and post-traumatic stress disorder.

PubMed

Lian, Yulong; Xiao, Jing; Wang, Qian; Ning, Li; Guan, Suzhen; Ge, Hua; Li, Fuye; Liu, Jiwen

2014-08-12

It is debatable whether or not glucocorticoid receptor (GR) polymorphisms moderate susceptibility to PTSD. Our objective was to examine the effects of stressful life events, social support, GR genotypes, and gene-environment interactions on the etiology of PTSD. Three tag single nucleotide polymorphisms, trauma events, stressful life events, and social support were assessed in 460 patients with PTSD and 1158 control subjects from a Chinese Han population. Gene-environment interactions were analyzed by generalized multifactor dimensionality reduction (GMDR). Variation in GR at rs41423247 and rs258747, stressful life events, social support, and the number of traumatic events were each separately associated with the risk for PTSD. A gene-environment interaction among the polymorphisms, rs41423247 and rs258747, the number of traumatic events, stressful life events, and social support resulted in an increased risk for PTSD. High-risk individuals (a large number of traumatic events, G allele of rs258747 and rs41423247, high level stressful life events, and low social support) had a 3.26-fold increased risk of developing PTSD compared to low-risk individuals. The association was statistically significant in the sub-groups with and without childhood trauma. Our data support the notion that stressful life events, the number of trauma events, and social support may play a contributing role in the risk for PTSD by interacting with GR gene polymorphisms.

Gene-environment interaction in the etiology of mathematical ability using SNP sets.

PubMed

Docherty, Sophia J; Kovas, Yulia; Plomin, Robert

2011-01-01

Mathematics ability and disability is as heritable as other cognitive abilities and disabilities, however its genetic etiology has received relatively little attention. In our recent genome-wide association study of mathematical ability in 10-year-old children, 10 SNP associations were nominated from scans of pooled DNA and validated in an individually genotyped sample. In this paper, we use a 'SNP set' composite of these 10 SNPs to investigate gene-environment (GE) interaction, examining whether the association between the 10-SNP set and mathematical ability differs as a function of ten environmental measures in the home and school in a sample of 1888 children with complete data. We found two significant GE interactions for environmental measures in the home and the school both in the direction of the diathesis-stress type of GE interaction: The 10-SNP set was more strongly associated with mathematical ability in chaotic homes and when parents are negative.

Bisphenol-A and Female Infertility: A Possible Role of Gene-Environment Interactions

PubMed Central

Huo, Xiaona; Chen, Dan; He, Yonghua; Zhu, Wenting; Zhou, Wei; Zhang, Jun

2015-01-01

Background: Bisphenol-A (BPA) is widely used and ubiquitous in the environment. Animal studies indicate that BPA affects reproduction, however, the gene-environment interaction mechanism(s) involved in this association remains unclear. We performed a literature review to summarize the evidence on this topic. Methods: A comprehensive search was conducted in PubMed using as keywords BPA, gene, infertility and female reproduction. Full-text articles in both human and animals published in English prior to December 2014 were selected. Results: Evidence shows that BPA can interfere with endocrine function of hypothalamic-pituitary axis, such as by changing gonadotropin-releasing hormones (GnRH) secretion in hypothalamus and promoting pituitary proliferation. Such actions affect puberty, ovulation and may even result in infertility. Ovary, uterus and other reproductive organs are also targets of BPA. BPA exposure impairs the structure and functions of female reproductive system in different times of life cycle and may contribute to infertility. Both epidemiological and experimental evidences demonstrate that BPA affects reproduction-related gene expression and epigenetic modification that are closely associated with infertility. The detrimental effects on reproduction may be lifelong and transgenerational. Conclusions: Evidence on gene-environment interactions, especially from human studies, is still limited. Further research on this topic is warranted. PMID:26371021

On the use of sibling recurrence risks to select environmental factors liable to interact with genetic risk factors.

PubMed

Kazma, Rémi; Bonaïti-Pellié, Catherine; Norris, Jill M; Génin, Emmanuelle

2010-01-01

Gene-environment interactions are likely to be involved in the susceptibility to multifactorial diseases but are difficult to detect. Available methods usually concentrate on some particular genetic and environmental factors. In this paper, we propose a new method to determine whether a given exposure is susceptible to interact with unknown genetic factors. Rather than focusing on a specific genetic factor, the degree of familial aggregation is used as a surrogate for genetic factors. A test comparing the recurrence risks in sibs according to the exposure of indexes is proposed and its power is studied for varying values of model parameters. The Exposed versus Unexposed Recurrence Analysis (EURECA) is valuable for common diseases with moderate familial aggregation, only when the role of exposure has been clearly outlined. Interestingly, accounting for a sibling correlation for the exposure increases the power of EURECA. An application on a sample ascertained through one index affected with type 2 diabetes is presented where gene-environment interactions involving obesity and physical inactivity are investigated. Association of obesity with type 2 diabetes is clearly evidenced and a potential interaction involving this factor is suggested in Hispanics (P=0.045), whereas a clear gene-environment interaction is evidenced involving physical inactivity only in non-Hispanic whites (P=0.028). The proposed method might be of particular interest before genetic studies to help determine the environmental risk factors that will need to be accounted for to increase the power to detect genetic risk factors and to select the most appropriate samples to genotype.

Gene-environment interplay in the etiology of psychosis.

PubMed

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

2018-01-15

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

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

PubMed

Sánchez, Brisa N; Kang, Shan; Mukherjee, Bhramar

2012-06-01

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 Study of lead exposure, iron metabolism genes, and birth weight. © 2011, The International Biometric Society.

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

Assessing interactions between HLA-DRB1*15 and infectious mononucleosis on the risk of multiple sclerosis.

PubMed

Disanto, Giulio; Hall, Carolina; Lucas, Robyn; Ponsonby, Anne-Louise; Berlanga-Taylor, Antonio J; Giovannoni, Gavin; Ramagopalan, Sreeram V

2013-09-01

Gene-environment interactions may shed light on the mechanisms underlying multiple sclerosis (MS). We pooled data from two case-control studies on incident demyelination and used different methods to assess interaction between HLA-DRB1*15 (DRB1-15) and history of infectious mononucleosis (IM). Individuals exposed to both factors were at substantially increased risk of disease (OR=7.32, 95% CI=4.92-10.90). In logistic regression models, DRB1-15 and IM status were independent predictors of disease while their interaction term was not (DRB1-15*IM: OR=1.35, 95% CI=0.79-2.23). However, interaction on an additive scale was evident (Synergy index=2.09, 95% CI=1.59-2.59; excess risk due to interaction=3.30, 95%CI=0.47-6.12; attributable proportion due to interaction=45%, 95% CI=22-68%). This suggests, if the additive model is appropriate, the DRB1-15 and IM may be involved in the same causal process leading to MS and highlights the benefit of reporting gene-environment interactions on both a multiplicative and additive scale.

Genetic variation in biotransformation enzymes, air pollution exposures, and risk of spina bifida.

PubMed

Padula, Amy M; Yang, Wei; Schultz, Kathleen; Lurmann, Fred; Hammond, S Katharine; Shaw, Gary M

2018-05-01

Spina bifida is a birth defect characterized by incomplete closure of the embryonic neural tube. Genetic factors as well as environmental factors have been observed to influence risks for spina bifida. Few studies have investigated possible gene-environment interactions that could contribute to spina bifida risk. The aim of this study is to examine the interaction between gene variants in biotransformation enzyme pathways and ambient air pollution exposures and risk of spina bifida. We evaluated the role of air pollution exposure during pregnancy and gene variants of biotransformation enzymes from bloodspots and buccal cells in a California population-based case-control (86 cases of spina bifida and 208 non-malformed controls) study. We considered race/ethnicity and folic acid vitamin use as potential effect modifiers and adjusted for those factors and smoking. We observed gene-environment interactions between each of the five pollutants and several gene variants: NO (ABCC2), NO 2 (ABCC2, SLC01B1), PM 10 (ABCC2, CYP1A1, CYP2B6, CYP2C19, CYP2D6, NAT2, SLC01B1, SLC01B3), PM 2.5 (CYP1A1 and CYP1A2). These analyses show positive interactions between air pollution exposure during early pregnancy and gene variants associated with metabolizing enzymes. These exploratory results suggest that some individuals based on their genetic background may be more susceptible to the adverse effects of pollution. © 2018 Wiley Periodicals, Inc.

MAOA, childhood maltreatment and antisocial behavior: Meta-analysis of a gene-environment interaction

PubMed Central

Byrd, Amy L.; Manuck, Stephen B.

2013-01-01

Background In a seminal study of gene-environment interaction, childhood maltreatment predicted antisocial behavior more strongly in males carrying an MAOA promoter variant of lesser, compared to higher, transcriptional efficiency. Many further investigations have been reported, including studies of other early environmental exposures and females. Here we report a meta-analysis of studies testing the interaction of MAOA genotype and childhood adversities on antisocial outcomes in predominantly non-clinical samples. Method Included were 27 peer-reviewed, English-language studies published through August, 2012, that contained indicators of maltreatment or “other” family (e.g., parenting, sociodemographic) hardships; MAOA genotype; indices of aggressive and antisocial behavior; and statistical test of genotype-environment interaction. Studies of forensic and exclusively clinical samples, clinical cohorts lacking proportionally matched controls, or outcomes non-specific for antisocial behavior were excluded. The Liptak-Stouffer weighted Z-test for meta-analysis was implemented to maximize study inclusion and calculated separately for male and female cohorts. Results Across 20 male cohorts, early adversity presaged antisocial outcomes more strongly for low, relative to high, activity MAOA genotype (P=.0044). Stratified analyses showed the interaction specific to maltreatment (P=.0000008) and robust to several sensitivity analyses. Across 11 female cohorts, MAOA did not interact with combined early life adversities, whereas maltreatment alone predicted antisocial behaviors preferentially, but weakly, in females of high activity MAOA genotype (P=.02). Conclusions We found common regulatory variation in MAOA to moderate effects of childhood maltreatment on male antisocial behaviors, confirming a sentinel finding in research on gene-environment interaction. An analogous, but less consistent, finding in females warrants further investigation. PMID:23786983

MAOA, childhood maltreatment, and antisocial behavior: meta-analysis of a gene-environment interaction.

PubMed

Byrd, Amy L; Manuck, Stephen B

2014-01-01

In a seminal study of gene-environment interaction, childhood maltreatment predicted antisocial behavior more strongly in male subjects carrying an MAOA promoter variant of lesser, compared with higher, transcriptional efficiency. Many further investigations have been reported, including studies of other early environmental exposures and female subjects. Here, we report a meta-analysis of studies testing the interaction of MAOA genotype and childhood adversities on antisocial outcomes in predominantly nonclinical samples. Included were 27 peer-reviewed, English-language studies published through August, 2012, that contained indicators of maltreatment or other family (e.g., parenting, sociodemographic) hardships; MAOA genotype; indices of aggressive and antisocial behavior; and statistical test of genotype-environment interaction. Studies of forensic and exclusively clinical samples, clinical cohorts lacking proportionally matched control subjects, or outcomes nonspecific for antisocial behavior were excluded. The Liptak-Stouffer weighted Z-test for meta-analysis was implemented to maximize study inclusion and calculated separately for male and female cohorts. Across 20 male cohorts, early adversity presaged antisocial outcomes more strongly for low-activity, relative to high- activity, MAOA genotype (p = .0044). Stratified analyses showed the interaction specific to maltreatment (p = .00000082) and robust to several sensitivity analyses. Across 11 female cohorts, MAOA did not interact with combined early life adversities, whereas maltreatment alone predicted antisocial behaviors preferentially, but weakly, in female subjects of high-activity MAOA genotype (p = .02). We found common regulatory variation in MAOA to moderate effects of childhood maltreatment on male antisocial behaviors, confirming a sentinel finding in research on gene-environment interaction. An analogous, but less consistent, finding in female subjects warrants further investigation. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Genetic Interactions with Prenatal Social Environment: Effects on Academic and Behavioral Outcomes

ERIC Educational Resources Information Center

Conley, Dalton; Rauscher, Emily

2013-01-01

Numerous studies report gene-environment interactions, suggesting that specific alleles have different effects on social outcomes depending on environment. In all these studies, however, environmental conditions are potentially endogenous to unmeasured genetic characteristics. That is, it could be that the observed interaction effects actually…

Nature versus nurture: A systematic approach to elucidate gene-environment interactions in the development of myopic refractive errors.

PubMed

Miraldi Utz, Virginia

2017-01-01

Myopia is the most common eye disorder and major cause of visual impairment worldwide. As the incidence of myopia continues to rise, the need to further understand the complex roles of molecular and environmental factors controlling variation in refractive error is of increasing importance. Tkatchenko and colleagues applied a systematic approach using a combination of gene set enrichment analysis, genome-wide association studies, and functional analysis of a murine model to identify a myopia susceptibility gene, APLP2. Differential expression of refractive error was associated with time spent reading for those with low frequency variants in this gene. This provides support for the longstanding hypothesis of gene-environment interactions in refractive error development.

Differences and similarities in the serotonergic diathesis for suicide attempts and mood disorders: a 22-year longitudinal gene-environment study.

PubMed

Brezo, J; Bureau, A; Mérette, C; Jomphe, V; Barker, E D; Vitaro, F; Hébert, M; Carbonneau, R; Tremblay, R E; Turecki, G

2010-08-01

To investigate similarities and differences in the serotonergic diathesis for mood disorders and suicide attempts, we conducted a study in a cohort followed longitudinally for 22 years. A total of 1255 members of this cohort, which is representative of the French-speaking population of Quebec, were investigated. Main outcome measures included (1) mood disorders (bipolar disorder and major depression) and suicide attempts by early adulthood; (2) odds ratios and probabilities associated with 143 single nucleotide polymorphisms in 11 serotonergic genes, acting directly or as moderators in gene-environment interactions with childhood sexual or childhood physical abuse (CPA), and in gene-gene interactions; (3) regression coefficients for putative endophenotypes for mood disorders (childhood anxiousness) and suicide attempts (childhood disruptiveness). Five genes showed significant adjusted effects (HTR2A, TPH1, HTR5A, SLC6A4 and HTR1A). Of these, HTR2A variation influenced both suicide attempts and mood disorders, although through different mechanisms. In suicide attempts, HTR2A variants (rs6561333, rs7997012 and rs1885884) were involved through interactions with histories of sexual and physical abuse whereas in mood disorders through one main effect (rs9316235). In terms of phenotype-specific contributions, TPH1 variation (rs10488683) was relevant only in the diathesis for suicide attempts. Three genes contributed exclusively to mood disorders, one through a main effect (HTR5A (rs1657268)) and two through gene-environment interactions with CPA (HTR1A (rs878567) and SLC6A4 (rs3794808)). Childhood anxiousness did not mediate the effects of HTR2A and HTR5A on mood disorders, nor did childhood disruptiveness mediate the effects of TPH1 on suicide attempts. Of the serotonergic genes implicated in mood disorders and suicidal behaviors, four exhibited phenotype-specific effects, suggesting that despite their high concordance and common genetic determinants, suicide attempts and mood disorders may also have partially independent etiological pathways. To identify where these pathways diverge, we need to understand the differential, phenotype-specific gene-environment interactions such as the ones observed in the present study, using suitably powered samples.

Cortico-limbic connectivity in MAOA-L carriers is vulnerable to acute tryptophan depletion.

PubMed

Eisner, Patrick; Klasen, Martin; Wolf, Dhana; Zerres, Klaus; Eggermann, Thomas; Eisert, Albrecht; Zvyagintsev, Mikhail; Sarkheil, Pegah; Mathiak, Krystyna A; Zepf, Florian; Mathiak, Klaus

2017-03-01

A gene-environment interaction between expression genotypes of the monoamine oxidase A (MAOA) and adverse childhood experience increases the risk of antisocial behavior. However, the neural underpinnings of this interaction remain uninvestigated. A cortico-limbic circuit involving the prefrontal cortex (PFC) and the amygdala is central to the suppression of aggressive impulses and is modulated by serotonin (5-HT). MAOA genotypes may modulate the vulnerability of this circuit and increase the risk for emotion regulation deficits after specific life events. Acute tryptophan depletion (ATD) challenges 5-HT regulation and may identify vulnerable neuronal circuits, contributing to the gene-environment interaction. Functional magnetic resonance imaging measured the resting-state state activity in 64 healthy males in a double-blind, placebo-controlled study. Cortical maps of amygdala correlation identified the impact of ATD and its interaction with low- (MAOA-L) and high-expression variants (MAOA-H) of MAOA on cortico-limbic connectivity. Across all Regions of Interest (ROIs) exhibiting an ATD effect on cortico-limbic connectivity, MAOA-L carriers were more susceptible to ATD than MAOA-H carriers. In particular, the MAOA-L group exhibited a larger reduction of amygdala connectivity with the right prefrontal cortex and a larger increase of amygdala connectivity with the insula and dorsal PCC. MAOA-L carriers were more susceptable to a central 5-HT challenge in cortico-limbic networks. Such vulnerability of the cortical serotonergic system may contribute to the emergence of antisocial behavior after systemic challenges, observed as gene-environment interaction. Hum Brain Mapp 38:1622-1635, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Effect of summer daylight exposure and genetic background on growth in growth hormone-deficient children.

PubMed

De Leonibus, C; Chatelain, P; Knight, C; Clayton, P; Stevens, A

2016-11-01

The response to growth hormone in humans is dependent on phenotypic, genetic and environmental factors. The present study in children with growth hormone deficiency (GHD) collected worldwide characterised gene-environment interactions on growth response to recombinant human growth hormone (r-hGH). Growth responses in children are linked to latitude, and we found that a correlate of latitude, summer daylight exposure (SDE), was a key environmental factor related to growth response to r-hGH. In turn growth response was determined by an interaction between both SDE and genes known to affect growth response to r-hGH. In addition, analysis of associated networks of gene expression implicated a role for circadian clock pathways and specifically the developmental transcription factor NANOG. This work provides the first observation of gene-environment interactions in children treated with r-hGH.

Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions

PubMed Central

Cha, Jeeyeon; Bartos, Amanda; Egashira, Mahiro; Haraguchi, Hirofumi; Saito-Fujita, Tomoko; Leishman, Emma; Bradshaw, Heather; Dey, Sudhansu K.; Hirota, Yasushi

2013-01-01

There are currently more than 15 million preterm births each year. We propose that gene-environment interaction is a major contributor to preterm birth. To address this experimentally, we generated a mouse model with uterine deletion of Trp53, which exhibits approximately 50% incidence of spontaneous preterm birth due to premature decidual senescence with increased mTORC1 activity and COX2 signaling. Here we provide evidence that this predisposition provoked preterm birth in 100% of females exposed to a mild inflammatory insult with LPS, revealing the high significance of gene-environment interactions in preterm birth. More intriguingly, preterm birth was rescued in LPS-treated Trp53-deficient mice when they were treated with a combination of rapamycin (mTORC1 inhibitor) and progesterone (P4), without adverse effects on maternal or fetal health. These results provide evidence for the cooperative contributions of two sites of action (decidua and ovary) toward preterm birth. Moreover, a similar signature of decidual senescence with increased mTORC1 and COX2 signaling was observed in women undergoing preterm birth. Collectively, our findings show that superimposition of inflammation on genetic predisposition results in high incidence of preterm birth and suggest that combined treatment with low doses of rapamycin and P4 may help reduce the incidence of preterm birth in high-risk women. PMID:23979163

Dissecting gene-environment interactions: A penalized robust approach accounting for hierarchical structures.

PubMed

Wu, Cen; Jiang, Yu; Ren, Jie; Cui, Yuehua; Ma, Shuangge

2018-02-10

Identification of gene-environment (G × E) interactions associated with disease phenotypes has posed a great challenge in high-throughput cancer studies. The existing marginal identification methods have suffered from not being able to accommodate the joint effects of a large number of genetic variants, while some of the joint-effect methods have been limited by failing to respect the "main effects, interactions" hierarchy, by ignoring data contamination, and by using inefficient selection techniques under complex structural sparsity. In this article, we develop an effective penalization approach to identify important G × E interactions and main effects, which can account for the hierarchical structures of the 2 types of effects. Possible data contamination is accommodated by adopting the least absolute deviation loss function. The advantage of the proposed approach over the alternatives is convincingly demonstrated in both simulation and a case study on lung cancer prognosis with gene expression measurements and clinical covariates under the accelerated failure time model. Copyright © 2017 John Wiley & Sons, Ltd.

Gene-Environment Interaction in the Etiology of Mathematical Ability Using SNP Sets

PubMed Central

Kovas, Yulia; Plomin, Robert

2010-01-01

Mathematics ability and disability is as heritable as other cognitive abilities and disabilities, however its genetic etiology has received relatively little attention. In our recent genome-wide association study of mathematical ability in 10-year-old children, 10 SNP associations were nominated from scans of pooled DNA and validated in an individually genotyped sample. In this paper, we use a ‘SNP set’ composite of these 10 SNPs to investigate gene-environment (GE) interaction, examining whether the association between the 10-SNP set and mathematical ability differs as a function of ten environmental measures in the home and school in a sample of 1888 children with complete data. We found two significant GE interactions for environmental measures in the home and the school both in the direction of the diathesis-stress type of GE interaction: The 10-SNP set was more strongly associated with mathematical ability in chaotic homes and when parents are negative. PMID:20978832

Oxytocin receptors (OXTR) and early parental care: An interaction that modulates psychiatric disorders.

PubMed

Cataldo, Ilaria; Azhari, Atiqah; Lepri, Bruno; Esposito, Gianluca

2017-10-21

Oxytocin plays an important role in the modulation of social behavior in both typical and atypical contexts. Also, the quality of early parental care sets the foundation for long-term psychosocial development. Here, we review studies that investigated how oxytocin receptor (OXTR) interacts with early parental care experiences to influence the development of psychiatric disorders. Using Pubmed, Scopus and PsycInfo databases, we utilized the keyword "OXTR" before subsequently searching for specific OXTR single nucleotide polymorphisms (SNPs), generating a list of 598 studies in total. The papers were catalogued in a database and filtered for gene-environment interaction, psychiatric disorders and involvement of parental care. In particular, rs53576 and rs2254298 were found to be significantly involved in gene-environment interactions that modulated risk for psychopathology and the following psychiatric disorders: disruptive behavior, depression, anxiety, eating disorder and borderline personality disorder. These results illustrate the importance of OXTR in mediating the impact of parental care on the emergence of psychopathology. Copyright © 2017 Elsevier Ltd. All rights reserved.

Molecular epidemiology, and possible real-world applications in breast cancer.

PubMed

Ito, Hidemi; Matsuo, Keitaro

2016-01-01

Gene-environment interaction, a key idea in molecular epidemiology, has enabled the development of personalized medicine. This concept includes personalized prevention. While genome-wide association studies have identified a number of genetic susceptibility loci in breast cancer risk, however, the application of this knowledge to practical prevention is still underway. Here, we briefly review the history of molecular epidemiology and its progress in breast cancer epidemiology. We then introduce our experience with the trial combination of GWAS-identified loci and well-established lifestyle and reproductive risk factors in the risk prediction of breast cancer. Finally, we report our exploration of the cumulative risk of breast cancer based on this risk prediction model as a potential tool for individual risk communication, including genetic risk factors and gene-environment interaction with obesity.

Gene-environment interactions in cancer epidemiology: a National Cancer Institute Think Tank report.

PubMed

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

2013-11-01

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 (0.01 < MAF < 0.05) genetic variants associated with cancer. The marginal effects of most of these variants have been small (odds ratios: 1.1-1.4). There remain unanswered questions on how best to incorporate the joint effects of genes and environment, including gene-environment (G × E) 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 10-11, 2012. The objective of the Think Tank was to facilitate discussions on (1) the state of the science, (2) the goals of G × E 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 G × E 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. © 2013 WILEY PERIODICALS, INC.

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. © 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Association of Positive and Negative Parenting Behavior with Childhood ADHD: Interactions with Offspring Monoamine Oxidase A (MAO-A) Genotype

ERIC Educational Resources Information Center

Li, James J.; Lee, Steve S.

2012-01-01

Relatively little is known about the potential interplay between genetic and environmental influences on attention-deficit/hyperactivity disorder (ADHD), including gene-environment interaction (GxE). There is evidence that parenting behavior interacts with offspring genotype in the development of externalizing problems, but studies have largely…

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. © 2015 Wiley Periodicals, Inc.

Original BPC3 Research Plan

Cancer.gov

The Breast and Prostate Cancer and Hormone-Related Gene Variant Study allows large-scale analyses of breast and prostate cancer risk in relation to genetic polymorphisms and gene-environment interactions that affect hormone metabolism.

The role of gene-environment interplay in occupational and environmental diseases: current concepts and knowledge gaps.

PubMed

Kwo, Elizabeth; Christiani, David

2017-03-01

The interplay between genetic susceptibilities and environmental exposures in the pathogenesis of a variety of diseases is an area of increased scientific, epidemiologic, and social interest. Given the variation in methodologies used in the field, this review aims to create a framework to help understand occupational exposures as they currently exist and provide a foundation for future inquiries into the biological mechanisms of the gene-environment interactions. Understanding of this complex interplay will be important in the context of occupational health, given the public health concerns surrounding a variety of occupational exposures. Studies found evidence that suggest genetics influence the progression of disease postberyllium exposure through genetically encoded major histocompatibility complex, class II, DP alpha 2 (HLA-DP2)-peptide complexes as it relates to T-helper cells. This was characterized at the molecular level by the accumulation of Be-responsive CD4 T cells in the lung, which resulted in posttranslational change in the HLA-DPB1 complex. These studies provide important evidence of gene-environment association, and many provide insights into specific pathogenic mechanisms. The following includes a review of the literature regarding gene-environment associations with a focus on pulmonary diseases as they relate to the workplace.

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

Genetic Influences on Peer and Family Relationships Across Adolescent Development: Introduction to the Special Issue.

PubMed

Mullineaux, Paula Y; DiLalla, Lisabeth Fisher

2015-07-01

Nearly all aspects of human development are influenced by genetic and environmental factors, which conjointly shape development through several gene-environment interplay mechanisms. More recently, researchers have begun to examine the influence of genetic factors on peer and family relationships across the pre-adolescent and adolescent time periods. This article introduces the special issue by providing a critical overview of behavior genetic methodology and existing research demonstrating gene-environment processes operating on the link between peer and family relationships and adolescent adjustment. The overview is followed by a summary of new research studies, which use genetically informed samples to examine how peer and family environment work together with genetic factors to influence behavioral outcomes across adolescence. The studies in this special issue provide further evidence of gene-environment interplay through innovative behavior genetic methodological approaches across international samples. Results from the quantitative models indicate environmental moderation of genetic risk for coercive adolescent-parent relationships and deviant peer affiliation. The molecular genetics studies provide support for a gene-environment interaction differential susceptibility model for dopamine regulation genes across positive and negative peer and family environments. Overall, the findings from the studies in this special issue demonstrate the importance of considering how genes and environments work in concert to shape developmental outcomes during adolescence.

The interaction of miR-34b/c polymorphisms and negative life events increases susceptibility to major depressive disorder in Han Chinese population.

PubMed

Xu, Cheng; Yang, Chunxia; Zhang, Aixia; Xu, Yong; Li, Xinrong; Liu, Zhifen; Liu, Sha; Sun, Ning; Zhang, Kerang

2017-06-09

Previous studies have shown that microRNAs(miRNAs) are involved in the pathogenesis of MDD; in particular, miR-34b/c has been implicated in MDD risk and found to exert antidepressant effects. However, the effects of miR-34b/c polymorphisms on MDD risk have not been investigated. In this study, we evaluated the effect of miR-34b/c gene polymorphisms and their interaction with negative life events in relation to MDD, using data from 381 Han Chinese patients with MDD and 291 healthy volunteers. Allelic, genotypic, haplotypic, and gene-environment associations were analyzed using UNPHASED and SPSS software. After discarding data with extremely severe negative life events in our study population, we found an association between rs4938723, rs2187473 polymorphisms and MDD in the dominant models (TC/CC vs. TT, OR=1.45, P=0.027; TC/CC vs. TT, OR=3.32, P=0.030). In haplotype analysis, the C-G haplotype (rs4938723/rs28757623) showed the strongest association with MDD (OR=1.95, P=0.026). Additionally, we found significant gene-environment combination rs4938723 C allele, rs28757623 G allele and high level of negative life events (C-G-HN) was significantly associated with MDD (OR, 3.85; 95% CI, 1.62-9.13). In addition, the combination of (C-C-HN) is of significance (OR, 2.99; 95% CI, 1.36-6.60), indicating that the rs28757623 C allele may contribute to the risk of MDD as well. The sample size was small and the role of miR-34b/c polymorphisms for MDD should be assessed using independent samples from other ethnic populations. Our results suggest that miR-34b/c is a susceptibility factor for MDD stratified by negative life events and that rs4938723 is a significant association locus for gene-environment interaction in relation to MDD risk. Copyright © 2017 Elsevier B.V. All rights reserved.

A haplotype of polymorphisms in ASE-1, RAI and ERCC1 and the effects of tobacco smoking and alcohol consumption on risk of colorectal cancer: a Danish prospective case-cohort study.

PubMed

Hansen, Rikke D; Sørensen, Mette; Tjønneland, Anne; Overvad, Kim; Wallin, Håkan; Raaschou-Nielsen, Ole; Vogel, Ulla

2008-02-20

Single nucleotide polymorphisms (SNPs) are the most frequent type of genetic variation in the human genome, and are of interest for the study of susceptibility to and protection from diseases. The haplotype at chromosome 19q13.2-3 encompassing the three SNPs ASE-1 G-21A, RAI IVS1 A4364G and ERCC1 Asn118Asn have been associated with risk of breast cancer and lung cancer. Haplotype carriers are defined as the homozygous carriers of RAI IVS1 A4364GA, ERCC1 Asn118AsnT and ASE-1 G-21AG. We aimed to evaluate whether the three polymorphisms and the haplotype are associated to risk of colorectal cancer, and investigated gene-environment associations between the polymorphisms and the haplotype and smoking status at enrolment, smoking duration, average smoking intensity and alcohol consumption, respectively, in relation to risk of colorectal cancer. Associations between the three individual polymorphisms, the haplotype and risk of colorectal cancer were examined, as well as gene-environment interaction, in a Danish case-cohort study including 405 cases and a comparison group of 810 persons. Incidence rate ratio (IRR) were estimated by the Cox proportional hazards model stratified according to gender, and two-sided 95% confidence intervals (CI) and p-values were calculated based on robust estimates of the variance-covariance matrix and Wald's test of the Cox regression parameter. No consistent associations between the three individual polymorphisms, the haplotype and risk of colorectal cancer were found. No statistically significant interactions between the genotypes and the lifestyle exposures smoking or alcohol consumption were observed. Our results suggest that the ASE-1 G-21A, RAI IVS1 A4364G and ERCC1 Asn118Asn polymorphisms and the previously identified haplotype are not associated with risk of colorectal cancer. We found no evidence of gene-environment interaction between the three polymorphisms and the haplotype and smoking intensity and alcohol consumption, respectively, in relation to the risk of colorectal cancer.

Sensitivity to Peer Evaluation and Its Genetic and Environmental Determinants: Findings from a Population-Based Twin Study.

PubMed

Klippel, Annelie; Reininghaus, Ulrich; Viechtbauer, Wolfgang; Decoster, Jeroen; Delespaul, Philippe; Derom, Cathérine; de Hert, Marc; Jacobs, Nele; Menne-Lothmann, Claudia; Rutten, Bart; Thiery, Evert; van Os, Jim; van Winkel, Ruud; Myin-Germeys, Inez; Wichers, Marieke

2018-02-23

Adolescents and young adults are highly focused on peer evaluation, but little is known about sources of their differential sensitivity. We examined to what extent sensitivity to peer evaluation is influenced by interacting environmental and genetic factors. A sample of 354 healthy adolescent twin pairs (n = 708) took part in a structured, laboratory task in which they were exposed to peer evaluation. The proportion of the variance in sensitivity to peer evaluation due to genetic and environmental factors was estimated, as was the association with specific a priori environmental risk factors. Differences in sensitivity to peer evaluation between adolescents were explained mainly by non-shared environmental influences. The results on shared environmental influences were not conclusive. No impact of latent genetic factors or gene-environment interactions was found. Adolescents with lower self-rated positions on the social ladder or who reported to have been bullied more severely showed significantly stronger responses to peer evaluation. Not genes, but subjective social status and past experience of being bullied seem to impact sensitivity to peer evaluation. This suggests that altered response to peer evaluation is the outcome of cumulative sensitization to social interactions.

Gene-environment interactions between smoking and a haplotype of RAI, ASE-1 and ERCC1 polymorphisms among women in relation to risk of lung cancer in a population-based study.

PubMed

Vogel, Ulla; Sørensen, Mette; Hansen, Rikke Dalgaard; Tjønneland, Anne; Overvad, Kim; Wallin, Håkan; Nexø, Bjørn A; Raaschou-Nielsen, Ole

2007-03-08

Homozygous carriers of a haplotype consisting of ERCC1 Asn118Asn(A), ASE-1 G-21A(G), RAI IVS1 A4364G(A) are at increased risk of lung cancer especially among women. Here, we analyse for gene-environment interactions with the predefined haplotype in a case cohort study including 428 lung cancer cases and a comparison group of 800 persons, all from the prospective Diet, Cancer and Health cohort of 57,000 Danes. At high smoking intensity (>20g tobacco/day), there was only additional risk of smoking intensity among women who were homozygous carriers of the haplotype (IRR=2.03; 95% CI: 1.10-3.73 per 5 additional g tobacco/day).

Influence on serum asymmetric dimethylarginine (ADMA) concentrations of human paraoxonase 1 polymorphism (Q192R) and exposure to polycyclic aromatic hydrocarbons (PAHs) in Mexican women, a gene-environment interaction.

PubMed

Ochoa-Martínez, Ángeles C; Ruíz-Vera, Tania; Almendarez-Reyna, Claudia I; Orta-García, Sandra T; Pérez-Maldonado, Iván N

2017-11-01

It has been demonstrated that Cardiovascular Diseases (CVD) are a consequence of the combination of genetic and environmental factors and/or the interaction between them. Therefore, the aim of this study was to evaluate the impact of polycyclic aromatic hydrocarbon (PAHs) exposure and PON1 Q192R polymorphism (genetic susceptibility) on serum asymmetric dimethylarginine (ADMA) levels in Mexican women (n = 206). Urinary 1-hydroxypyrene concentrations (1-OHP; exposure biomarker for PAHs) were quantified using a high-performance liquid chromatography technique, PON1 Q192R polymorphism was genotyped using TaqMan probes and serum ADMA concentrations were evaluated using a commercially available ELISA kit. Urinary 1-OHP levels detected in this study ranged from 0.07 to 9.37 μmol/mol of creatinine (0.13-18.0 μg/g of creatinine). Regarding allele frequency (PON1 Q192R polymorphism), the 192Q-allele frequency was 0.43 and for the 192R-allele it was 0.57. In relation to serum ADMA levels, the levels ranged from 0.06 to 1.46 μmol/L. Moreover, multiple linear regression analysis was performed and associations between urinary 1-OHP levels (β = 0.05, p = 0.002), PON1 Q192R polymorphism (β = 0.04, p = 0.003) and serum ADMA concentrations were found. Besides, an interaction (gene-environment interaction) of both independent variables (1-OHP and PON1 polymorphism) on serum ADMA levels was found (β = 0.04, p = 0.02) in the constructed multiple linear model. Therefore, according to the significance of this research, it is necessary to execute health programs to reduce cardiovascular risk in the assessed population. Copyright © 2017 Elsevier Ltd. All rights reserved.

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 caused by known mutations and chromosomal aberrations. Notably, such a human brain model will be a versatile tool for more complex testing platforms and strategies as well as research into central nervous system physiology and pathology. PMID:24564953

Gender specific gene-environment interactions on laboratory-assessed aggression.

PubMed

Verona, Edelyn; Joiner, Thomas E; Johnson, Frank; Bender, Theodore W

2006-01-01

We examined gene-environment interactive effects on aggressive behavior among men and women genotyped (short versus long alleles) for the serotonin transporter gene. Aggressive behavior was indexed via a laboratory paradigm that measured the intensity and duration of shocks delivered to a putative "employee". Half of the participants were exposed to a physical stressor during the procedure (stress) and half were not (no-stress). Participants' physiological responses were gauged via acoustic startle eyeblink reactions (startle reactivity). Results were that men with the homozygous short (s/s) genotype showed increased aggression only under stress, whereas women and men carrying the long allele did not show differences in aggression in stress versus no-stress. However, although stress exposure produced increases in startle reactivity, there were no genotype or gender differences in physiology. These results replicate longitudinal research findings confirming the interactive effects of genes and environment on behavioral reactivity and on the development of externalizing psychopathological syndromes, at least in men.

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

PubMed

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

2014-05-01

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.

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...

The Behavioural Phenotype of Smith-Magenis Syndrome: Evidence for a Gene-Environment Interaction

ERIC Educational Resources Information Center

Taylor, L.; Oliver, C.

2008-01-01

Background: Behaviour problems and a preference for adult contact are reported to be prominent in the phenotype of Smith-Magenis syndrome. In this study we examined the relationship between social interactions and self-injurious and aggressive/disruptive behaviour in Smith-Magenis syndrome to explore potential operant reinforcement of problem…

Family Conflict Interacts with Genetic Liability in Predicting Childhood and Adolescent Depression

ERIC Educational Resources Information Center

Rice, Frances; Harold, Gordon T.; Shelton, Katherine H.; Thapar, Anita

2006-01-01

Objective: To test for gene-environment interaction with depressive symptoms and family conflict. Specifically, to first examine whether the influence of family conflict in predicting depressive symptoms is increased in individuals at genetic risk of depression. Second, to test whether the genetic component of variance in depressive symptoms…

LPHN3 and Attention-Deficit/Hyperactivity Disorder: Interaction with Maternal Stress during Pregnancy

ERIC Educational Resources Information Center

Choudhry, Zia; Sengupta, Sarojini M.; Grizenko, Natalie; Fortier, Marie-Eve; Thakur, Geeta A.; Bellingham, Johanne; Joober, Ridha

2012-01-01

Background: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous behavioral disorder, complex both in etiology and clinical expression. Both genetic and environmental factors have been implicated, and it has been suggested that gene-environment interactions may play a pivotal role in the disorder. Recently, a significant association…

Review: the Contribution of both Nature and Nurture to Carcinogenesis and Progression in Solid Tumours.

PubMed

Hyndman, Iain Joseph

2016-04-01

Cancer is a leading cause of mortality worldwide. Cancer arises due to a series of somatic mutations that accumulate within the nucleus of a cell which enable the cell to proliferate in an unregulated manner. These mutations arise as a result of both endogenous and exogenous factors. Genes that are commonly mutated in cancer cells are involved in cell cycle regulation, growth and proliferation. It is known that both nature and nurture play important roles in cancer development through complex gene-environment interactions; however, the exact mechanism of these interactions in carcinogenesis is presently unclear. Key environmental factors that play a role in carcinogenesis include smoking, UV light and oncoviruses. Angiogenesis, inflammation and altered cell metabolism are important factors in carcinogenesis and are influenced by both genetic and environmental factors. Although the exact mechanism of nature-nurture interactions in solid tumour formation are not yet fully understood, it is evident that neither nature nor nurture can be considered in isolation. By understanding more about gene-environment interactions, it is possible that cancer mortality could be reduced.

The association of interacting neighborhood gene-environment risk with cortisol and blood pressure in African-American adults

PubMed Central

Coulon, Sandra M.; Wilson, Dawn K.; Van Horn, M. L.; Hand, Gregory A.; Kresovich, Stephen

2016-01-01

Background African-American adults are disproportionately affected by stress-related chronic conditions like high blood pressure (BP), and both environmental stress and genetic risk may play a role in its development. Purpose This study tested whether the dual risk of low neighborhood socioeconomic status (SES) and glucocorticoid genetic sensitivity interacted to predict waking cortisol and BP. Methods Cross-sectional waking cortisol and BP were collected from 208 African-American adults who were participating in a follow-up visit as part of the Positive Action for Today’s Health trial. Three single nucleotide polymorphisms were genotyped, salivary cortisol samples were collected, and neighborhood SES was calculated using 2010 Census data. Results The sample was mostly female (65%), with weight classified as overweight or obese (MBMI=32.74, SD=8.88), and a mean age of 55.64 (SD=15.21). The gene-by-neighborhood SES interaction predicted cortisol (B=0.235, p=.001, r2=.036), but not BP. For adults with high genetic risk, waking cortisol was lower with lower SES but higher with higher SES (B=0.87). Lower neighborhood SES was also related to higher systolic BP (B=−0.794, p=.028). Conclusions Findings demonstrated an interaction whereby African-American adults with high genetic sensitivity had high levels of waking cortisol with higher neighborhood SES, and low levels with lower neighborhood SES. This moderation effect is consistent with a differential susceptibility gene-environment pattern, rather than a dual-risk pattern. These findings contribute to a growing body of evidence that demonstrates the importance of investigating complex gene-environment relations in order to better understand stress-related health disparities. PMID:26685668

Understanding the Relative Contributions of Direct Environmental Effects and Passive Genotype-Environment Correlations in the Association between Familial Risk Factors and Child Disruptive Behavior Disorders

PubMed Central

Bornovalova, Marina A.; Cummings, Jenna R.; Hunt, Elizabeth; Blazei, Ryan; Malone, Steve; Iacono, William G.

2013-01-01

Background: Previous work reports an association between familial risk factors stemming from parental characteristics and offspring disruptive behavior disorders (DBDs). This association may reflect a) the direct effects of familial environment, and b) a passive gene-environment correlation, wherein the parents provide both the genes and the environment. The current study examined the contributions of direct environmental influences and passive gene-environment correlations by comparing the effects of familial risk factors on child DBDs in genetically related (biological) and non-related (adoptive) families. Method: Participants were 402 adoptive and 204 biological families. Familial environment was defined as maternal and paternal maladaptive parenting and antisociality, marital conflict, and divorce; offspring DBDs included attention deficit/hyperactivity disorder, conduct disorder, and oppositional defiant disorder. Mixed-level regressions estimated the main effects of familial environment, adoption status, and the familial environment by adoption status interaction term, which tested for a presence of passive gene-environment correlations. Results: There was a main effect of maternal and paternal maladaptive parenting and marital discord on child DBDs, indicating a direct environmental effect. There was no direct environmental effect of maternal or paternal antisociality, but maternal and paternal antisociality had stronger associations with child DBDs in biological families than adoptive families, indicating the presence of a passive gene-environment correlation. Conclusions: Many familial risk factors affected children equally across genetically-related and non-related families, providing evidence for direct environmental effects. The relationship of parental antisociality and offspring DBDs was best explained by a passive gene-environment correlation, where a general vulnerability toward externalizing psychopathology is passed down by the parents to the children. PMID:23714724

Breast and Prostate Cancer and Hormone-Related Gene Variant Study

Cancer.gov

The Breast and Prostate Cancer and Hormone-Related Gene Variant Study allows large-scale analyses of breast and prostate cancer risk in relation to genetic polymorphisms and gene-environment interactions that affect hormone metabolism.

Animal models of gene-environment interaction in schizophrenia: a dimensional perspective

PubMed Central

Ayhan, Yavuz; McFarland, Ross; Pletnikov, Mikhail V.

2015-01-01

Schizophrenia has long been considered as a disorder with multifactorial origins. Recent discoveries have advanced our understanding of the genetic architecture of the disease. However, even with the increase of identified risk variants, heritability estimates suggest an important contribution of non-genetic factors. Various environmental risk factors have been proposed to play a role in the etiopathogenesis of schizophrenia. These include season of birth, maternal infections, obstetric complications, adverse events at early childhood, and drug abuse. Despite the progress in identification of genetic and environmental risk factors, we still have a limited understanding of the mechanisms whereby gene-environment interactions (GxE) operate in schizophrenia and psychoses at large. In this review we provide a critical analysis of current animal models of GxE relevant to psychotic disorders and propose that dimensional perspective will advance our understanding of the complex mechanisms of these disorders. PMID:26510407

Gene-environment interaction in posttraumatic stress disorder

PubMed Central

Nugent, Nicole R.; Amstadter, Ananda B.

2009-01-01

The purpose of this article is to encourage research investigating the role of measured gene-environment interaction (G × E) in the etiology of posttraumatic stress disorder (PTSD). PTSD is uniquely suited to the study of G × E as the diagnosis requires exposure to a potentially-traumatic life event. PTSD is also moderately heritable; however, the role of genetic factors in PTSD etiology has been largely neglected both by trauma researchers and psychiatric geneticists. First, we summarize evidence for genetic influences on PTSD from family, twin, and molecular genetic studies. Second, we discuss the key challenges in G × E studies of PTSD and offer practical strategies for addressing these challenges and for discovering replicable G × E for PTSD. Finally, we propose some promising new directions for PTSD G × E research. We suggest that G × E research in PTSD is essential to understanding vulnerability and resilience following exposure to a traumatic event. PMID:18297420

Life Events, Genetic Susceptibility, and Smoking among Adolescents

PubMed Central

Pampel, Fred C.; Boardman, Jason D.; Daw, Jonathan; Stallings, Michael C.; Smolen, Andrew; Haberstick, Brett; Widaman, Keith F.; Neppl, Tricia K.; Conger, Rand D.

2015-01-01

Although stressful life events during adolescence are associated with the adoption of unhealthy behaviors such as smoking, both social circumstances and physical traits can moderate the relationship. This study builds on the stress paradigm and gene-environment approach to social behavior by examining how a polymorphism in the serotonin transporter gene 5-HTTLPR moderates the effect of life events on adolescent smoking. Tests of interaction hypotheses use data from the Family Transitions Project, a longitudinal study of 7th graders followed for 5 years. A sibling-pair design with separate models for the gender composition of pairs (brothers, sisters, or brother/sister) controls for unmeasured family background. The results show that negative life events are significantly and positively associated with smoking. Among brother pairs but not other pairs, the results provide evidence of gene-environment interaction by showing that life events more strongly influence smoking behavior for those with more copies of the 5-HTTLPR S allele. PMID:26463545

Review of the Gene-Environment Interaction Literature in Cancer: What Do We Know?

PubMed

Simonds, Naoko I; Ghazarian, Armen A; Pimentel, Camilla B; Schully, Sheri D; Ellison, Gary L; Gillanders, Elizabeth M; Mechanic, Leah E

2016-07-01

Risk of cancer is determined by a complex interplay of genetic and environmental factors. Although the study of gene-environment interactions (G×E) has been an active area of research, little is reported about the known findings in the literature. To examine the state of the science in G×E research in cancer, we performed a systematic review of published literature using gene-environment or pharmacogenomic flags from two curated databases of genetic association studies, the Human Genome Epidemiology (HuGE) literature finder and Cancer Genome-Wide Association and Meta Analyses Database (CancerGAMAdb), from January 1, 2001, to January 31, 2011. A supplemental search using HuGE was conducted for articles published from February 1, 2011, to April 11, 2013. A 25% sample of the supplemental publications was reviewed. A total of 3,019 articles were identified in the original search. From these articles, 243 articles were determined to be relevant based on inclusion criteria (more than 3,500 interactions). From the supplemental search (1,400 articles identified), 29 additional relevant articles (1,370 interactions) were included. The majority of publications in both searches examined G×E in colon, rectal, or colorectal; breast; or lung cancer. Specific interactions examined most frequently included environmental factors categorized as energy balance (e.g., body mass index, diet), exogenous (e.g., oral contraceptives) and endogenous hormones (e.g., menopausal status), chemical environment (e.g., grilled meats), and lifestyle (e.g., smoking, alcohol intake). In both searches, the majority of interactions examined were using loci from candidate genes studies and none of the studies were genome-wide interaction studies (GEWIS). The most commonly reported measure was the interaction P-value, of which a sizable number of P-values were considered statistically significant (i.e., <0.05). In addition, the magnitude of interactions reported was modest. Observations of published literature suggest that opportunity exists for increased sample size in G×E research, including GWAS-identified loci in G×E studies, exploring more GWAS approaches in G×E such as GEWIS, and improving the reporting of G×E findings. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Review of the Gene-Environment Interaction Literature in Cancer: What do we know?

PubMed Central

Simonds, Naoko I.; Ghazarian, Armen A.; Pimentel, Camilla B.; Schully, Sheri D.; Ellison, Gary L.; Gillanders, Elizabeth M.; Mechanic, Leah E.

2016-01-01

Background Risk of cancer is determined by a complex interplay of genetic and environmental factors. Although the study of gene-environment (GxE) interactions has been an active area of research, little is reported about the known findings in the literature. Methods To examine the state of the science in GxE research in cancer, we performed a systematic review of published literature using gene-environment or pharmacogenomic flags from two curated databases of genetic association studies, the Human Genome Epidemiology (HuGE) literature finder and Cancer Genome-Wide Association and Meta Analyses Database (CancerGAMAdb), from January 1, 2001, to January 31, 2011. A supplemental search using HuGE was conducted for articles published February 1, 2011, to April 11, 2013. A 25% sample of the supplemental publications was reviewed. Results A total of 3,019 articles were identified in the original search. From these articles, 243 articles were determined to be relevant based on inclusion criteria (more than 3,500 interactions). From the supplemental search (1,400 articles identified), 29 additional relevant articles (1,370 interactions) were included. The majority of publications in both searches examined GxE in colon, rectal, or colorectal cancer types; breast; or lung cancer. Specific interactions examined most frequently included environmental factors categorized as energy balance (e.g., body mass index (BMI), diet), exogenous (e.g., oral contraceptives) and endogenous hormones (e.g., menopausal status), chemical environment (e.g., grilled meats), and lifestyle (e.g., smoking, alcohol intake). In both searches, the majority of interactions examined were using loci from candidate genes studies and none of the studies were genome-wide interaction studies (GEWIS). The most commonly reported measure was the interaction p-value, of which a sizable number of p-values were considered statistically significant (i.e., < 0.05). In addition, the magnitudes of interactions reported were modest. Conclusion Observations of published literature suggest that opportunity exists for increased sample size in GxE research, including GWAS identified loci in GxE studies, exploring more GWAS approaches in GxE such as GEWIS, and improving the reporting of GxE findings. PMID:27061572

Correcting systematic inflation in genetic association tests that consider interaction effects: application to a genome-wide association study of posttraumatic stress disorder.

PubMed

Almli, Lynn M; Duncan, Richard; Feng, Hao; Ghosh, Debashis; Binder, Elisabeth B; Bradley, Bekh; Ressler, Kerry J; Conneely, Karen N; Epstein, Michael P

2014-12-01

Genetic association studies of psychiatric outcomes often consider interactions with environmental exposures and, in particular, apply tests that jointly consider gene and gene-environment interaction effects for analysis. Using a genome-wide association study (GWAS) of posttraumatic stress disorder (PTSD), we report that heteroscedasticity (defined as variability in outcome that differs by the value of the environmental exposure) can invalidate traditional joint tests of gene and gene-environment interaction. To identify the cause of bias in traditional joint tests of gene and gene-environment interaction in a PTSD GWAS and determine whether proposed robust joint tests are insensitive to this problem. The PTSD GWAS data set consisted of 3359 individuals (978 men and 2381 women) from the Grady Trauma Project (GTP), a cohort study from Atlanta, Georgia. The GTP performed genome-wide genotyping of participants and collected environmental exposures using the Childhood Trauma Questionnaire and Trauma Experiences Inventory. We performed joint interaction testing of the Beck Depression Inventory and modified PTSD Symptom Scale in the GTP GWAS. We assessed systematic bias in our interaction analyses using quantile-quantile plots and genome-wide inflation factors. Application of the traditional joint interaction test to the GTP GWAS yielded systematic inflation across different outcomes and environmental exposures (inflation-factor estimates ranging from 1.07 to 1.21), whereas application of the robust joint test to the same data set yielded no such inflation (inflation-factor estimates ranging from 1.01 to 1.02). Simulated data further revealed that the robust joint test is valid in different heteroscedasticity models, whereas the traditional joint test is invalid. The robust joint test also has power similar to the traditional joint test when heteroscedasticity is not an issue. We believe the robust joint test should be used in candidate-gene studies and GWASs of psychiatric outcomes that consider environmental interactions. To make the procedure useful for applied investigators, we created a software tool that can be called from the popular PLINK package for analysis.

Correcting Systematic Inflation in Genetic Association Tests That Consider Interaction Effects

PubMed Central

Almli, Lynn M.; Duncan, Richard; Feng, Hao; Ghosh, Debashis; Binder, Elisabeth B.; Bradley, Bekh; Ressler, Kerry J.; Conneely, Karen N.; Epstein, Michael P.

2015-01-01

IMPORTANCE Genetic association studies of psychiatric outcomes often consider interactions with environmental exposures and, in particular, apply tests that jointly consider gene and gene-environment interaction effects for analysis. Using a genome-wide association study (GWAS) of posttraumatic stress disorder (PTSD), we report that heteroscedasticity (defined as variability in outcome that differs by the value of the environmental exposure) can invalidate traditional joint tests of gene and gene-environment interaction. OBJECTIVES To identify the cause of bias in traditional joint tests of gene and gene-environment interaction in a PTSD GWAS and determine whether proposed robust joint tests are insensitive to this problem. DESIGN, SETTING, AND PARTICIPANTS The PTSD GWAS data set consisted of 3359 individuals (978 men and 2381 women) from the Grady Trauma Project (GTP), a cohort study from Atlanta, Georgia. The GTP performed genome-wide genotyping of participants and collected environmental exposures using the Childhood Trauma Questionnaire and Trauma Experiences Inventory. MAIN OUTCOMES AND MEASURES We performed joint interaction testing of the Beck Depression Inventory and modified PTSD Symptom Scale in the GTP GWAS. We assessed systematic bias in our interaction analyses using quantile-quantile plots and genome-wide inflation factors. RESULTS Application of the traditional joint interaction test to the GTP GWAS yielded systematic inflation across different outcomes and environmental exposures (inflation-factor estimates ranging from 1.07 to 1.21), whereas application of the robust joint test to the same data set yielded no such inflation (inflation-factor estimates ranging from 1.01 to 1.02). Simulated data further revealed that the robust joint test is valid in different heteroscedasticity models, whereas the traditional joint test is invalid. The robust joint test also has power similar to the traditional joint test when heteroscedasticity is not an issue. CONCLUSIONS AND RELEVANCE We believe the robust joint test should be used in candidate-gene studies and GWASs of psychiatric outcomes that consider environmental interactions. To make the procedure useful for applied investigators, we created a software tool that can be called from the popular PLINK package for analysis. PMID:25354142

The heritable basis of gene-environment interactions in cardiometabolic traits.

PubMed

Poveda, Alaitz; Chen, Yan; Brändström, Anders; Engberg, Elisabeth; Hallmans, Göran; Johansson, Ingegerd; Renström, Frida; Kurbasic, Azra; Franks, Paul W

2017-03-01

Little is known about the heritable basis of gene-environment interactions in humans. We therefore screened multiple cardiometabolic traits to assess the probability that they are influenced by genotype-environment interactions. Fourteen established environmental risk exposures and 11 cardiometabolic traits were analysed in the VIKING study, a cohort of 16,430 Swedish adults from 1682 extended pedigrees with available detailed genealogical, phenotypic and demographic information, using a maximum likelihood variance decomposition method in Sequential Oligogenic Linkage Analysis Routines software. All cardiometabolic traits had statistically significant heritability estimates, with narrow-sense heritabilities (h 2 ) ranging from 24% to 47%. Genotype-environment interactions were detected for age and sex (for the majority of traits), physical activity (for triacylglycerols, 2 h glucose and diastolic BP), smoking (for weight), alcohol intake (for weight, BMI and 2 h glucose) and diet pattern (for weight, BMI, glycaemic traits and systolic BP). Genotype-age interactions for weight and systolic BP, genotype-sex interactions for BMI and triacylglycerols and genotype-alcohol intake interactions for weight remained significant after multiple test correction. Age, sex and alcohol intake are likely to be major modifiers of genetic effects for a range of cardiometabolic traits. This information may prove valuable for studies that seek to identify specific loci that modify the effects of lifestyle in cardiometabolic disease.

Local area disadvantage and gambling involvement and disorder: Evidence for gene-environment correlation and interaction.

PubMed

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

2015-08-01

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 2 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. (c) 2015 APA, all rights reserved).

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

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…

Genome-Wide Interaction Analysis of Air Pollution Exposure and Childhood Asthma with Functional Follow-up.

PubMed

Gref, Anna; Merid, Simon K; Gruzieva, Olena; Ballereau, Stéphane; Becker, Allan; Bellander, Tom; Bergström, Anna; Bossé, Yohan; Bottai, Matteo; Chan-Yeung, Moira; Fuertes, Elaine; Ierodiakonou, Despo; Jiang, Ruiwei; Joly, Stéphane; Jones, Meaghan; Kobor, Michael S; Korek, Michal; Kozyrskyj, Anita L; Kumar, Ashish; Lemonnier, Nathanaël; MacIntyre, Elaina; Ménard, Camille; Nickle, David; Obeidat, Ma'en; Pellet, Johann; Standl, Marie; Sääf, Annika; Söderhäll, Cilla; Tiesler, Carla M T; van den Berge, Maarten; Vonk, Judith M; Vora, Hita; Xu, Cheng-Jian; Antó, Josep M; Auffray, Charles; Brauer, Michael; Bousquet, Jean; Brunekreef, Bert; Gauderman, W James; Heinrich, Joachim; Kere, Juha; Koppelman, Gerard H; Postma, Dirkje; Carlsten, Christopher; Pershagen, Göran; Melén, Erik

2017-05-15

The evidence supporting an association between traffic-related air pollution exposure and incident childhood asthma is inconsistent and may depend on genetic factors. To identify gene-environment interaction effects on childhood asthma using genome-wide single-nucleotide polymorphism (SNP) data and air pollution exposure. Identified loci were further analyzed at epigenetic and transcriptomic levels. We used land use regression models to estimate individual air pollution exposure (represented by outdoor NO 2 levels) at the birth address and performed a genome-wide interaction study for doctors' diagnoses of asthma up to 8 years in three European birth cohorts (n = 1,534) with look-up for interaction in two separate North American cohorts, CHS (Children's Health Study) and CAPPS/SAGE (Canadian Asthma Primary Prevention Study/Study of Asthma, Genetics and Environment) (n = 1,602 and 186 subjects, respectively). We assessed expression quantitative trait locus effects in human lung specimens and blood, as well as associations among air pollution exposure, methylation, and transcriptomic patterns. In the European cohorts, 186 SNPs had an interaction P < 1 × 10 -4 and a look-up evaluation of these disclosed 8 SNPs in 4 loci, with an interaction P < 0.05 in the large CHS study, but not in CAPPS/SAGE. Three SNPs within adenylate cyclase 2 (ADCY2) showed the same direction of the interaction effect and were found to influence ADCY2 gene expression in peripheral blood (P = 4.50 × 10 -4 ). One other SNP with P < 0.05 for interaction in CHS, rs686237, strongly influenced UDP-Gal:betaGlcNAc β-1,4-galactosyltransferase, polypeptide 5 (B4GALT5) expression in lung tissue (P = 1.18 × 10 -17 ). Air pollution exposure was associated with differential discs, large homolog 2 (DLG2) methylation and expression. Our results indicated that gene-environment interactions are important for asthma development and provided supportive evidence for interaction with air pollution for ADCY2, B4GALT5, and DLG2.

Prevention of asthma: where are we in the 21st century?

PubMed

Propp, Phaedra; Becker, Allan

2013-12-01

Asthma is the most common chronic disease of childhood and, in the latter part of the 20th century, reached epidemic proportions. Asthma is generally believed to result from gene-environment interactions. There is consensus that a 'window of opportunity' exists during pregnancy and early in life when environmental factors may influence its development. We review multiple environmental, biologic and sociologic factors that may be important in the development of asthma. Meta-analyses of studies have demonstrated that multifaceted interventions are required in order to develop asthma prevention. Multifaceted allergen reduction studies have shown clinical benefits. Asthma represents a dysfunctional interaction with our genes and the environment to which they are exposed, especially in fetal and early infant life. The increasing prevalence of asthma also may be an indication of increased population risk for the development of other chronic non-communicable autoimmune diseases. This review will focus on the factors which may be important in the primary prevention of asthma. Better understanding of the complex gene-environment interactions involved in the development of asthma will provide insight into personalized interventions for asthma prevention.

[From stone-craved genes to Michelangelo: significance and different aspects of gene-environment interaction].

PubMed

Lazary, Judit

2017-12-01

Although genetic studies have improved a lot in recent years, without clinical relevance sometimes their significance is devalued. Reviewing the major milestones of psychogenomics it can be seen that break-through success is just a question of time. Investigations of direct effect of genetic variants on phenotypes have not yielded positive findings. However, an important step was taken by adapting the gene-environment interaction model. In this model genetic vulnerability stepped into the place of "stone craved" pathology. Further progress happened when studies of environmental factors were combined with genetic function (epigenetics). This model provided the possibility for investigation of therapeutic interventions as environmental factors and it was proven that effective treatments exert a modifying effect on gene expression. Moreover, recent developments focus on therapeutic manipulation of gene function (e.g. chemogenetics). Instead of "stone craved" genes up-to-date dynamically interacting gene function became the basis of psychogenomics in which correction of the expression is a potential therapeutic tool. Keeping in mind these trends and developments, there is no doubt that genetics will be a fundamental part of daily clinical routine in the future.

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.

Linking Gene, Brain, and Behavior

PubMed Central

Schmidt, Louis A.; Fox, Nathan A.; Perez-Edgar, Koraly; Hamer, Dean H.

2009-01-01

Gene-environment interactions involving exogenous environmental factors are known to shape behavior and personality development. Although gene-environment interactions involving endogenous environmental factors are hypothesized to play an equally important role, this conceptual approach has not been empirically applied in the study of early-developing temperament in humans. Here we report evidence for a gene-endoenvironment (i.e., resting frontal brain electroencephalogram, EEG, asymmetry) interaction in predicting child temperament. The DRD4 gene (long allele vs. short allele) moderated the relation between resting frontal EEG asymmetry (left vs. right) at 9 months and temperament at 48 months. Children who exhibited left frontal EEG asymmetry at 9 months and who possessed the DRD4 long allele were significantly more soothable at 48 months than other children. Among children with right frontal EEG asymmetry at 9 months, those with the DRD4 long allele had significantly more difficulties focusing and sustaining attention at 48 months than those with the DRD4 short allele. Resting frontal EEG asymmetry did not influence temperament in the absence of the DRD4 long allele. We discuss how the interaction of genetic and endoenvironment factors may confer risk and protection for different behavioral styles in children. PMID:19493320

GENE-ENVIRONMENT INTERACTIONS: A REVIEW OF EFFECTS ON REPRODUCTION AND DEVELOPMENT

EPA Science Inventory

Polymorphisms in genes can lead to differences in the level of susceptibility of individuals to potentially adverse effects of environmental influences, such as chemical exposure, on prenatal development or male or female reproductive function. We have reviewed the literature in ...

Early Life Precursors, Epigenetics, and the Development of Food Allergy1

PubMed Central

Hong, Xiumei; Wang, Xiaobin

2012-01-01

Food allergy (FA), a major clinical and public health concern worldwide, is caused by a complex interplay of environmental exposures, genetic variants, gene-environment interactions, and epigenetic alterations. This review summarizes recent advances surrounding these key factors, with a particular focus on the potential role of epigenetics in the development of FA. Epidemiologic studies have reported a number of non-genetic factors that may influence the risk of FA, such as timing of food introduction and feeding pattern, diet/nutrition, exposure to environmental tobacco smoking, prematurity and low birthweight, microbial exposure, and race/ethnicity. Current studies on the genetics of FA are mainly conducted using candidate gene approaches, which have linked more than 10 genes to the genetic susceptibility of FA. Studies on gene-environment interactions of FA are very limited. Epigenetic alteration has been proposed as one of the mechanisms to mediate the influence of early-life environmental exposures and gene-environment interactions on the development of diseases later in life. The role of epigenetics in the regulation of the immune system and the epigenetic effects of some FA-associated environmental exposures are discussed in this review. There is a particular lack of large-scale prospective birth cohort studies that simultaneously assess the inter-relationships of early life exposures, genetic susceptibility, epigenomic alterations and the development of FA. The identification of these key factors and their independent and joint contributions to FA will allow us to gain important insight into the biological mechanisms by which environmental exposures and genetic susceptibility affect the risk of FA, and will provide essential information to develop more effective new paradigms in the diagnosis, prevention and management of FA. PMID:22777545

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. © 2015 WILEY PERIODICALS, INC.

Gene-environment interactions in the aetiology of systemic lupus erythematosus.

PubMed

Jönsen, Andreas; Bengtsson, Anders A; Nived, Ola; Truedsson, Lennart; Sturfelt, Gunnar

2007-12-01

Systemic lupus erythematosus (SLE) is a disease that displays a multitude of symptoms and a vast array of autoantibodies. The disease course may vary substantially between patients. The current understanding of SLE aetiology includes environmental factors acting on a genetically prone individual during an undetermined time period resulting in autoimmunity and finally surpassing that individual's disease threshold. Genetic differences and environmental factors may interact specifically in the pathogenetic processes and may influence disease development and modify the disease course. Identification of these factors and their interactions in the pathogenesis of SLE is vital in understanding the disease and may contribute to identify new treatment targets and perhaps also aid in disease prevention. However, there are several problems that need to be overcome, such as the protracted time frame of environmental influence, time dependent epigenetic alterations and the possibility that different pathogenetic pathways may result in a similar disease phenotype. This is mirrored by the relatively few studies that suggest specific gene-environment interactions. These include an association between SLE diagnosis and glutation S-transferase gene variants combined with occupational sun exposure as well as variants of the N-acetyl transferase gene in combination with either aromatic amine exposure or hydralazine. With increased knowledge on SLE pathogenesis, the role of environmental factors and their genetic interactions may be further elucidated.

Comparison of weighting approaches for genetic risk scores in gene-environment interaction studies.

PubMed

Hüls, Anke; Krämer, Ursula; Carlsten, Christopher; Schikowski, Tamara; Ickstadt, Katja; Schwender, Holger

2017-12-16

Weighted genetic risk scores (GRS), defined as weighted sums of risk alleles of single nucleotide polymorphisms (SNPs), are statistically powerful for detection gene-environment (GxE) interactions. To assign weights, the gold standard is to use external weights from an independent study. However, appropriate external weights are not always available. In such situations and in the presence of predominant marginal genetic effects, we have shown in a previous study that GRS with internal weights from marginal genetic effects ("GRS-marginal-internal") are a powerful and reliable alternative to single SNP approaches or the use of unweighted GRS. However, this approach might not be appropriate for detecting predominant interactions, i.e. interactions showing an effect stronger than the marginal genetic effect. In this paper, we present a weighting approach for such predominant interactions ("GRS-interaction-training") in which parts of the data are used to estimate the weights from the interaction terms and the remaining data are used to determine the GRS. We conducted a simulation study for the detection of GxE interactions in which we evaluated power, type I error and sign-misspecification. We compared this new weighting approach to the GRS-marginal-internal approach and to GRS with external weights. Our simulation study showed that in the absence of external weights and with predominant interaction effects, the highest power was reached with the GRS-interaction-training approach. If marginal genetic effects were predominant, the GRS-marginal-internal approach was more appropriate. Furthermore, the power to detect interactions reached by the GRS-interaction-training approach was only slightly lower than the power achieved by GRS with external weights. The power of the GRS-interaction-training approach was confirmed in a real data application to the Traffic, Asthma and Genetics (TAG) Study (N = 4465 observations). When appropriate external weights are unavailable, we recommend to use internal weights from the study population itself to construct weighted GRS for GxE interaction studies. If the SNPs were chosen because a strong marginal genetic effect was hypothesized, GRS-marginal-internal should be used. If the SNPs were chosen because of their collective impact on the biological mechanisms mediating the environmental effect (hypothesis of predominant interactions) GRS-interaction-training should be applied.

Current BPC3 Research Plan

Cancer.gov

This will expand the BPC3 to serve as a rapid verification test set for SNPs identified in the scans other than the CGEMS scan, and to examine gene-environment interactions in the SNPs identified in CGEMS and other studies as being associated with breast and prostate cancer.

Epigenetic Contributions to Cognitive Aging: Disentangling Mindspan and Lifespan

ERIC Educational Resources Information Center

Spiegel, Amy M.; Sewal, Angila S.; Rapp, Peter R.

2014-01-01

Epigenetic modifications of chromatin structure provide a mechanistic interface for gene-environment interactions that impact the individualization of health trajectories across the lifespan. A growing body of research indicates that dysfunctional epigenetic regulation contributes to poor cognitive outcomes among aged populations. Here we review…

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. © 2015 New York Academy of Sciences.

Parental Divorce and Disordered Eating: An Investigation of a Gene-Environment Interaction

PubMed Central

Suisman, Jessica Lynn; Burt, S. Alexandra; McGue, Matt; Iacono, William G.; Klump, Kelly L.

2010-01-01

Objective We investigated gene-environment interactions (G×E) for associations between parental divorce and disordered eating (DE). Method Participants were 1,810 female twins from the Michigan State University Twin Registry and the Minnesota Twin Family Study. The Minnesota Eating Behaviors Survey was used to assess DE. We tested for G×E by comparing the heritability of DE in twins from divorced versus intact families. It was hypothesized that divorce would moderate the heritability of DE, in that heritability would be higher in twins from divorced than twins from intact families. Results As expected, the heritability of body dissatisfaction was significantly higher in twins from divorced than intact families. However, genetic influences were equal in twins from divorced and intact families for all other forms of DE. Discussion Although divorce did not moderate heritability of most DE symptoms, future research should replicate G×Es for body dissatisfaction and identify factors underlying this unique relationship. PMID:21312202

The association between the MAOA 2R genotype and delinquency over time among men: the interactive role of parental closeness and parental incarceration

PubMed Central

Roettger, Michael E.; Boardman, Jason D.; Harris, Kathleen Mullan; Guo, Guang

2017-01-01

Using a panel of 6,001 males from the National Longitudinal Study of Adolescent and Adult Health, we examine potential moderation by paternal incarceration and parent-child closeness altering the relationship between the rare 2R MAOA genotype and delinquency. By jointly examining moderation patterns for both the mother and father with the transmission of the MAOA genotype from mother to son, we are able to make inferences about the specific genetic model that best explains these outcomes. In line with prior research, we find a direct relationship between the MAOA 2R genotype and delinquency, independent of parental incarceration and closeness. Examining moderation patterns, we find that delinquency risk for the 2R allele is buffered for males close to their biological or social father, but not their biological mother. We conclude that the 2R delinquency association is not due to passive gene-environment correlation but is best characterized as a social control gene-environment interaction. PMID:29033475

Parental divorce and disordered eating: an investigation of a gene-environment interaction.

PubMed

Suisman, Jessica L; Burt, S Alexandra; McGue, Matt; Iacono, William G; Klump, Kelly L

2011-03-01

We investigated gene-environment interactions (GxE) for associations between parental divorce and disordered eating (DE). Participants were 1,810 female twins from the Michigan State University Twin Registry and the Minnesota Twin Family Study. The Minnesota Eating Behaviors Survey was used to assess DE. We tested for GxE by comparing the heritability of DE in twins from divorced versus intact families. It was hypothesized that divorce would moderate the heritability of DE, in that heritability would be higher in twins from divorced than twins from intact families. As expected, the heritability of body dissatisfaction was significantly higher in twins from divorced than intact families. However, genetic influences were equal in twins from divorced and intact families for all other forms of DE. Although divorce did not moderate heritability of most DE symptoms, future research should replicate GxEs for body dissatisfaction and identify factors underlying this unique relationship. Copyright © 2010 Wiley Periodicals, Inc.

Association Between Four Polymorphisms in lncRNA and Risk of Lung Cancer in a Chinese Never-Smoking Female Population.

PubMed

Gao, Min; Li, Hang; Lv, Xiaoting; Zhou, Baosen; Yin, Zhihua

2018-06-07

Long noncoding RNAs (lncRNAs) play important roles in the development of human cancers. This is the first case-control study of the association between specific polymorphisms in lncRNA genes and the risk of lung cancer, as well as the gene-environment interaction between the polymorphisms and cooking oil fume exposure in Chinese never-smoking females. A hospital-based case-control study was carried out in Shenyang, Liaoning province. The study included 395 cases and 556 controls. The polymorphisms of rs4785367, rs3803662, rs10750417, and rs1814343 in lncRNA genes were analyzed. The gene-environment interactions were explored on both additive and multiplicative scale. In addition, the results were listed as follows: for rs3803662, compared with the individuals carrying homozygous TT genotype, those with homozygous CC genotype had the decreased risk of lung cancer (adjusted odds ratio [OR] = 0.61, 95% confidence interval [CI] = 0.40-0.92, p = 0.018). As for rs4785367, compared with homozygous TT, homozygous CC could lessen the risk of lung cancer (adjusted OR = 0.54, 95% CI = 0.33-0.89, p = 0.016). The recessive models of rs3803662 and rs4785367 showed significant association (adjusted OR = 0.65, 95% CIs = 0.44-0.97, p = 0.033; adjusted OR = 0.54, 95% CIs = 0.33-0.88, p = 0.014). The C allele of rs3803662 was suggested to be protective allele of lung cancer (adjusted OR = 0.80, 95% CI = 0.66-0.97, p = 0.023). However, rs10750417 and rs1814343 polymorphisms were not significantly associated with lung cancer risks. The measures of additive interaction and logistic models suggested that the gene-environment interactions were not statistically significant on both additive and multiplicative scales.

A Combinatorial Approach to Detecting Gene-Gene and Gene-Environment Interactions in Family Studies

PubMed Central

Lou, Xiang-Yang; Chen, Guo-Bo; Yan, Lei; Ma, Jennie Z.; Mangold, Jamie E.; Zhu, Jun; Elston, Robert C.; Li, Ming D.

2008-01-01

Widespread multifactor interactions present a significant challenge in determining risk factors of complex diseases. Several combinatorial approaches, such as the multifactor dimensionality reduction (MDR) method, have emerged as a promising tool for better detecting gene-gene (G × G) and gene-environment (G × E) interactions. We recently developed a general combinatorial approach, namely the generalized multifactor dimensionality reduction (GMDR) method, which can entertain both qualitative and quantitative phenotypes and allows for both discrete and continuous covariates to detect G × G and G × E interactions in a sample of unrelated individuals. In this article, we report the development of an algorithm that can be used to study G × G and G × E interactions for family-based designs, called pedigree-based GMDR (PGMDR). Compared to the available method, our proposed method has several major improvements, including allowing for covariate adjustments and being applicable to arbitrary phenotypes, arbitrary pedigree structures, and arbitrary patterns of missing marker genotypes. Our Monte Carlo simulations provide evidence that the PGMDR method is superior in performance to identify epistatic loci compared to the MDR-pedigree disequilibrium test (PDT). Finally, we applied our proposed approach to a genetic data set on tobacco dependence and found a significant interaction between two taste receptor genes (i.e., TAS2R16 and TAS2R38) in affecting nicotine dependence. PMID:18834969

Integrating nutrigenomics data to identify cardiometabolic gene-environment interactions

USDA-ARS?s Scientific Manuscript database

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...

Gene-environment interactions of circadian-related genes for cardiometabolic traits

USDA-ARS?s Scientific Manuscript database

Objective: Common circadian-related gene variants associate with increased risk for metabolic alterations including type 2 diabetes. However, little is known about whether diet and sleep could modify associations between circadian-related variants (CLOCK-rs1801260, CRY2-rs11605924, MTNR1B-rs1387153,...

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:26873362

Interpretations of education about gene-environment influences on health in rural Ethiopia: the context of a neglected tropical disease

PubMed Central

Tora, Abebayehu; Ayode, Desta; Tadele, Getnet; Farrell, David; Davey, Gail; McBride, Colleen M.

2016-01-01

Background Misunderstandings of the role of genetics in disease development are associated with stigmatizing behaviors and fatalistic attitudes about prevention. This report describes an evaluation of community understanding of an educational module about genetic and environmental influences on the development of podoconiosis, a neglected tropical disease endemic in highland Ethiopia. Methods A qualitative process assessment was conducted as part of a large prospective intervention trial in August 2013, in Wolaita Zone, southern Ethiopia. Sixty five participants were purposively selected from 600 households randomized to receive the inherited susceptibility module. The educational module used pictorial representations and oral explanations of the interaction of inherited sensitivity and soil exposure and was delivered by lay health educators in participants' homes. Data were collected using semi-structured individual interviews (IDIs) or focus group discussions (FGDs). Results Qualitative analyses showed that most participants improved their understanding of inherited soil sensitivity and susceptibility to podoconiosis. Participants linked their new understanding to decreased stigma-related attitudes. The module also corrected misconceptions that the condition was contagious, again diminishing stigmatizing attitudes. Lastly, these improvements in understanding increased the perceived value of foot protection. Conclusions Taken together, these improvements support the acceptability, feasibility and potential benefits of implementing gene-environment education in low and middle income countries. PMID:27114426

Attachment style and oxytocin receptor gene variation interact in influencing social anxiety.

PubMed

Notzon, S; Domschke, K; Holitschke, K; Ziegler, C; Arolt, V; Pauli, P; Reif, A; Deckert, J; Zwanzger, P

2016-01-01

Social anxiety has been suggested to be promoted by an insecure attachment style. Oxytocin is discussed as a mediator of trust and social bonding as well as a modulator of social anxiety. Applying a gene-environment (G × E) interaction approach, in the present pilot study the main and interactive effects of attachment styles and oxytocin receptor (OXTR) gene variation were probed in a combined risk factor model of social anxiety in healthy probands. Participants (N = 388; 219 females, 169 males; age 24.7 ± 4.7 years) were assessed for anxiety in social situations (Social Phobia and Anxiety Inventory) depending on attachment style (Adult Attachment Scale, AAS) and OXTR rs53576 A/G genotype. A less secure attachment style was significantly associated with higher social anxiety. This association was partly modulated by OXTR genotype, with a stronger negative influence of a less secure attachment style on social anxiety in A allele carriers as compared to GG homozygotes. The present pilot data point to a strong association of less secure attachment and social anxiety as well as to a gene-environment interaction effect of OXTR rs53576 genotype and attachment style on social anxiety possibly constituting a targetable combined risk marker of social anxiety disorder.

Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes

USDA-ARS?s Scientific Manuscript database

Bronchial asthma is a chronic inflammatory disease resulting from complex gene-environment interactions. Natural microbial exposure has been identified as an important environmental condition that provides asthma protection in a prenatal window of opportunity. Epigenetic regulation is an important m...

Detection and characterization of gene-gene and gene-environment interactions in common human diseases and complex clinical endpoints

EPA Science Inventory

Biological organisms are complex systems that dynamically integrate inputs from a multitude of physiological and environmental factors. Therefore, in addressing questions concerning the etiology of complex health outcomes, it is essential that the systemic nature of biology be ta...

Moderating Effects of Autism on Parent Views of Genetic Screening for Aggression

ERIC Educational Resources Information Center

May, Michael E.; Brandt, Rachel C.; Bohannan, Joseph K.

2012-01-01

Advances in gene-environment interaction research have revealed genes that are associated with aggression. However, little is known about parent perceptions of genetic screening for behavioral symptoms like aggression as opposed to diagnosing disabilities. These perceptions may influence future research endeavors involving genetic linkage studies…

Gene-environment interactions of circadian-related genes for cardiometabolic traits

USDA-ARS?s Scientific Manuscript database

Common circadian-related gene variants associate with increased risk for metabolic alterations including type 2 diabetes. However, little is known about whether diet and sleep could modify associations between circadian-related variants (CLOCK-rs1801260, CRY2-rs11605924, MTNR1B-rs1387153, MTNR1B-rs1...

Early-life estrogen exposure and uterine pathogenesis: ?A model for gene-environment interactions

EPA Science Inventory

Aberrant cellular differentiation early in life can contribute to increased cancer risk later in life. In a classic model of this effect, female mice exposed on postnatal day (PND) 1-5 to the synthetic estrogen diethylstilbestrol (DES) have a high incidence of uterine carcinoma. ...

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.

Design, Utility, and History of the Colorado Adoption Project: Examples Involving Adjustment Interactions1

PubMed Central

Rhea, Sally Ann; Bricker, Josh B.; Corley, Robin P.; DeFries, John C.; Wadsworth, Sally J.

2013-01-01

This paper describes the Colorado Adoption Project (CAP), a longitudinal study in behavioral development, and discusses how adoption studies may be used to assess genetic and environmental etiologies of individual differences for important developmental outcomes. Previous CAP research on adjustment outcomes in childhood and adolescence which found significant interactions, including gene-environment interactions, is reviewed. New research suggests mediating effects of menarche and religiosity on age at first sex in this predominantly middle-class, Caucasian sample. PMID:23833552

The interaction of combined effects of the BDNF and PRKCG genes and negative life events in major depressive disorder.

PubMed

Yang, Chunxia; Sun, Ning; Liu, Zhifen; Li, Xinrong; Xu, Yong; Zhang, Kerang

2016-03-30

Major depressive disorder (MDD) is a mental disorder that results from complex interplay between multiple and partially overlapping sets of susceptibility genes and environmental factors. The brain derived neurotrophic factor (BDNF) and Protein kinase C gamma type (PRKCG) are logical candidate genes in MDD. Among diverse environmental factors, negative life events have been suggested to exert a crucial impact on brain development. In the present study, we hypothesized that interactions between genetic variants in BDNF and PRKCG and negative life events may play an important role in the development of MDD. We recruited a total of 406 patients with MDD and 391 age- and gender-matched control subjects. Gene-environment interactions were analyzed using generalized multifactor dimensionality reduction (GMDR). Under a dominant model, we observed a significant three-way interaction among BDNF rs6265, PRKCG rs3745406, and negative life events. The gene-environment combination of PRKCG rs3745406 C allele, BDNF rs6265 G allele and high level of negative life events (C-G-HN) was significantly associated with MDD (OR, 5.97; 95% CI, 2.71-13.15). To our knowledge, this is the first report of evidence that the BDNF-PRKCG interaction may modify the relationship between negative life events and MDD in the Chinese population. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

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. (c) 2015 APA, all rights reserved).

Annual Research Review: The role of the environment in the developmental psychopathology of autism spectrum condition.

PubMed

Mandy, William; Lai, Meng-Chuan

2016-03-01

Although autism spectrum condition (ASC) is strongly genetic in origin, accumulating evidence points to the critical roles of various environmental influences on its emergence and subsequent developmental course. A developmental psychopathology framework was used to synthesise literature on environmental factors associated with the onset and course of ASC (based on a systematic search of the literature using PubMed, PsychInfo and Google Scholar databases). Particular emphasis was placed on gene-environment interplay, including gene-environment interaction (G × E) and gene-environment correlation (rGE). Before conception, advanced paternal and maternal ages may independently enhance offspring risk for ASC. Exogenous prenatal risks are evident (e.g. valproate and toxic chemicals) or possible (e.g. selective serotonin reuptake inhibitors), and processes endogenous to the materno-foeto-placental unit (e.g. maternal diabetes, enhanced steroidogenic activities and maternal immune activation) likely heighten offspring vulnerability to ASC. Folate intake is a prenatal protective factor, with a particular window of action around 4 weeks preconception and during the first trimester. These prenatal risks and protective mechanisms appear to involve G × E and potentially rGE. A variety of perinatal risks are related to offspring ASC risk, possibly reflecting rGE. Postnatal social factors (e.g. caregiver-infant interaction, severe early deprivation) during the first years of life may operate through rGE to influence the likelihood of manifesting a full ASC phenotype from a 'prodromal' phase (a proposal distinct to the discredited and harmful 'refrigerator mother hypothesis'); and later postnatal risks, after the full manifestation of ASC, shape life span development through transactions mediated by rGE. There is no evidence that vaccination is a postnatal risk for ASC. Future investigations should consider the specificity of risks for ASC versus other atypical neurodevelopmental trajectories, timing of risk and protective mechanisms, animal model systems to study mechanisms underlying gene-environment interplay, large-sample genome-envirome designs to address G × E and longitudinal studies to elucidate how rGE plays out over time. Clinical and public health implications are discussed. © 2016 Association for Child and Adolescent Mental Health.

A combination test for detection of gene-environment interaction in cohort studies.

PubMed

Coombes, Brandon; Basu, Saonli; McGue, Matt

2017-07-01

Identifying gene-environment (G-E) interactions can contribute to a better understanding of disease etiology, which may help researchers develop disease prevention strategies and interventions. One big criticism of studying G-E interaction is the lack of power due to sample size. Studies often restrict the interaction search to the top few hundred hits from a genome-wide association study or focus on potential candidate genes. In this paper, we test interactions between a candidate gene and an environmental factor to improve power by analyzing multiple variants within a gene. We extend recently developed score statistic based genetic association testing approaches to the G-E interaction testing problem. We also propose tests for interaction using gene-based summary measures that pool variants together. Although it has recently been shown that these summary measures can be biased and may lead to inflated type I error, we show that under several realistic scenarios, we can still provide valid tests of interaction. These tests use significantly less degrees of freedom and thus can have much higher power to detect interaction. Additionally, we demonstrate that the iSeq-aSum-min test, which combines a gene-based summary measure test, iSeq-aSum-G, and an interaction-based summary measure test, iSeq-aSum-I, provides a powerful alternative to test G-E interaction. We demonstrate the performance of these approaches using simulation studies and illustrate their performance to study interaction between the SNPs in several candidate genes and family climate environment on alcohol consumption using the Minnesota Center for Twin and Family Research dataset. © 2017 WILEY PERIODICALS, INC.

Challenges and Opportunities in Genome-Wide Environmental Interaction (GWEI) studies

PubMed Central

Aschard, Hugues; Lutz, Sharon; Maus, Bärbel; Duell, Eric J.; Fingerlin, Tasha; Chatterjee, Nilanjan; Kraft, Peter; Van Steen, Kristel

2012-01-01

The interest in performing gene-environment interaction studies has seen a significant increase with the increase of advanced molecular genetics techniques. Practically, it became possible to investigate the role of environmental factors in disease risk and hence to investigate their role as genetic effect modifiers. The understanding that genetics is important in the uptake and metabolism of toxic substances is an example of how genetic profiles can modify important environmental risk factors to disease. Several rationales exist to set up gene-environment interaction studies and the technical challenges related to these studies – when the number of environmental or genetic risk factors is relatively small – has been described before. In the post-genomic era, it is now possible to study thousands of genes and their interaction with the environment. This brings along a whole range of new challenges and opportunities. Despite a continuing effort in developing efficient methods and optimal bioinformatics infrastructures to deal with the available wealth of data, the challenge remains how to best present and analyze Genome-Wide Environmental Interaction (GWEI) studies involving multiple genetic and environmental factors. Since GWEIs are performed at the intersection of statistical genetics, bioinformatics and epidemiology, usually similar problems need to be dealt with as for Genome-Wide Association gene-gene Interaction (GWAI) studies. However, additional complexities need to be considered which are typical for large-scale epidemiological studies, but are also related to “joining” two heterogeneous types of data in explaining complex disease trait variation or for prediction purposes. PMID:22760307

Quantitative gene-gene and gene-environment mapping for leaf shape variation using tree-based models

USDA-ARS?s Scientific Manuscript database

Leaf shape traits have long been a focus of many disciplines, but searching for complex genetic and environmental interactive mechanisms regulating leaf shape variation has not yet been well developed. The question of the respective roles of gene and environment and how they interplay to modulate l...

Heritability for Adolescent Antisocial Behavior Differs with Socioeconomic Status: Gene-Environment Interaction

ERIC Educational Resources Information Center

Tuvblad, Catherine; Grann, Martin; Lichtenstein, Paul

2006-01-01

Background: Socioeconomic status is often assumed to be of importance for the development of antisocial behavior, yet it explains only a fraction of the variance. One explanation for this paradox could be that socioeconomic status moderates the influence of genetic and environmental effects on antisocial behavior. Method: TCHAD is a Swedish…

Evidence of Reactive Gene-Environment Correlation in Preschoolers' Prosocial Play with Unfamiliar Peers

ERIC Educational Resources Information Center

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

2015-01-01

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…

Chronic and Acute Stress, Gender, and Serotonin Transporter Gene-Environment Interactions Predicting Depression Symptoms in Youth

ERIC Educational Resources Information Center

Hammen, Constance; Brennan, Patricia A.; Keenan-Miller, Danielle; Hazel, Nicholas A.; Najman, Jake M.

2010-01-01

Background: Many recent studies of serotonin transporter gene by environment effects predicting depression have used stress assessments with undefined or poor psychometric methods, possibly contributing to wide variation in findings. The present study attempted to distinguish between effects of acute and chronic stress to predict depressive…

A Partial Least Square Approach for Modeling Gene-gene and Gene-environment Interactions When Multiple Markers Are Genotyped

PubMed Central

Wang, Tao; Ho, Gloria; Ye, Kenny; Strickler, Howard; Elston, Robert C.

2008-01-01

Genetic association studies achieve an unprecedented level of resolution in mapping disease genes by genotyping dense SNPs in a gene region. Meanwhile, these studies require new powerful statistical tools that can optimally handle a large amount of information provided by genotype data. A question that arises is how to model interactions between two genes. Simply modeling all possible interactions between the SNPs in two gene regions is not desirable because a greatly increased number of degrees of freedom can be involved in the test statistic. We introduce an approach to reduce the genotype dimension in modeling interactions. The genotype compression of this approach is built upon the information on both the trait and the cross-locus gametic disequilibrium between SNPs in two interacting genes, in such a way as to parsimoniously model the interactions without loss of useful information in the process of dimension reduction. As a result, it improves power to detect association in the presence of gene-gene interactions. This approach can be similarly applied for modeling gene-environment interactions. We compare this method with other approaches: the corresponding test without modeling any interaction, that based on a saturated interaction model, that based on principal component analysis, and that based on Tukey’s 1-df model. Our simulations suggest that this new approach has superior power to that of the other methods. In an application to endometrial cancer case-control data from the Women’s Health Initiative (WHI), this approach detected AKT1 and AKT2 as being significantly associated with endometrial cancer susceptibility by taking into account their interactions with BMI. PMID:18615621

A partial least-square approach for modeling gene-gene and gene-environment interactions when multiple markers are genotyped.

PubMed

Wang, Tao; Ho, Gloria; Ye, Kenny; Strickler, Howard; Elston, Robert C

2009-01-01

Genetic association studies achieve an unprecedented level of resolution in mapping disease genes by genotyping dense single nucleotype polymorphisms (SNPs) in a gene region. Meanwhile, these studies require new powerful statistical tools that can optimally handle a large amount of information provided by genotype data. A question that arises is how to model interactions between two genes. Simply modeling all possible interactions between the SNPs in two gene regions is not desirable because a greatly increased number of degrees of freedom can be involved in the test statistic. We introduce an approach to reduce the genotype dimension in modeling interactions. The genotype compression of this approach is built upon the information on both the trait and the cross-locus gametic disequilibrium between SNPs in two interacting genes, in such a way as to parsimoniously model the interactions without loss of useful information in the process of dimension reduction. As a result, it improves power to detect association in the presence of gene-gene interactions. This approach can be similarly applied for modeling gene-environment interactions. We compare this method with other approaches, the corresponding test without modeling any interaction, that based on a saturated interaction model, that based on principal component analysis, and that based on Tukey's one-degree-of-freedom model. Our simulations suggest that this new approach has superior power to that of the other methods. In an application to endometrial cancer case-control data from the Women's Health Initiative, this approach detected AKT1 and AKT2 as being significantly associated with endometrial cancer susceptibility by taking into account their interactions with body mass index.

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

Response to angiotensin-converting enzyme inhibition is selectively blunted by high sodium in angiotensin-converting enzyme DD genotype: evidence for gene-environment interaction in healthy volunteers.

PubMed

Lely, A Titia; Heerspink, Hiddo J Lambers; Zuurman, Mike; Visser, Folkert W; Kocks, Menno J A; Boomsma, Frans; Navis, Gerjan

2010-12-01

Renin-angiotensin-aldosterone system blockade is a cornerstone in cardiovascular protection. Angiotensin-converting enzyme (ACE)-DD genotype has been associated with resistance to angiotensin-converting enzyme inhibition (ACEi), but data are conflicting. As sodium intake modifies the effect of ACEi as well as the genotype-phenotype relationship, we hypothesize gene-environment interaction between sodium-status, the response to ACEi, and ACE genotype. Thirty-five male volunteers (26 ± 9 years; II n = 6, ID n = 18, DD n = 11) were studied during placebo and ACEi (double blind, enalapril 20 mg/day) on low [7 days 50 mmol Na/day (low salt)] and high [7 days 200 mmol Na/day (high salt)] sodium, with a washout of 6 weeks in-between. After each period mean arterial pressure (MAP) was measured before and during graded infusion of angiotensin II (Ang II). During high salt, ACEi reduced MAP in II and ID, but not in DD [II: 88 (78-94) versus 76 (72-88); ID: 87 (84-91) versus 83 (79-87); both P < 0.05 and DD: 86 (82-96) versus 88 (80-90); ns, P < 0.05 between genotypes]. However, during low salt, ACEi reduced MAP in all genotype groups [II: 83 (78-89) versus 77 (72-83); ID: 88 (84-91) versus 82 (78-86); DD: 84 (80-91) versus 81 (75-85); all P < 0.05]. During high salt + ACEi, the Ang II response was blunted in DD, with an 18% rise in MAP during the highest dose versus 22 and 31% in ID and II (P < 0.05). Low salt annihilated these differences. In healthy participants, the MAP response to ACEi is selectively blunted in DD genotype during high salt, accompanied by blunted sensitivity to Ang II. Low salt corrects both abnormalities. Further analysis of this gene-environment interaction in patients may contribute to strategies for improvement of individual treatment efficacy.

Gene-environment interaction between adiponectin gene polymorphisms and environmental factors on the risk of diabetic retinopathy.

PubMed

Li, Yuan; Wu, Qun Hong; Jiao, Ming Li; Fan, Xiao Hong; Hu, Quan; Hao, Yan Hua; Liu, Ruo Hong; Zhang, Wei; Cui, Yu; Han, Li Yuan

2015-01-01

To evaluate whether the adiponectin gene is associated with diabetic retinopathy (DR) risk and interaction with environmental factors modifies the DR risk, and to investigate the relationship between serum adiponectin levels and DR. Four adiponectin polymorphisms were evaluated in 372 DR cases and 145 controls. Differences in environmental factors between cases and controls were evaluated by unconditional logistic regression analysis. The model-free multifactor dimensionality reduction method and traditional multiple regression models were applied to explore interactions between the polymorphisms and environmental factors. Using the Bonferroni method, we found no significant associations between four adiponectin polymorphisms and DR susceptibility. Multivariate logistic regression found that physical activity played a protective role in the progress of DR, whereas family history of diabetes (odds ratio 1.75) and insulin therapy (odds ratio 1.78) were associated with an increased risk for DR. The interaction between the C-11377 G (rs266729) polymorphism and insulin therapy might be associated with DR risk. Family history of diabetes combined with insulin therapy also increased the risk of DR. No adiponectin gene polymorphisms influenced the serum adiponectin levels. Serum adiponectin levels did not differ between the DR group and non-DR group. No significant association was identified between four adiponectin polymorphisms and DR susceptibility after stringent Bonferroni correction. The interaction between C-11377G (rs266729) polymorphism and insulin therapy, as well as the interaction between family history of diabetes and insulin therapy, might be associated with DR susceptibility.

Classification and Clustering Methods for Multiple Environmental Factors in Gene-Environment Interaction: Application to the Multi-Ethnic Study of Atherosclerosis.

PubMed

Ko, Yi-An; Mukherjee, Bhramar; Smith, Jennifer A; Kardia, Sharon L R; Allison, Matthew; Diez Roux, Ana V

2016-11-01

There has been an increased interest in identifying gene-environment interaction (G × E) in the context of multiple environmental exposures. Most G × E studies analyze one exposure at a time, but we are exposed to multiple exposures in reality. Efficient analysis strategies for complex G × E with multiple environmental factors in a single model are still lacking. Using the data from the Multiethnic Study of Atherosclerosis, we illustrate a two-step approach for modeling G × E with multiple environmental factors. First, we utilize common clustering and classification strategies (e.g., k-means, latent class analysis, classification and regression trees, Bayesian clustering using Dirichlet Process) to define subgroups corresponding to distinct environmental exposure profiles. Second, we illustrate the use of an additive main effects and multiplicative interaction model, instead of the conventional saturated interaction model using product terms of factors, to study G × E with the data-driven exposure subgroups defined in the first step. We demonstrate useful analytical approaches to translate multiple environmental exposures into one summary class. These tools not only allow researchers to consider several environmental exposures in G × E analysis but also provide some insight into how genes modify the effect of a comprehensive exposure profile instead of examining effect modification for each exposure in isolation.

Gene-environment interactions in geriatric depression.

PubMed

Lotrich, Francis E

2011-06-01

In older adults, several environmental challenges can potentially trigger the onset of an episode of major depression. Vulnerability to these challenges can be influenced by genetics. There is accumulating evidence for an interaction between stress and a serotonin transporter polymorphism, though there is also heterogeneity among studies. Other relevant genes include those encoding for the neuroendocrine stress axis, growth factors, and other monoaminergic systems. Each of these may interact with either predisposing traumas in early childhood or precipitating events later in life. Copyright © 2011 Elsevier Inc. All rights reserved.

Leveraging Gene-Environment Interactions and Endotypes for Asthma Gene Discovery

PubMed Central

Bønnelykke, Klaus; Ober, Carole

2016-01-01

Asthma is a heterogeneous clinical syndrome that includes subtypes of disease with different underlying causes and disease mechanisms. Asthma is caused by a complex interaction between genes and environmental exposures; early-life exposures in particular play an important role. Asthma is also heritable, and a number of susceptibility variants have been discovered in genome-wide association studies, although the known risk alleles explain only a small proportion of the heritability. In this review, we present evidence supporting the hypothesis that focusing on more specific asthma phenotypes, such as childhood asthma with severe exacerbations, and on relevant exposures that are involved in gene-environment interactions (GEIs), such as rhinovirus infections, will improve detection of asthma genes and our understanding of the underlying mechanisms. We will discuss the challenges of considering GEIs and the advantages of studying responses to asthma-associated exposures in clinical birth cohorts, as well as in cell models of GEIs, to dissect the context-specific nature of genotypic risks, to prioritize variants in genome-wide association studies, and to identify pathways involved in pathogenesis in subgroups of patients. We propose that such approaches, in spite of their many challenges, present great opportunities for better understanding of asthma pathogenesis and heterogeneity and, ultimately, for improving prevention and treatment of disease. PMID:26947980

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

Privacy and ethics in pediatric environmental health research-part II: protecting families and communities.

PubMed

Fisher, Celia B

2006-10-01

In pediatric environmental health research, information about family members is often directly sought or indirectly obtained in the process of identifying child risk factors and helping to tease apart and identify interactions between genetic and environmental factors. However, federal regulations governing human subjects research do not directly address ethical issues associated with protections for family members who are not identified as the primary "research participant." Ethical concerns related to family consent and privacy become paramount as pediatric environmental health research increasingly turns to questions of gene-environment interactions. In this article I identify issues arising from and potential solutions for the privacy and informed consent challenges of pediatric environmental health research intended to adequately protect the rights and welfare of children, family members, and communities. I first discuss family members as secondary research participants and then the specific ethical challenges of longitudinal research on late-onset environmental effects and gene-environment interactions. I conclude with a discussion of the confidentiality and social risks of recruitment and data collection of research conducted within small or unique communities, ethnic minority populations, and low-income families. The responsible conduct of pediatric environmental health research must be conceptualized as a goodness of fit between the specific research context and the unique characteristics of subjects and other family stakeholders.

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. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

BDNF Val66Met polymorphism, life stress and depression: A meta-analysis of gene-environment interaction.

PubMed

Zhao, Mingzhe; Chen, Lu; Yang, Jiarun; Han, Dong; Fang, Deyu; Qiu, Xiaohui; Yang, Xiuxian; Qiao, Zhengxue; Ma, Jingsong; Wang, Lin; Jiang, Shixiang; Song, Xuejia; Zhou, Jiawei; Zhang, Jian; Chen, Mingqi; Qi, Dong; Yang, Yanjie; Pan, Hui

2018-02-01

Depression is thought to be multifactorial in etiology, including genetic and environmental components. While a number of gene-environment interaction studies have been carried out, meta-analyses are scarce. The present meta-analysis aimed to quantify evidence on the interaction between brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and stress in depression. Included were 31 peer-reviewed with a pooled total of 21060 participants published before October 2016 and literature searches were conducted using PubMed, Wolters Kluwer, Web of Science, EBSCO, Elsevier Science Direct and Baidu Scholar databases. The results indicated that the Met allele of BDNF Val66Met polymorphism significantly moderated the relationship between stress and depression (Z=2.666, p = 0.003). The results of subgroup analysis concluded that stressful life events and childhood adversity separately interacted with the Met allele of BDNF Val66Met polymorphism in depression (Z = 2.552, p = 0.005; Z = 1.775, p = 0.03). The results could be affected by errors or bias in primary studies which had small sample sizes with relatively lower statistic power. We could not estimate how strong the interaction effect between gene and environment was. We found evidence that supported the hypothesis that BDNF Val66Met polymorphism moderated the relationship between stress and depression, despite the fact that many included individual studies did not show this effect. Copyright © 2017 Elsevier B.V. All rights reserved.

Exposure enriched outcome dependent designs for longitudinal studies of gene-environment interaction.

PubMed

Sun, Zhichao; Mukherjee, Bhramar; Estes, Jason P; Vokonas, Pantel S; Park, Sung Kyun

2017-08-15

Joint effects of genetic and environmental factors have been increasingly recognized in the development of many complex human diseases. Despite the popularity of case-control and case-only designs, longitudinal cohort studies that can capture time-varying outcome and exposure information have long been recommended for gene-environment (G × E) interactions. To date, literature on sampling designs for longitudinal studies of G × E interaction is quite limited. We therefore consider designs that can prioritize a subsample of the existing cohort for retrospective genotyping on the basis of currently available outcome, exposure, and covariate data. In this work, we propose stratified sampling based on summaries of individual exposures and outcome trajectories and develop a full conditional likelihood approach for estimation that adjusts for the biased sample. We compare the performance of our proposed design and analysis with combinations of different sampling designs and estimation approaches via simulation. We observe that the full conditional likelihood provides improved estimates for the G × E interaction and joint exposure effects over uncorrected complete-case analysis, and the exposure enriched outcome trajectory dependent design outperforms other designs in terms of estimation efficiency and power for detection of the G × E interaction. We also illustrate our design and analysis using data from the Normative Aging Study, an ongoing longitudinal cohort study initiated by the Veterans Administration in 1963. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Interpretations of education about gene-environment influences on health in rural Ethiopia: the context of a neglected tropical disease.

PubMed

Tora, Abebayehu; Ayode, Desta; Tadele, Getnet; Farrell, David; Davey, Gail; McBride, Colleen M

2016-07-01

Misunderstandings of the role of genetics in disease development are associated with stigmatizing behaviors and fatalistic attitudes about prevention. This report describes an evaluation of community understanding of an educational module about genetic and environmental influences on the development of podoconiosis, a neglected tropical disease endemic in highland Ethiopia. A qualitative process assessment was conducted as part of a large prospective intervention trial in August 2013, in Wolaita Zone, southern Ethiopia. Sixty five participants were purposively selected from 600 households randomized to receive the inherited susceptibility module. The educational module used pictorial representations and oral explanations of the interaction of inherited sensitivity and soil exposure and was delivered by lay health educators in participants' homes. Data were collected using semi-structured individual interviews (IDIs) or focus group discussions (FGDs). Qualitative analyses showed that most participants improved their understanding of inherited soil sensitivity and susceptibility to podoconiosis. Participants linked their new understanding to decreased stigma-related attitudes. The module also corrected misconceptions that the condition was contagious, again diminishing stigmatizing attitudes. Lastly, these improvements in understanding increased the perceived value of foot protection. Taken together, these improvements support the acceptability, feasibility and potential benefits of implementing gene-environment education in low and middle income countries. © The Author 2016. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.

Gene--Environment Interplay and Delinquent Involvement: Evidence of Direct, Indirect, and Interactive Effects

ERIC Educational Resources Information Center

Beaver, Kevin M.; DeLisi, Matt; Wright, John Paul; Vaughn, Michael G.

2009-01-01

Behavioral genetic research has revealed that biogenic factors play a role in the development of antisocial behaviors. Much of this research has also explicated the way in which the environment and genes may combine to create different phenotypes. The authors draw heavily from this literature and use data from the National Longitudinal Study of…

Maternal Warmth and Directiveness Jointly Moderate the Etiology of Childhood Conduct Problems

ERIC Educational Resources Information Center

Burt, S. Alexandra; Klahr, Ashlea M.; Neale, Michael C.; Klump, Kelly L.

2013-01-01

Background: Prior studies exploring gene-environment interactions (GxE) in the development of youth conduct problems (CP) have focused almost exclusively on single-risk experiences, despite research indicating that the presence of other risk factors and or the absence of protective factors can accentuate the influence of a given risk factor on CP.…

Gene-Environment Interaction in Teacher-Rated Internalizing and Externalizing Problem Behavior in 7- to 12-Year-Old Twins

ERIC Educational Resources Information Center

Lamb, Diane J.; Middeldorp, Christel M.; Van Beijsterveldt, Catarina E. M.; Boomsma, Dorret I.

2012-01-01

Background: Internalizing and externalizing problem behavior at school can have major consequences for a child and is predictive for disorders later in life. Teacher ratings are important to assess internalizing and externalizing problems at school. Genetic epidemiological studies on teacher-rated problem behavior are relatively scarce and the…

Biometric Modeling of Gene-Environment Interplay: The Intersection of Theory and Method and Applications for Social Inequality

PubMed Central

South, Susan C.; Hamdi, Nayla; Krueger, Robert F.

2015-01-01

For more than a decade, biometric moderation models have been used to examine whether genetic and environmental influences on individual differences might vary within the population. These quantitative gene × environment interaction (G×E) models not only have the potential to elucidate when genetic and environmental influences on a phenotype might differ, but why, as they provide an empirical test of several theoretical paradigms that serve as useful heuristics to explain etiology—diathesis-stress, bioecological, differential susceptibility, and social control. In the current manuscript, we review how these developmental theories align with different patterns of findings from statistical models of gene-environment interplay. We then describe the extant empirical evidence, using work by our own research group and others, to lay out genetically-informative plausible accounts of how phenotypes related to social inequality—physical health and cognition—might relate to these theoretical models. PMID:26426103

Biometric Modeling of Gene-Environment Interplay: The Intersection of Theory and Method and Applications for Social Inequality.

PubMed

South, Susan C; Hamdi, Nayla R; Krueger, Robert F

2017-02-01

For more than a decade, biometric moderation models have been used to examine whether genetic and environmental influences on individual differences might vary within the population. These quantitative Gene × Environment interaction models have the potential to elucidate not only when genetic and environmental influences on a phenotype might differ, but also why, as they provide an empirical test of several theoretical paradigms that serve as useful heuristics to explain etiology-diathesis-stress, bioecological, differential susceptibility, and social control. In the current article, we review how these developmental theories align with different patterns of findings from statistical models of gene-environment interplay. We then describe the extant empirical evidence, using work by our own research group and others, to lay out genetically informative plausible accounts of how phenotypes related to social inequality-physical health and cognition-might relate to these theoretical models. © 2015 Wiley Periodicals, Inc.

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

Detection of gene-environment interactions in the presence of linkage disequilibrium and noise by using genetic risk scores with internal weights from elastic net regression.

PubMed

Hüls, Anke; Ickstadt, Katja; Schikowski, Tamara; Krämer, Ursula

2017-06-12

For the analysis of gene-environment (GxE) interactions commonly single nucleotide polymorphisms (SNPs) are used to characterize genetic susceptibility, an approach that mostly lacks power and has poor reproducibility. One promising approach to overcome this problem might be the use of weighted genetic risk scores (GRS), which are defined as weighted sums of risk alleles of gene variants. The gold-standard is to use external weights from published meta-analyses. In this study, we used internal weights from the marginal genetic effects of the SNPs estimated by a multivariate elastic net regression and thereby provided a method that can be used if there are no external weights available. We conducted a simulation study for the detection of GxE interactions and compared power and type I error of single SNPs analyses with Bonferroni correction and corresponding analysis with unweighted and our weighted GRS approach in scenarios with six risk SNPs and an increasing number of highly correlated (up to 210) and noise SNPs (up to 840). Applying weighted GRS increased the power enormously in comparison to the common single SNPs approach (e.g. 94.2% vs. 35.4%, respectively, to detect a weak interaction with an OR ≈ 1.04 for six uncorrelated risk SNPs and n = 700 with a well-controlled type I error). Furthermore, weighted GRS outperformed the unweighted GRS, in particular in the presence of SNPs without any effect on the phenotype (e.g. 90.1% vs. 43.9%, respectively, when 20 noise SNPs were added to the six risk SNPs). This outperforming of the weighted GRS was confirmed in a real data application on lung inflammation in the SALIA cohort (n = 402). However, in scenarios with a high number of noise SNPs (>200 vs. 6 risk SNPs), larger sample sizes are needed to avoid an increased type I error, whereas a high number of correlated SNPs can be handled even in small samples (e.g. n = 400). In conclusion, weighted GRS with weights from the marginal genetic effects of the SNPs estimated by a multivariate elastic net regression were shown to be a powerful tool to detect gene-environment interactions in scenarios of high Linkage disequilibrium and noise.

Genome-wide assessment of gene-by-smoking interactions in COPD.

PubMed

Park, Boram; Koo, So-My; An, Jaehoon; Lee, MoonGyu; Kang, Hae Yeon; Qiao, Dandi; Cho, Michael H; Sung, Joohon; Silverman, Edwin K; Yang, Hyeon-Jong; Won, Sungho

2018-06-18

Cigarette smoke exposure is a major risk factor in chronic obstructive pulmonary disease (COPD) and its interactions with genetic variants could affect lung function. However, few gene-smoking interactions have been reported. In this report, we evaluated the effects of gene-smoking interactions on lung function using Korea Associated Resource (KARE) data with the spirometric variables-forced expiratory volume in 1 s (FEV 1 ). We found that variations in FEV 1 were different among smoking status. Thus, we considered a linear mixed model for association analysis under heteroscedasticity according to smoking status. We found a previously identified locus near SOX9 on chromosome 17 to be the most significant based on a joint test of the main and interaction effects of smoking. Smoking interactions were replicated with Gene-Environment of Interaction and phenotype (GENIE), Multi-Ethnic Study of Atherosclerosis-Lung (MESA-Lung), and COPDGene studies. We found that individuals with minor alleles, rs17765644, rs17178251, rs11870732, and rs4793541, tended to have lower FEV 1 values, and lung function decreased much faster with age for smokers. There have been very few reports to replicate a common variant gene-smoking interaction, and our results revealed that statistical models for gene-smoking interaction analyses should be carefully selected.

The Socio-Economic Gradient in Children's Reading Skills and the Role of Genetics

ERIC Educational Resources Information Center

Jerrim, John; Vignoles, Anna; Lingam, Raghu; Friend, Angela

2015-01-01

By the time children leave primary school there is a large socio-economic gap in their reading proficiency. There are a number of potential explanations for this socio-economic gap and in this paper we investigate the role of three particular genes and gene-environment interactions in determining children's reading skills, using the Avon…

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. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Commentary: Fundamental problems with candidate gene-by-environment interaction studies - reflections on Moore and Thoemmes (2016).

PubMed

Border, Richard; Keller, Matthew C

2017-03-01

Moore and Thoemmes elaborate on one particular source of difficulty in the study of candidate gene-by-environment interactions (cG × E): how different biologically plausible configurations of gene-environment covariation can bias estimates of cG × E when not explicitly modeled. However, even if cG × E investigators were able to account for the sources of bias Moore and Thoemmes elaborate, it is unlikely that conventional approaches would yield reliable results. Published cG × E findings to date have generally employed inadequate analytic procedures, have relied on samples orders of magnitude too small to detect plausible effects, and have relied on a particular candidate gene approach that has been unfruitful and largely jettisoned in mainstream genetic analyses of complex traits. Analytic procedures for the study of gene-environment interplay must evolve to meet the challenges that the genetic architecture of complex traits presents, and investigators must collaborate on grander scales if we hope to begin to understand how specific genes and environments combine to affect behavior. © 2017 Association for Child and Adolescent Mental Health.

Social Relationships Moderate Genetic Influences on Heavy Drinking in Young Adulthood.

PubMed

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

2017-11-01

Social relationships, such as committed partnerships, limit risky behaviors like heavy drinking, in part, because of increased social control. The current analyses examine whether involvement in committed relationships or social support extend beyond a main effect to limit genetic liability in heavy drinking (gene-environment interaction) during young adulthood. Using data from the young adult wave of the Finnish Twin Study, FinnTwin12 (n = 3,269), we tested whether involvement in romantic partnerships or social support moderated genetic influences on heavy drinking using biometric twin modeling for gene-environment interaction. Involvement in a romantic partnership was associated with a decline in genetic variance in both males and females, although the overall magnitude of genetic influence was greater in males. Sex differences emerged for social support: increased social support was associated with increased genetic influence for females and reduced genetic influence for males. These findings demonstrate that social relationships are important moderators of genetic influences on young adult alcohol use. Mechanisms of social control that are important in limiting genetic liability during adolescence extend into young adulthood. In addition, although some relationships limit genetic liability equally, others, such as extensive social networks, may operate differently across sex.

A distinct and replicable variant of the squamous cell carcinoma gene inositol polyphosphate-5-phosphatase modifies the susceptibility of arsenic-associated skin lesions in Bangladesh.

PubMed

Seow, Wei Jie; Pan, Wen-Chi; Kile, Molly L; Tong, Lin; Baccarelli, Andrea A; Quamruzzaman, Quazi; Rahman, Mahmuder; Mostofa, Golam; Rakibuz-Zaman, Muhammad; Kibriya, Muhammad; Ahsan, Habibul; Lin, Xihong; Christiani, David C

2015-07-01

Single-nucleotide polymorphisms (SNPs) in inflammation, one-carbon metabolism, and skin cancer genes might influence susceptibility to arsenic-induced skin lesions. A case-control study was conducted in Pabna, Bangladesh (2001-2003), and the drinking-water arsenic concentration was measured for each participant. A panel of 25 candidate SNPs was analyzed in 540 cases and 400 controls. Logistic regression was used to estimate the association between each SNP and the potential for gene-environment interactions in the skin lesion risk, with adjustments for relevant covariates. Replication testing was conducted in an independent Bangladesh population with 488 cases and 2,794 controls. In the discovery population, genetic variants in the one-carbon metabolism genes phosphatidylethanolamine N-methyltransferase (rs2278952, P for interaction  = .004; rs897453, P for interaction = .05) and dihydrofolate reductase (rs1650697, P for interaction = .02), the inflammation gene interleukin 10 (rs3024496, P for interaction =.04), and the skin cancer genes inositol polyphosphate-5-phosphatase (INPP5A; rs1133400, P for interaction = .03) and xeroderma pigmentosum complementation group C (rs2228000, P for interaction = .01) significantly modified the association between arsenic and skin lesions after adjustments for multiple comparisons. The significant gene-environment interaction between a SNP in the INPP5A gene (rs1133400) and water arsenic with respect to the skin lesion risk was successfully replicated in an independent population (P for interaction = .03). Minor allele carriers of the skin cancer gene INPP5A modified the odds of arsenic-induced skin lesions in both main and replicative populations. Genetic variation in INPP5A appears to have a role in susceptibility to arsenic toxicity. © 2015 American Cancer Society.

Polygenic interactions with environmental adversity in the aetiology of major depressive disorder.

PubMed

Mullins, N; Power, R A; Fisher, H L; Hanscombe, K B; Euesden, J; Iniesta, R; Levinson, D F; Weissman, M M; Potash, J B; Shi, J; Uher, R; Cohen-Woods, S; Rivera, M; Jones, L; Jones, I; Craddock, N; Owen, M J; Korszun, A; Craig, I W; Farmer, A E; McGuffin, P; Breen, G; Lewis, C M

2016-03-01

Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene-environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD. The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them. PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10(-6)). SLEs and CT were also associated with MDD status (p = 2.19 × 10(-4) and p = 5.12 × 10(-20), respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples. CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene-environment interactions in complex traits.

Changes in the striatal proteome of YAC128Q mice exhibit gene-environment interactions between mutant huntingtin and manganese.

PubMed

Wegrzynowicz, Michal; Holt, Hunter K; Friedman, David B; Bowman, Aaron B

2012-02-03

Huntington's disease (HD) is a neurodegenerative disorder caused by expansion of a CAG repeat within the Huntingtin (HTT) gene, though the clinical presentation of disease and age-of-onset are strongly influenced by ill-defined environmental factors. We recently reported a gene-environment interaction wherein expression of mutant HTT is associated with neuroprotection against manganese (Mn) toxicity. Here, we are testing the hypothesis that this interaction may be manifested by altered protein expression patterns in striatum, a primary target of both neurodegeneration in HD and neurotoxicity of Mn. To this end, we compared striatal proteomes of wild-type and HD (YAC128Q) mice exposed to vehicle or Mn. Principal component analysis of proteomic data revealed that Mn exposure disrupted a segregation of WT versus mutant proteomes by the major principal component observed in vehicle-exposed mice. Identification of altered proteins revealed novel markers of Mn toxicity, particularly proteins involved in glycolysis, excitotoxicity, and cytoskeletal dynamics. In addition, YAC128Q-dependent changes suggest that axonal pathology may be an early feature in HD pathogenesis. Finally, for several proteins, genotype-specific responses to Mn were observed. These differences include increased sensitivity to exposure in YAC128Q mice (UBQLN1) and amelioration of some mutant HTT-induced alterations (SAE1, ENO1). We conclude that the interaction of Mn and mutant HTT may suppress proteomic phenotypes of YAC128Q mice, which could reveal potential targets in novel treatment strategies for HD.

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

PubMed

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

2017-09-29

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

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

PubMed Central

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

2017-01-01

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

Sleep Duration and Body Mass Index in Twins: A Gene-Environment Interaction

PubMed Central

Watson, Nathaniel F.; Harden, Kathryn Paige; Buchwald, Dedra; Vitiello, Michael V.; Pack, Allan I.; Weigle, David S.; Goldberg, Jack

2012-01-01

Study Objectives: To examine whether sleep duration modifies genetic and environmental influences on body mass index (BMI). Design: Genotype-environment interaction twin study. Setting: University of Washington Twin Registry. Patients or Participants: A population-based sample of US twins (1,088 pairs, 604 monozygotic, 484 dizygotic; 66% female; mean age = 36.6 yr, standard deviation (SD) = 15.9 yr). Interventions: N/A. Measurements and Results: Participants self-reported information on height, weight, and sleep. Mean BMI was calculated as 25.3 kg/m2 (SD = 5.4) and mean habitual sleep duration was 7.2 hr/night (SD = 1.2). Data were analyzed using biometric genetic interaction models. Overall the heritability of sleep duration was 34%. Longer sleep duration was associated with decreased BMI (P < 0.05). The heritability of BMI when sleep duration was < 7 hr (h2 = 70%) was more than twice as large as the heritability of BMI when sleep duration was ≥ 9 hr (h2 = 32%); this interaction was significant (P < 0.05). Conclusions: Shorter sleep duration is associated with increased BMI and increased genetic influences on BMI, suggesting that shorter sleep duration increases expression of genetic risks for high body weight. At the same time, longer sleep duration may suppress genetic influences on body weight. Future research aiming to identify specific genotypes for BMI may benefit by considering the moderating role of sleep duration. Citation: Watson NF; Harden KP; Buchwald D; Vitiello MV; Pack AI; Weigle DS; Goldberg J. Sleep duration and body mass index in twins: a gene-environment interaction. SLEEP 2012;35(5):597-603. PMID:22547885

Gene-environment interaction and male reproductive function

PubMed Central

Axelsson, Jonatan; Bonde, Jens Peter; Giwercman, Yvonne L.; Rylander, Lars; Giwercman, Aleksander

2010-01-01

As genetic factors can hardly explain the changes taking place during short time spans, environmental and lifestyle-related factors have been suggested as the causes of time-related deterioration of male reproductive function. However, considering the strong heterogeneity of male fecundity between and within populations, genetic variants might be important determinants of the individual susceptibility to the adverse effects of environment or lifestyle. Although the possible mechanisms of such interplay in relation to the reproductive system are largely unknown, some recent studies have indicated that specific genotypes may confer a larger risk of male reproductive disorders following certain exposures. This paper presents a critical review of animal and human evidence on how genes may modify environmental effects on male reproductive function. Some examples have been found that support this mechanism, but the number of studies is still limited. This type of interaction studies may improve our understanding of normal physiology and help us to identify the risk factors to male reproductive malfunction. We also shortly discuss other aspects of gene-environment interaction specifically associated with the issue of reproduction, namely environmental and lifestyle factors as the cause of sperm DNA damage. It remains to be investigated to what extent such genetic changes, by natural conception or through the use of assisted reproductive techniques, are transmitted to the next generation, thereby causing increased morbidity in the offspring. PMID:20348940

Physical activity attenuates genetic effects on BMI: Results from a study of Chinese adult twins.

PubMed

Wang, Biqi; Gao, Wenjing; Lv, Jun; Yu, Canqing; Wang, Shengfeng; Pang, Zengchang; Cong, Liming; Dong, Zhong; Wu, Fan; Wang, Hua; Wu, Xianping; Jiang, Guohong; Wang, Xiaojie; Wang, Binyou; Cao, Weihua; Li, Liming

2016-03-01

This study aimed to examine the gene-environment interaction of physical activity and body mass index (BMI) using the Chinese National Twin Registry (CNTR). A total of 19,308 same-sex adult twins from CNTR were included in the analysis. Twin zygosity was determined by self-reported questionnaire. Height and weight were measured using self-reported questionnaire. The vigorous physical activity was defined as greater or equal to five times a week of at least 30 min moderate- or high-intensity physical activity. A twin structural equation model was used to analyze the gene-environment interaction of vigorous exercise with BMI among 13,506 monozygotic twins and 5,802 dizygotic twins. A structural equation model adjusting for age and sex found vigorous exercise significantly moderated the additive genetic effects (P < 0.001) and shared environmental effects (P < 0.001) on BMI. The genetic contributions to BMI were significantly lower for people who adopted a physically active lifestyle [h(2) = 40%, 95% confidence interval (CI): 35%-46%] than those who were relative sedentary (h(2) = 59%, 95% CI: 52%-66%). The observed gene-physical activity interaction was more pronounced in men than women. Our results suggested that adopting a physically active lifestyle may help to reduce the genetic influence on BMI among the Chinese population. © 2016 The Obesity Society.

Quantitative gene-gene and gene-environment mapping for leaf shape variation using tree-based models.

PubMed

Fu, Guifang; Dai, Xiaotian; Symanzik, Jürgen; Bushman, Shaun

2017-01-01

Leaf shape traits have long been a focus of many disciplines, but the complex genetic and environmental interactive mechanisms regulating leaf shape variation have not yet been investigated in detail. The question of the respective roles of genes and environment and how they interact to modulate leaf shape is a thorny evolutionary problem, and sophisticated methodology is needed to address it. In this study, we investigated a framework-level approach that inputs shape image photographs and genetic and environmental data, and then outputs the relative importance ranks of all variables after integrating shape feature extraction, dimension reduction, and tree-based statistical models. The power of the proposed framework was confirmed by simulation and a Populus szechuanica var. tibetica data set. This new methodology resulted in the detection of novel shape characteristics, and also confirmed some previous findings. The quantitative modeling of a combination of polygenetic, plastic, epistatic, and gene-environment interactive effects, as investigated in this study, will improve the discernment of quantitative leaf shape characteristics, and the methods are ready to be applied to other leaf morphology data sets. Unlike the majority of approaches in the quantitative leaf shape literature, this framework-level approach is data-driven, without assuming any pre-known shape attributes, landmarks, or model structures. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

Genetics of borderline personality disorder: systematic review and proposal of an integrative model.

PubMed

Amad, Ali; Ramoz, Nicolas; Thomas, Pierre; Jardri, Renaud; Gorwood, Philip

2014-03-01

Borderline personality disorder (BPD) is one of the most common mental disorders and is characterized by a pervasive pattern of emotional lability, impulsivity, interpersonal difficulties, identity disturbances, and disturbed cognition. Here, we performed a systematic review of the literature concerning the genetics of BPD, including familial and twin studies, association studies, and gene-environment interaction studies. Moreover, meta-analyses were performed when at least two case-control studies testing the same polymorphism were available. For each gene variant, a pooled odds ratio (OR) was calculated using fixed or random effects models. Familial and twin studies largely support the potential role of a genetic vulnerability at the root of BPD, with an estimated heritability of approximately 40%. Moreover, there is evidence for both gene-environment interactions and correlations. However, association studies for BPD are sparse, making it difficult to draw clear conclusions. According to our meta-analysis, no significant associations were found for the serotonin transporter gene, the tryptophan hydroxylase 1 gene, or the serotonin 1B receptor gene. We hypothesize that such a discrepancy (negative association studies but high heritability of the disorder) could be understandable through a paradigm shift, in which "plasticity" genes (rather than "vulnerability" genes) would be involved. Such a framework postulates a balance between positive and negative events, which interact with plasticity genes in the genesis of BPD. Copyright © 2014 Elsevier Ltd. All rights reserved.

The Dopamine D2 Receptor Gene, Perceived Parental Support, and Adolescent Loneliness: Longitudinal Evidence for Gene-Environment Interactions

ERIC Educational Resources Information Center

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

2011-01-01

Background: Loneliness is a common problem in adolescence. Earlier research focused on genes within the serotonin and oxytocin systems, but no studies have examined the role of dopamine-related genes in loneliness. In the present study, we focused on the dopamine D2 receptor gene (DRD2). Methods: Associations among the DRD2, sex, parental support,…

Gene-Environment Contributions to the Development of Infant Vagal Reactivity: The Interaction of Dopamine and Maternal Sensitivity

ERIC Educational Resources Information Center

Propper, Cathi; Moore, Ginger A.; Mills-Koonce, W. Roger; Halpern, Carolyn Tucker; Hill-Soderlund, Ashley L.; Calkins, Susan D.; Carbone, Mary Anna; Cox, Martha

2008-01-01

This study investigated dopamine receptor genes ("DRD2" and "DRD4") and maternal sensitivity as predictors of infant respiratory sinus arrhythmia (RSA) and RSA reactivity, purported indices of vagal tone and vagal regulation, in a challenge task at 3, 6, and 12 months in 173 infant-mother dyads. Hierarchical linear modeling (HLM) revealed that at…

Bridging the gap between research into biological and psychosocial models of psychosis.

PubMed

Murray, Robin M; Sideli, Lucia; LA Cascia, Caterina; LA Barbera, Daniele

2015-06-25

Paul Bebbington's recent Special Article provides an excellent synthesis of recent advances in psychosocial research on psychosis. However, we doubt that a model based solely on social epidemiology and cognitive theory can totally describe psychosis, and to be fair, Bebbington does not suggest that it does. A complete model must also incorporate what we have learned from non-social epidemiology, neuroscience, and genetics. Evidence indicates that both the social risk factors that interest Bebbington and biological risk factors, such as abuse of stimulants and cannabis, can provoke psychotic symptoms by dysregulating striatal dopamine. The role of neurodevelopmental deviance also needs to be considered in the etiology of schizophrenia-like psychosis. Moreover, the striking advances in our understanding of the genetic architecture of psychosis open an exciting door into studies examining gene-environment correlation and gene-environment interaction. In short, Bebbington demonstrates the value of cognitive and social researchers talking to each other, but the occasional chat with the more biologically inclined could produce a more comprehensive model.

A "candidate-interactome" aggregate analysis of genome-wide association data in multiple sclerosis.

PubMed

Mechelli, Rosella; Umeton, Renato; Policano, Claudia; Annibali, Viviana; Coarelli, Giulia; Ricigliano, Vito A G; Vittori, Danila; Fornasiero, Arianna; Buscarinu, Maria Chiara; Romano, Silvia; Salvetti, Marco; Ristori, Giovanni

2013-01-01

Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a "candidate interactome" (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms.

A family-based study of gene variants and maternal folate and choline in neuroblastoma: A Report from the Children’s Oncology Group

PubMed Central

Mazul, Angela L; Siega-Riz, Anna Maria; Weinberg, Clarice R; Engel, Stephanie M.; Zou, Fei; Carrier, Kathryn S.; Basta, Patricia V; Vaksman, Zalman; Maris, John M; Diskin, Sharon J; Maxen, Charlene; Naranjo, Arlene; Olshan, Andrew F

2016-01-01

Purpose Neuroblastoma is a childhood cancer of the sympathetic nervous system with embryonic origins. Previous epidemiologic studies suggest maternal vitamin supplementation during pregnancy reduces the risk of neuroblastoma. We hypothesized offspring and maternal genetic variants in folate-related and choline-related genes are associated with neuroblastoma and modify the effects of maternal intake of folate, choline and folic acid. Methods The Neuroblastoma Epidemiology in North America (NENA) study recruited 563 affected children and their parents through the Children’s Oncology Group’s Childhood Cancer Research Network. We used questionnaires to ascertain pre-pregnancy supplementation and estimate usual maternal dietary intake of folate, choline and folic acid. We genotyped 955 genetic variants related to folate or choline using DNA extracted from saliva samples and used a log-linear model to estimate both child and maternal risk ratios and stratum-specific risk ratios for gene-environment interactions. Results Overall, no maternal or offspring genotypic results met criteria for a false discovery rate (FDR) Q-value <0.2. Associations were also null for gene-environment interaction with pre-pregnancy vitamin supplementation, dietary folic acid and folate. FDR significant gene-choline interactions were found for offspring SNPs rs10489810 and rs9966612 located in MTHFD1L and TYMS, respectively, with maternal choline dietary intake dichotomized at the first quartile. Conclusion These results suggest that variants related to one-carbon metabolism are not strongly associated with neuroblastoma. Choline-related variants may play a role; however, the functional consequences of the interacting variants are unknown and require independent replication. PMID:27541142

A family-based study of gene variants and maternal folate and choline in neuroblastoma: a report from the Children's Oncology Group.

PubMed

Mazul, Angela L; Siega-Riz, Anna Maria; Weinberg, Clarice R; Engel, Stephanie M; Zou, Fei; Carrier, Kathryn S; Basta, Patricia V; Vaksman, Zalman; Maris, John M; Diskin, Sharon J; Maxen, Charlene; Naranjo, Arlene; Olshan, Andrew F

2016-10-01

Neuroblastoma is a childhood cancer of the sympathetic nervous system with embryonic origins. Previous epidemiologic studies suggest maternal vitamin supplementation during pregnancy reduces the risk of neuroblastoma. We hypothesized offspring and maternal genetic variants in folate-related and choline-related genes are associated with neuroblastoma and modify the effects of maternal intake of folate, choline, and folic acid. The Neuroblastoma Epidemiology in North America (NENA) study recruited 563 affected children and their parents through the Children's Oncology Group's Childhood Cancer Research Network. We used questionnaires to ascertain pre-pregnancy supplementation and estimate usual maternal dietary intake of folate, choline, and folic acid. We genotyped 955 genetic variants related to folate or choline using DNA extracted from saliva samples and used a log-linear model to estimate both child and maternal risk ratios and stratum-specific risk ratios for gene-environment interactions. Overall, no maternal or offspring genotypic results met criteria for a false discovery rate (FDR) Q-value <0.2. Associations were also null for gene-environment interaction with pre-pregnancy vitamin supplementation, dietary folic acid, and folate. FDR-significant gene-choline interactions were found for offspring SNPs rs10489810 and rs9966612 located in MTHFD1L and TYMS, respectively, with maternal choline dietary intake dichotomized at the first quartile. These results suggest that variants related to one-carbon metabolism are not strongly associated with neuroblastoma. Choline-related variants may play a role; however, the functional consequences of the interacting variants are unknown and require independent replication.

Gene by Environment Interaction and Resilience: Effects of Child Maltreatment and Serotonin, Corticotropin Releasing Hormone, Dopamine, and Oxytocin Genes

PubMed Central

Cicchetti, Dante; Rogosch, Fred A.

2013-01-01

In this investigation, gene-environment interaction effects in predicting resilience in adaptive functioning among maltreated and nonmaltreated low-income children (N = 595) were examined. A multi-component index of resilient functioning was derived and levels of resilient functioning were identified. Variants in four genes, 5-HTTLPR, CRHR1, DRD4 -521C/T, and OXTR, were investigated. In a series of ANCOVAs, child maltreatment demonstrated a strong negative main effect on children’s resilient functioning, whereas no main effects for any of the genotypes of the respective genes were found. However, gene-environment interactions involving genotypes of each of the respective genes and maltreatment status were obtained. For each respective gene, among children with a specific genotype, the relative advantage in resilient functioning of nonmaltreated compared to maltreated children was stronger than was the case for nonmaltreated and maltreated children with other genotypes of the respective gene. Across the four genes, a composite of the genotypes that more strongly differentiated resilient functioning between nonmaltreated and maltreated children provided further evidence of genetic variations influencing resilient functioning in nonmaltreated children, whereas genetic variation had a negligible effect on promoting resilience among maltreated children. Additional effects were observed for children based on the number of subtypes of maltreatment children experienced, as well as for abuse and neglect subgroups. Finally, maltreated and nonmaltreated children with high levels of resilience differed in their average number of differentiating genotypes. These results suggest that differential resilient outcomes are based on the interaction between genes and developmental experiences. PMID:22559122

A “Candidate-Interactome” Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis

PubMed Central

Policano, Claudia; Annibali, Viviana; Coarelli, Giulia; Ricigliano, Vito A. G.; Vittori, Danila; Fornasiero, Arianna; Buscarinu, Maria Chiara; Romano, Silvia; Salvetti, Marco; Ristori, Giovanni

2013-01-01

Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a “candidate interactome” (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms. PMID:23696811

Information-Theoretic Metrics for Visualizing Gene-Environment Interactions

PubMed Central

Chanda, Pritam ; Zhang, Aidong ; Brazeau, Daniel ; Sucheston, Lara ; Freudenheim, Jo L. ; Ambrosone, Christine ; Ramanathan, Murali 

2007-01-01

The purpose of our work was to develop heuristics for visualizing and interpreting gene-environment interactions (GEIs) and to assess the dependence of candidate visualization metrics on biological and study-design factors. Two information-theoretic metrics, the k-way interaction information (KWII) and the total correlation information (TCI), were investigated. The effectiveness of the KWII and TCI to detect GEIs in a diverse range of simulated data sets and a Crohn disease data set was assessed. The sensitivity of the KWII and TCI spectra to biological and study-design variables was determined. Head-to-head comparisons with the relevance-chain, multifactor dimensionality reduction, and the pedigree disequilibrium test (PDT) methods were obtained. The KWII and TCI spectra, which are graphical summaries of the KWII and TCI for each subset of environmental and genotype variables, were found to detect each known GEI in the simulated data sets. The patterns in the KWII and TCI spectra were informative for factors such as case-control misassignment, locus heterogeneity, allele frequencies, and linkage disequilibrium. The KWII and TCI spectra were found to have excellent sensitivity for identifying the key disease-associated genetic variations in the Crohn disease data set. In head-to-head comparisons with the relevance-chain, multifactor dimensionality reduction, and PDT methods, the results from visual interpretation of the KWII and TCI spectra performed satisfactorily. The KWII and TCI are promising metrics for visualizing GEIs. They are capable of detecting interactions among numerous single-nucleotide polymorphisms and environmental variables for a diverse range of GEI models. PMID:17924337

Ranking and characterization of established BMI and lipid associated loci as candidates for gene-environment interactions

PubMed Central

Luan, Jian'an; Mihailov, Evelin; Metspalu, Andres; Forouhi, Nita G.; Magnusson, Patrik K. E.; Pedersen, Nancy L.; Hallmans, Göran; Chu, Audrey Y.; Justice, Anne E.; Graff, Mariaelisa; Rose, Lynda M.; Langenberg, Claudia; Cupples, L. Adrienne; Ridker, Paul M.; Ong, Ken K.; Loos, Ruth J. F.; Chasman, Daniel I.; Ingelsson, Erik; Kilpeläinen, Tuomas O.; Scott, Robert A.; Mägi, Reedik

2017-01-01

Phenotypic variance heterogeneity across genotypes at a single nucleotide polymorphism (SNP) may reflect underlying gene-environment (G×E) or gene-gene interactions. We modeled variance heterogeneity for blood lipids and BMI in up to 44,211 participants and investigated relationships between variance effects (Pv), G×E interaction effects (with smoking and physical activity), and marginal genetic effects (Pm). Correlations between Pv and Pm were stronger for SNPs with established marginal effects (Spearman’s ρ = 0.401 for triglycerides, and ρ = 0.236 for BMI) compared to all SNPs. When Pv and Pm were compared for all pruned SNPs, only BMI was statistically significant (Spearman’s ρ = 0.010). Overall, SNPs with established marginal effects were overrepresented in the nominally significant part of the Pv distribution (Pbinomial <0.05). SNPs from the top 1% of the Pm distribution for BMI had more significant Pv values (PMann–Whitney = 1.46×10−5), and the odds ratio of SNPs with nominally significant (<0.05) Pm and Pv was 1.33 (95% CI: 1.12, 1.57) for BMI. Moreover, BMI SNPs with nominally significant G×E interaction P-values (Pint<0.05) were enriched with nominally significant Pv values (Pbinomial = 8.63×10−9 and 8.52×10−7 for SNP × smoking and SNP × physical activity, respectively). We conclude that some loci with strong marginal effects may be good candidates for G×E, and variance-based prioritization can be used to identify them. PMID:28614350

Sample size requirements for indirect association studies of gene-environment interactions (G x E).

PubMed

Hein, Rebecca; Beckmann, Lars; Chang-Claude, Jenny

2008-04-01

Association studies accounting for gene-environment interactions (G x E) may be useful for detecting genetic effects. Although current technology enables very dense marker spacing in genetic association studies, the true disease variants may not be genotyped. Thus, causal genes are searched for by indirect association using genetic markers in linkage disequilibrium (LD) with the true disease variants. Sample sizes needed to detect G x E effects in indirect case-control association studies depend on the true genetic main effects, disease allele frequencies, whether marker and disease allele frequencies match, LD between loci, main effects and prevalence of environmental exposures, and the magnitude of interactions. We explored variables influencing sample sizes needed to detect G x E, compared these sample sizes with those required to detect genetic marginal effects, and provide an algorithm for power and sample size estimations. Required sample sizes may be heavily inflated if LD between marker and disease loci decreases. More than 10,000 case-control pairs may be required to detect G x E. However, given weak true genetic main effects, moderate prevalence of environmental exposures, as well as strong interactions, G x E effects may be detected with smaller sample sizes than those needed for the detection of genetic marginal effects. Moreover, in this scenario, rare disease variants may only be detectable when G x E is included in the analyses. Thus, the analysis of G x E appears to be an attractive option for the detection of weak genetic main effects of rare variants that may not be detectable in the analysis of genetic marginal effects only.

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

PubMed

Lobach, Iryna; Fan, Ruzong; Manga, Prashiela

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.

Vantage Sensitivity: Environmental Sensitivity to Positive Experiences as a Function of Genetic Differences.

PubMed

Pluess, Michael

2017-02-01

A large number of gene-environment interaction studies provide evidence that some people are more likely to be negatively affected by adverse experiences as a function of specific genetic variants. However, such "risk" variants are surprisingly frequent in the population. Evolutionary analysis suggests that genetic variants associated with increased risk for maladaptive development under adverse environmental conditions are maintained in the population because they are also associated with advantages in response to different contextual conditions. These advantages may include (a) coexisting genetic resilience pertaining to other adverse influences, (b) a general genetic susceptibility to both low and high environmental quality, and (c) a coexisting propensity to benefit disproportionately from positive and supportive exposures, as reflected in the recent framework of vantage sensitivity. After introducing the basic properties of vantage sensitivity and highlighting conceptual similarities and differences with diathesis-stress and differential susceptibility patterns of gene-environment interaction, selected and recent empirical evidence for the notion of vantage sensitivity as a function of genetic differences is reviewed. The unique contribution that the new perspective of vantage sensitivity may make to our understanding of social inequality will be discussed after suggesting neurocognitive and molecular mechanisms hypothesized to underlie the propensity to benefit disproportionately from benevolent experiences. © 2015 Wiley Periodicals, Inc.

Gene-Environment Interaction in Adults’ IQ Scores: Measures of Past and Present Environment

PubMed Central

Willemsen, Gonneke; de Geus, Eco J. C.; Boomsma, Dorret I.; Posthuma, Danielle

2008-01-01

Gene-environment interaction was studied in a sample of young (mean age 26 years, N = 385) and older (mean age 49 years, N = 370) adult males and females. Full scale IQ scores (FSIQ) were analyzed using biometric models in which additive genetic (A), common environmental (C), and unique environmental (E) effects were allowed to depend on environmental measures. Moderators under study were parental and partner educational level, as well as urbanization level and mean real estate price of the participants’ residential area. Mean effects were observed for parental education, partner education and urbanization level. On average, FSIQ scores were roughly 5 points higher in participants with highly educated parents, compared to participants whose parents were less well educated. In older participants, IQ scores were about 2 points higher when their partners were highly educated. In younger males, higher urbanization levels were associated with slightly higher FSIQ scores. Our analyses also showed increased common environmental variation in older males whose parents were more highly educated, and increased unique environmental effects in older males living in more affluent areas. Contrary to studies in children, however, the variance attributable to additive genetic effects was stable across all levels of the moderators under study. Most results were replicated for VIQ and PIQ. PMID:18535898

Is exposure to cyanobacteria an environmental risk factor for amyotrophic lateral sclerosis and other neurodegenerative diseases?

USGS Publications Warehouse

Bradley, Walter G.; Borenstein, Amy R.; Nelson, Lorene M.; Codd, Geoffrey A.; Rosen, Barry H.; Stommel, Elijah W.; Cox, Paul Alan

2013-01-01

There is a broad scientific consensus that amyotrophic lateral sclerosis (ALS) is caused by gene-environment interactions. Mutations in genes underlying familial ALS (fALS) have been discovered in only 5–10% of the total population of ALS patients. Relatively little attention has been paid to environmental and lifestyle factors that may trigger the cascade of motor neuron death leading to the syndrome of ALS, although exposure to chemicals including lead and pesticides, and to agricultural environments, smoking, certain sports, and trauma have all been identified with an increased risk of ALS. There is a need for research to quantify the relative roles of each of the identified risk factors for ALS. Recent evidence has strengthened the theory that chronic environmental exposure to the neurotoxic amino acid β-N-methylamino-L-alanine (BMAA) produced by cyanobacteria may be an environmental risk factor for ALS. Here we describe methods that may be used to assess exposure to cyanobacteria, and hence potentially to BMAA, namely an epidemiologic questionnaire and direct and indirect methods for estimating the cyanobacterial load in ecosystems. Rigorous epidemiologic studies could determine the risks associated with exposure to cyanobacteria, and if combined with genetic analysis of ALS cases and controls could reveal etiologically important gene-environment interactions in genetically vulnerable individuals.

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. Copyright © 2016 Elsevier Ltd. All rights reserved.

Molecular Pathways: Gene-environment interactions regulating dietary fiber induction of proliferation and apoptosis via butyrate for cancer prevention

PubMed Central

Bultman, Scott J.

2013-01-01

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

Education and Alcohol Use: A Study of Gene-Environment Interaction in Young Adulthood

PubMed Central

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

2016-01-01

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=3,402), 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

Are there genetic influences on addiction: evidence from family, adoption and twin studies.

PubMed

Agrawal, Arpana; Lynskey, Michael T

2008-07-01

In this exciting era of gene discovery, we review evidence from family, adoption and twin studies that examine the genetic basis for addiction. With a focus on the classical twin design that utilizes data on monozygotic and dizygotic twins, we discuss support in favor of heritable influences on alcohol, nicotine, cannabis and other illicit drug dependence. We review whether these genetic factors also influence earlier stages (e.g. experimentation) of the addictive process and whether there are genetic influences specific to each psychoactive substance. Converging evidence from these studies supports the role of moderate to high genetic influences on addiction with estimates ranging from 0.30 to 0.70. The changing role of these heritable factors as a function of gender, age and cultural characteristics is also discussed. We highlight the importance of the interplay between genes and the environment as it relates to risk for addiction and the utility of the children-of-twins design for emerging studies of gene-environment interaction is presented. Despite the advances being made by low-cost high-throughput whole genome association assays, we posit that information garnered from twin studies, especially extended twin designs with power to examine gene-environment interactions, will continue to form the foundation for genomic research.

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

Shared epitope-aryl hydrocarbon receptor crosstalk underlies the mechanism of gene-environment interaction in autoimmune arthritis.

PubMed

Fu, Jiaqi; Nogueira, Sarah V; Drongelen, Vincent van; Coit, Patrick; Ling, Song; Rosloniec, Edward F; Sawalha, Amr H; Holoshitz, Joseph

2018-05-01

The susceptibility to autoimmune diseases is affected by genetic and environmental factors. In rheumatoid arthritis (RA), the shared epitope (SE), a five-amino acid sequence motif encoded by RA-associated HLA-DRB1 alleles, is the single most significant genetic risk factor. The risk conferred by the SE is increased in a multiplicative way by exposure to various environmental pollutants, such as cigarette smoke. The mechanism of this synergistic interaction is unknown. It is worth noting that the SE has recently been found to act as a signal transduction ligand that facilitates differentiation of Th17 cells and osteoclasts in vitro and in vivo. Intriguingly, the aryl hydrocarbon receptor (AhR), a transcription factor that mediates the xenobiotic effects of many pollutants, including tobacco combustion products, has been found to activate similar biologic effects. Prompted by these similarities, we sought to determine whether the SE and AhR signaling pathways interact in autoimmune arthritis. Here we uncovered a nuclear factor kappa B-mediated synergistic interaction between the SE and AhR pathways that leads to markedly enhanced osteoclast differentiation and Th17 polarization in vitro. Administration of AhR pathway agonists to transgenic mice carrying human SE-coding alleles resulted in a robust increase in arthritis severity, bone destruction, overabundance of osteoclasts, and IL17-expressing cells in the inflamed joints and draining lymph nodes of arthritic mice. Thus, this study identifies a previously unrecognized mechanism of gene-environment interaction that could provide insights into the well-described but poorly understood amplification of the genetic risk for RA upon exposure to environmental pollutants. Copyright © 2018 the Author(s). Published by PNAS.

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

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

2016-05-13

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).

Genetic determinants of prepubertal and pubertal growth and development.

PubMed

Thomis, Martine A; Towne, Bradford

2006-12-01

This article surveys the current general understanding of genetic influences on within- and between-population variation in growth and development in the context of establishing an International Growth Standard for Preadolescent and Adolescent Children. Traditional genetic epidemiologic analysis methods are reviewed, and evidence from family studies for genetic effects on different measures of growth and development is then presented. Findings from linkage and association studies seeking to identify specific genomic locations and allelic variants of genes influencing variation in growth and maturation are then summarized. Special mention is made of the need to study the interactions between genes and environments. At present, specific genes and polymorphisms contributing to variation in growth and maturation are only beginning to be identified. Larger genetic epidemiologic studies are needed in different parts of the world to better explore population differences in gene frequencies and gene-environment interactions. As advances continue to be made in molecular and statistical genetic methods, the genetic architecture of complex processes, including those of growth and development, will become better elucidated. For now, it can only be concluded that although the fundamental genetic underpinnings of the growth and development of children worldwide are likely to be essentially the same, there are also likely to be differences between populations in the frequencies of allelic gene variants that influence growth and maturation and in the nature of gene-environment interactions. This does not necessarily preclude an international growth reference, but it does have important implications for the form that such a reference might ultimately take.

Genotype × Environment Interaction in Smoking Behaviors: A Systematic Review.

PubMed

Do, Elizabeth K; Maes, Hermine H

2017-04-01

There has been rapid growth in research exploring gene-environment interaction (G×E) contributing to smoking behaviors. Yet, no systematic review exists to date. This article aims to review evidence on the contribution of G×E to the risk of smoking. Through a search of electronic databases (ie, Google Scholar, PubMed, ScienceDirect, and Elsevier) up until May 2014, 16 studies of G×E focused on smoking behaviors were identified. These studies were compared in terms of: research design and sample studied, measure of smoking behavior and environments used, genes explored, and G×E in relation to these factors. Thirteen of 16 studies (81.2%) found at least one significant G×E association. Wide variation in analytic methods was found across studies, especially with respect to the phenotypes of interest, environmental measures used, and tests conducted to estimate G×E. Heterogeneity across studies made it difficult to compare findings and evaluate the strength of evidence for G×E. G×E research on smoking contains studies that are methodologically different, making it difficult to assess the current state of the evidence. To decrease heterogeneity, we offer recommendations related to: (1) choice of measurement for environmental variables, (2) testing and reporting of main and interaction effects, (3) treatment of covariates, (4) reporting gene-environment correlation, and (5) conducting sensitivity analyses and checking for scaling artifacts. Continued study is needed to identify mechanisms by which genes and environmental factors combine to influence smoking behaviors. No comprehensive review of G×E studies of smoking behavior has previously been published. The present article seeks to fill this gap by providing a comprehensive review of: how G×E has been defined, how twin and molecular genetic methodologies have been used to test for G×E, and which genes and environmental factors are associated with smoking behaviors. Variations in methodological approaches make it difficult to interpret and summarize findings, so recommendations for future research are provided as a means to more easily compare and replicate findings across studies. © The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Wheezing exacerbations in early childhood: evaluation, treatment, and recent advances relevant to the genesis of asthma

PubMed Central

Miller, E. Kathryn; Avila, Pedro C.; Khan, Yasmin W.; Word, Carolyn R.; Pelz, Barry J.; Papadopoulos, Nikolaos G.; Peebles, R. Stokes; Heymann, Peter W.

2014-01-01

Children who begin wheezing during early childhood are seen frequently by health care providers in primary care, in hospitals and emergency departments, and by allergists and pulmonologists. When young children, like the 2 year-old case presented here, are evaluated for wheezing, a frequent challenge for clinicians is to determine whether the symptoms represent transient, viral-induced wheezing, or whether sufficient risk factors are present to suspect that the child may experience recurrent wheezing and develop asthma. Most factors influencing prognosis are not mutually exclusive, are interrelated (i.e., cofactors), and often represent gene-environment interactions. Many of these risk factors have been, and continue to be, investigated in prospective studies in order to decipher their relative importance with the goal of developing new therapies and interventions in the future. The etiologies of wheezing in young children, diagnostic methods, treatment, prognostic factors, and potential targets for prevention of the development of asthma are discussed. PMID:25213046

Gene-Gene and Gene-Environment Interactions in the Etiology of Breast Cancer

DTIC Science & Technology

2007-06-01

When you eat fried or baked pork or beef , you normally prefer that: Entire surface is brown with a slight burnt flavor 1...Uridine diphospho-glucuronosyltransferase 1A1 (UGT1A1) is involved in catalyzing estrogen, the hormone that plays a central role in the etiology of...relationship of UGT1A1 genotypes with plasma levels of estrone, estrone sulfate, estradiol, testosterone, and sex hormone binding globulins (SHBG

Genetic modification of the association between peripubertal dioxin exposure and pubertal onset in a cohort of Russian boys.

PubMed

Humblet, Olivier; Korrick, Susan A; Williams, Paige L; Sergeyev, Oleg; Emond, Claude; Birnbaum, Linda S; Burns, Jane S; Altshul, Larisa M; Patterson, Donald G; Turner, Wayman E; Lee, Mary M; Revich, Boris; Hauser, Russ

2013-01-01

Exposure to dioxins has been associated with delayed pubertal onset in both epidemiologic and animal studies. Whether genetic polymorphisms may modify this association is currently unknown. Identifying such genes could provide insight into mechanistic pathways. This is one of the first studies to assess genetic susceptibility to dioxins. We evaluated whether common polymorphisms in genes affecting either molecular responses to dioxin exposure or pubertal onset influence the association between peripubertal serum dioxin concentration and male pubertal onset. In this prospective cohort of Russian adolescent boys (n = 392), we assessed gene-environment interactions for 337 tagging single-nucleotide polymorphisms (SNPs) from 46 candidate genes and two intergenic regions. Dioxins were measured in the boys' serum at age 8-9 years. Pubertal onset was based on testicular volume and on genitalia staging. Statistical approaches for controlling for multiple testing were used, both with and without prescreening for marginal genetic associations. After accounting for multiple testing, two tag SNPs in the glucocorticoid receptor (GR/NR3C1) gene and one in the estrogen receptor-α (ESR1) gene were significant (q < 0.2) modifiers of the association between peripubertal serum dioxin concentration and male pubertal onset defined by genitalia staging, although not by testicular volume. The results were sensitive to whether multiple comparison adjustment was applied to all gene-environment tests or only to those with marginal genetic associations. Common genetic polymorphisms in the glucocorticoid receptor and estrogen receptor-α genes may modify the association between peripubertal serum dioxin concentration and pubertal onset. Further studies are warranted to confirm these findings.

When chocolate seeking becomes compulsion: gene-environment interplay.

PubMed

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

2015-01-01

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. 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. 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.

Gene-environment interplay in the link of friends' and nonfriends' behaviors with children's social reticence in a competitive situation.

PubMed

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

2014-03-01

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 nonfriends' behaviors and (b) children's social reticence were examined. The sample comprised 466 twin children (i.e., the target children), each of whom was assessed in kindergarten together with a same-sex friend and two nonfriend classmates of either sex. Multilevel regression analyses revealed that children with a genetic disposition for social reticence showed more reticent behavior in the competitive situation and were more likely to affiliate with reticent friends (i.e., rGE). Moreover, a higher level of children's reticent behavior was predicted by their friends' higher social reticence (particularly for girls) and their friends' higher social dominance, independently of children's genetic disposition. Children's social reticence was also predicted by their nonfriends' behaviors. Specifically, children were less reticent when male nonfriends showed high levels of social reticence in the competitive situation, and this was particularly true for children with a genetic disposition for social reticence (i.e., GxE). Moreover, children genetically vulnerable for social reticence seemed to foster dominant behavior in their female nonfriend peers (i.e., rGE). In turn, male nonfriends seemed to be more dominant as soon as the target children were reticent, even if the target children did not have a stable genetic disposition for this behavior. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Gene-environment interactions associated with CYP1A1 MspI and GST polymorphisms and the risk of upper aerodigestive tract cancers in an Indian population.

PubMed

Sam, Soya Sisy; Thomas, Vinod; Reddy, K S; Surianarayanan, Gopalakrishnan; Chandrasekaran, Adithan

2010-06-01

Genetic risk to tobacco related cancers are associated with polymorphisms in CYP1A1 and GST, which are involved in the metabolic activation and detoxification of carcinogens. The genetic variations in these drug-metabolizing enzymes may alter the susceptibility to UADT cancers triggered by environmental exposures. The hospital-based case-control study evaluated the impact of combined CYP1A1 MspI and GST (M1 & T1) polymorphisms among the individuals exposed to environmental risk factors as modulators in the risk of UADT cancers in Tamilians, a population of south India. The unrelated histopathologically confirmed 408 cases and 220 population-based controls matched by age and gender were genotyped for CYP1A1 MspI, GSTM1 and GSTT1 polymorphisms using PCR based methods. To investigate the potential gene-environment interactions, analyses were carried out stratifying by smoking and tobacco chewing status using SPSS software. The combination of genes and environment interactions by stratified analyses revealed significant interactions among the habitual tobacco smokers (CYP1A1 MspI & GSTM1 null: OR 14.06; 95% CI 3.90-50.68, CYP1A1 MspI & GSTT1 null: OR 33.28; 95% CI 4.24-261.19) and tobacco chewers (CYP1A1 MspI & GSTM1 null: OR 20.51; 95% CI 6.77-62.13, CYP1A1 MspI & GSTT1 null: OR 79.35; 95% CI 10.40-605.55) on the multiplicative scale. Our findings have indicated that the individuals polymorphic for CYP1A1 MspI either with GSTM1 null or with GSTT1 null genotypes revealed an increased risk for UADT cancers than that ascribed to a single susceptible gene among the tobacco users in the population [single gene risk among smokers and chewers, respectively, for CYP1A1 MspI (OR 6.43; 95% CI 3.69-11.21); (OR 10.24; 95% CI 5.95-17.60), GSTM1*0 (OR 3.77; 95% CI 1.94-7.37); (OR 7.97 95% CI 4.10-15.76) and GSTT1*0 (OR 6.95 95% CI 2.88-16.77); (OR 25.83 95% CI 7.78-85.76).

Interaction between MTHFR 677C>T and periconceptional folic acid supplementation in the risk of Hypospadias.

PubMed

Dokter, Elisabeth M J; van Rooij, Iris A L M; Wijers, Charlotte H W; Groothuismink, Johanne M; van der Biezen, Jan Jaap; Feitz, Wout F J; Roeleveld, Nel; van der Zanden, Loes F M

2016-04-01

Hypospadias is a congenital malformation with both environmental factors and genetic predisposition involved in the pathogenesis. The role of maternal periconceptional folic acid supplement use in the development of hypospadias is unclear. As folate levels may also be influenced by the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, we hypothesize that a gene-environment interaction between this polymorphism and folic acid use is involved in the etiology of hypospadias. We conducted a case-control study among 855 hypospadias cases and 713 population-based controls from the AGORA data- and biobank. Folic acid supplement use was derived from maternal questionnaires and infant and maternal DNA was used to determine the MTHFR C677T polymorphism using Taqman assays. We performed separate analyses for different hypospadias phenotypes (anterior/middle/posterior). Hypospadias was neither associated with folic acid use or the MTHFR C677T polymorphism, nor with their interaction. However, we did find an association with middle hypospadias when no supplements were used (odds ratio = 1.6; 95% confidence interval, 1.1-2.4), especially in infants carrying the CT/TT genotype (odds ratio = 2.5; 95% confidence interval, 1.4-4.7). In addition, more infants with these genotypes seemed to have posterior hypospadias, regardless of folic acid use. Our study does not suggest a major role for folic acid supplements or the MTHFR C677T polymorphism in the etiology of hypospadias in general, but not using folic acid and/or carrying the MTHFR C677T polymorphism may be associated with middle and posterior hypospadias. Therefore, we stress the importance of studying gene-environment interactions preferably in stratified analyses for different hypospadias phenotypes. © 2016 Wiley Periodicals, Inc.

Further Evidence That Cannabis Moderates Familial Correlation of Psychosis-Related Experiences

PubMed Central

van Winkel, Ruud

2015-01-01

Background Familial correlations underlie heritability estimates of psychosis. If gene-environment interactions are important, familial correlation will vary as a function of environmental exposure. Methods Associations between sibling and parental schizotypy (n = 669 pairs, n = 1222 observations), and between sibling schizotypy and patient CAPE psychosis (n = 978 pairs, n = 1723 observations) were examined as a function of sibling cannabis use. This design is based on the prediction that in unaffected siblings who are not exposed, vulnerability for psychosis will remain latent, whereas in case of exposure, latent psychosis vulnerability may become expressed, at the level of schizotypal symptoms, causing the phenotypic correlation between relatives to become “visible” under the influence of cannabis. Results Siblings exposed to recent cannabis use resembled their patient-relative more closely in terms of positive schizotypy (urinalysis(+):B = 0.30, P<.001; urinalysis(-):B = 0.10, p<0.001; p-interaction = 0.0135). Similarly, the familial correlation in positive schizotypy between parent and sibling was significantly greater in siblings recently exposed to cannabis (urinalysis(+):B = 0.78, P<.001; urinalysis(-):B = 0.43, p<0.001; p interaction = 0.0017). Results were comparable when using lifetime cannabis frequency of use as exposure instead of recent use. Parental schizotypy did not predict cannabis use in the healthy sibling, nor in the patient. Similarly, parental cannabis use was not associated with level of schizotypy in the sibling, nor with psychotic symptoms in the patient, making gene-environment correlation unlikely. Conclusion Familial correlation of psychosis-related experiences varies considerably as a function of exposure to cannabis, confirming the importance of gene-cannabis interaction in shifts of expression of psychosis-related experiences. PMID:26384217

The role of environmental heterogeneity in meta-analysis of gene-environment interactions with quantitative traits.

PubMed

Li, Shi; Mukherjee, Bhramar; Taylor, Jeremy M G; Rice, Kenneth M; Wen, Xiaoquan; Rice, John D; Stringham, Heather M; Boehnke, Michael

2014-07-01

With challenges in data harmonization and environmental heterogeneity across various data sources, meta-analysis of gene-environment interaction studies can often involve subtle statistical issues. In this paper, we study the effect of environmental covariate heterogeneity (within and between cohorts) on two approaches for fixed-effect meta-analysis: the standard inverse-variance weighted meta-analysis and a meta-regression approach. Akin to the results in Simmonds and Higgins (), we obtain analytic efficiency results for both methods under certain assumptions. The relative efficiency of the two methods depends on the ratio of within versus between cohort variability of the environmental covariate. We propose to use an adaptively weighted estimator (AWE), between meta-analysis and meta-regression, for the interaction parameter. The AWE retains full efficiency of the joint analysis using individual level data under certain natural assumptions. Lin and Zeng (2010a, b) showed that a multivariate inverse-variance weighted estimator retains full efficiency as joint analysis using individual level data, if the estimates with full covariance matrices for all the common parameters are pooled across all studies. We show consistency of our work with Lin and Zeng (2010a, b). Without sacrificing much efficiency, the AWE uses only univariate summary statistics from each study, and bypasses issues with sharing individual level data or full covariance matrices across studies. We compare the performance of the methods both analytically and numerically. The methods are illustrated through meta-analysis of interaction between Single Nucleotide Polymorphisms in FTO gene and body mass index on high-density lipoprotein cholesterol data from a set of eight studies of type 2 diabetes. © 2014 WILEY PERIODICALS, INC.

A genome-wide association and gene-environment interaction study for serum triglycerides levels in a healthy Chinese male population.

PubMed

Tan, Aihua; Sun, Jielin; Xia, Ning; Qin, Xue; Hu, Yanling; Zhang, Shijun; Tao, Sha; Gao, Yong; Yang, Xiaobo; Zhang, Haiying; Kim, Seong-Tae; Peng, Tao; Lin, Xiaoling; Li, Li; Mo, Linjian; Liang, Zhengjia; Shi, Deyi; Huang, Zhang; Huang, Xianghua; Liu, Ming; Ding, Qiang; Trent, Jeffrey M; Zheng, S Lilly; Mo, Zengnan; Xu, Jianfeng

2012-04-01

Triglyceride (TG) is a complex phenotype influenced by both genetic and environmental factors. Recent genome-wide association studies (GWAS) have identified genes or loci affecting lipid levels; however, such studies in Chinese populations are limited. A two-stage GWAS were conducted to identify genetic variants that were associated with TG in a Chinese population of 3495 men. Gene-environment interactions on serum TG levels were further investigated for the seven single nucleotide polymorphisms (SNPs) that were studied in both stages. Two previously reported SNPs (rs651821 in APOA5, rs328 in LPL) were replicated in the second stage, and the combined P-values were 9.19 × 10(-26) and 1.41 × 10(-9) for rs651821 and rs328, respectively. More importantly, a significant interaction between aldehyde dehydrogenase 2 (ALDH2) rs671 and alcohol consumption on serum TG levels were observed (P = 3.34 × 10(-5)). Rs671 was significantly associated with serum TG levels in drinkers (P = 1.90 × 10(-10)), while no association was observed in non-drinkers (P > 0.05). For drinkers, men carrying the AA/AG genotype have significantly lower serum TG levels, compared with men carrying the GG genotype. For men with the GG genotype, the serum TG levels increased with the quantity of alcohol intake (P = 1.28 × 10(-8) for trend test). We identified a novel, significant interaction effect between alcohol consumption and the ALDH2 rs671 polymorphism on TG levels, which suggests that the effect of alcohol intake on TG occurs in a two-faceted manner. Just one drink can increase TG level in susceptible individuals who carry the GG genotype, while individuals carrying AA/AG genotypes may actually benefit from moderate drinking.

The moderating effect of ANKK1 on the association of family environment with longitudinal executive function following traumatic brain injury in early childhood: A preliminary study.

PubMed

Smith-Paine, Julia; Wade, Shari L; Treble-Barna, Amery; Zhang, Nanhua; Zang, Huaiyu; Martin, Lisa J; Yeates, Keith Owen; Taylor, H Gerry; Kurowski, Brad G

2018-05-02

This study examined whether the ankyrin repeat and kinase domain containing 1 gene (ANKK1) C/T single-nucleotide polymorphism (SNP) rs1800497 moderated the association of family environment with long-term executive function (EF) following traumatic injury in early childhood. Caregivers of children with traumatic brain injury (TBI) and children with orthopedic injury (OI) completed the Behavior Rating Inventory of Executive Function (BRIEF) at post injury visits. DNA was collected to identify the rs1800497 genotype in the ANKK1 gene. General linear models examined gene-environment interactions as moderators of the effects of TBI on EF at two times post injury (12 months and 7 years). At 12 months post injury, analyses revealed a significant 3-way interaction of genotype with level of permissive parenting and injury type. Post-hoc analyses showed genetic effects were more pronounced for children with TBI from more positive family environments, such that children with TBI who were carriers of the risk allele (T-allele) had significantly poorer EF compared to non-carriers only when they were from more advantaged environments. At 7 years post injury, analyses revealed a significant 2-way interaction of genotype with level of authoritarian parenting. Post-hoc analyses found that carriers of the risk allele had significantly poorer EF compared to non-carriers only when they were from more advantaged environments. These results suggest a gene-environment interaction involving the ANKK1 gene as a predictor of EF in a pediatric injury population. The findings highlight the importance of considering environmental influences in future genetic studies on recovery following TBI and other traumatic injuries in childhood.

The effects of child maltreatment on early signs of antisocial behavior: Genetic moderation by Tryptophan Hydroxylase, Serotonin Transporter, and Monoamine Oxidase-A-Genes

PubMed Central

Cicchetti, Dante; Rogosch, Fred A.; Thibodeau, Eric

2013-01-01

Gene-environment interaction effects in predicting antisocial behavior in late childhood were investigated among maltreated and nonmaltreated low-income children (N = 627, M age = 11.27). Variants in three genes, TPH1, 5-HTTLPR, and MAOA uVNTR, were examined. In addition to child maltreatment status, we also considered the impact of maltreatment subtypes, developmental timing of maltreatment, and chronicity. Indicators of antisocial behavior were obtained from self-, peer-, and adult counselor-reports. In a series of ANCOVAs, child maltreatment and its parameters demonstrated strong main effects on early antisocial behavior as assessed by all forms of report. Genetic effects operated primarily in the context of gene-environment interactions, moderating the impact of child maltreatment on outcomes. Across the three genes, among nonmaltreated children no differences in antisocial behavior were found based on genetic variation. In contrast, among maltreated children specific polymorphisms of TPH1, 5-HTTLPR, and MAOA were each related to heightened self-report of antisocial behavior; the interaction of 5-HTTLPR and developmental timing of maltreatment also indicated more severe antisocial outcomes for children with early onset and recurrent maltreatment based on genotype. TPH1 and 5-HTTLPR interacted with maltreatment subtype to predict peer-report of antisocial behavior; genetic variation contributed to larger differences in antisocial behavior among abused children. TPH1 and 5-HTTLPR polymorphisms also moderated the effects of maltreatment subtype on adult report of antisocial behavior; again genetic effects were strongest for children who were abused. Additionally, TPH1 moderated the effect of developmental timing of maltreatment and chronicity on adult report of antisocial behavior. The findings elucidate how genetic variation contributes to identifying which maltreated children are most vulnerable to antisocial development. PMID:22781862

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…

Genetic and Environmental Influences on Depressive Symptoms in Chinese Adolescents

PubMed Central

Chen, Jie; Li, Xinying; Natsuaki, Misaki N.; Leve, Leslie D.; Harold, Gordon T.

2016-01-01

Adolescent depression is common and has become a major public health concern in China, yet little research has examined the etiology of depression in Chinese adolescents. In the present study, genetic and environmental influences on Chinese adolescent depressive symptoms were investigated in 1181 twin pairs residing in Beijing, China (ages 11 to 19 years). Child- and parent-versions of the Children’s Depression Inventory (CDI) were used to measure adolescents’ depressive symptoms. For self-reports, genetic factors, shared environmental factors, and non-shared environmental factors accounted for 50%, 5%, and 45% of the variation in depressive symptoms, respectively; for parent-reports, genetic factors, shared environmental factors, and non-shared environmental factors accounted for 51%, 18%, and 31% of the variation, respectively. These estimates are generally consistent with previous findings in Western adolescents, supporting the cross-cultural generalizability of etiological model of adolescent depression. Neither qualitative nor quantitative sex differences were found in the etiological model. Future studies are needed to investigate how genes and environments work together (gene-environment interaction, gene-environment correlation) to influence depression in Chinese adolescents. PMID:24311200

Genetic and environmental influences on depressive symptoms in Chinese adolescents.

PubMed

Chen, Jie; Li, Xinying; Natsuaki, Misaki N; Leve, Leslie D; Harold, Gordon T

2014-01-01

Adolescent depression is common and has become a major public health concern in China, yet little research has examined the etiology of depression in Chinese adolescents. In the present study, genetic and environmental influences on Chinese adolescent depressive symptoms were investigated in 1,181 twin pairs residing in Beijing, China (ages 11-19 years). Child- and parent-versions of the children's depression inventory were used to measure adolescents' depressive symptoms. For self-reports, genetic factors, shared environmental factors, and non-shared environmental factors accounted for 50, 5, and 45 % of the variation in depressive symptoms, respectively; for parent-reports, genetic factors, shared environmental factors, and non-shared environmental factors accounted for 51, 18, and 31 % of the variation, respectively. These estimates are generally consistent with previous findings in Western adolescents, supporting the cross-cultural generalizability of etiological model of adolescent depression. Neither qualitative nor quantitative sex differences were found in the etiological model. Future studies are needed to investigate how genes and environments work together (gene-environment interaction, gene-environment correlation) to influence depression in Chinese adolescents.

Gene-environment interactions linking air pollution and inflammation in Parkinson's disease.

PubMed

Lee, Pei-Chen; Raaschou-Nielsen, Ole; Lill, Christina M; Bertram, Lars; Sinsheimer, Janet S; Hansen, Johnni; Ritz, Beate

2016-11-01

Both air pollution exposure and systemic inflammation have been linked to Parkinson's disease (PD). In the PASIDA study, 408 incident cases of PD diagnosed in 2006-2009 and their 495 population controls were interviewed and provided DNA samples. Markers of long term traffic related air pollution measures were derived from geographic information systems (GIS)-based modeling. Furthermore, we genotyped functional polymorphisms in genes encoding proinflammatory cytokines, namely rs1800629 in TNFα (tumor necrosis factor alpha) and rs16944 in IL1B (interleukin-1β). In logistic regression models, long-term exposure to NO 2 increased PD risk overall (odds ratio (OR)=1.06 per 2.94μg/m 3 increase, 95% CI=1.00-1.13). The OR for PD in individuals with high NO 2 exposure (≧75th percentile) and the AA genotype of IL1B rs16944 was 3.10 (95% CI=1.14-8.38) compared with individuals with lower NO 2 exposure (<75th percentile) and the GG genotype. The interaction term was nominally significant on the multiplicative scale (p=0.01). We did not find significant gene-environment interactions with TNF rs1800629. Our finds may provide suggestive evidence that a combination of traffic-related air pollution and genetic variation in the proinflammatory cytokine gene IL1B contribute to risk of developing PD. However, as statistical evidence was only modest in this large sample we cannot rule out that these results represent a chance finding, and additional replication efforts are warranted. Copyright © 2016 Elsevier Inc. All rights reserved.

GENETICS OF WHITE MATTER DEVELOPMENT: A DTI STUDY OF 705 TWINS AND THEIR SIBLINGS AGED 12 TO 29

PubMed Central

Chiang, Ming-Chang; McMahon, Katie L.; de Zubicaray, Greig I.; Martin, Nicholas G.; Hickie, Ian; Toga, Arthur W.; Wright, Margaret J.; Thompson, Paul M.

2011-01-01

White matter microstructure is under strong genetic control, yet it is largely unknown how genetic influences change from childhood into adulthood. In one of the largest brain mapping studies ever performed, we determined whether the genetic control over white matter architecture depends on age, sex, socioeconomic status (SES), and intelligence quotient (IQ). We assessed white matter integrity voxelwise using diffusion tensor imaging at high magnetic field (4-Tesla), in 705 twins and their siblings (age range 12–29; 290 M/415 F). White matter integrity was quantified using a widely accepted measure, fractional anisotropy (FA). We fitted gene-environment interaction models pointwise, to visualize brain regions where age, sex, SES and IQ modulate heritability of fiber integrity. We hypothesized that environmental factors would start to outweigh genetic factors during late childhood and adolescence. Genetic influences were greater in adolescence versus adulthood, and greater in males than in females. Socioeconomic status significantly interacted with genes that affect fiber integrity: heritability was higher in those with higher SES. In people with above-average IQ, genetic factors explained over 800% of the observed FA variability in the thalamus, genu, posterior internal capsule, and superior corona radiata. In those with below-average IQ, however, only around 40% FA variability in the same regions was attributable to genetic factors. Genes affect fiber integrity, but their effects vary with age, sex, SES and IQ. Gene-environment interactions are vital to consider in the search for specific genetic polymorphisms that affect brain integrity and connectivity. PMID:20950689

Quantitative phenotyping via deep barcode sequencing.

PubMed

Smith, Andrew M; Heisler, Lawrence E; Mellor, Joseph; Kaper, Fiona; Thompson, Michael J; Chee, Mark; Roth, Frederick P; Giaever, Guri; Nislow, Corey

2009-10-01

Next-generation DNA sequencing technologies have revolutionized diverse genomics applications, including de novo genome sequencing, SNP detection, chromatin immunoprecipitation, and transcriptome analysis. Here we apply deep sequencing to genome-scale fitness profiling to evaluate yeast strain collections in parallel. This method, Barcode analysis by Sequencing, or "Bar-seq," outperforms the current benchmark barcode microarray assay in terms of both dynamic range and throughput. When applied to a complex chemogenomic assay, Bar-seq quantitatively identifies drug targets, with performance superior to the benchmark microarray assay. We also show that Bar-seq is well-suited for a multiplex format. We completely re-sequenced and re-annotated the yeast deletion collection using deep sequencing, found that approximately 20% of the barcodes and common priming sequences varied from expectation, and used this revised list of barcode sequences to improve data quality. Together, this new assay and analysis routine provide a deep-sequencing-based toolkit for identifying gene-environment interactions on a genome-wide scale.

Computational intelligence in bioinformatics: SNP/haplotype data in genetic association study for common diseases.

PubMed

Kelemen, Arpad; Vasilakos, Athanasios V; Liang, Yulan

2009-09-01

Comprehensive evaluation of common genetic variations through association of single-nucleotide polymorphism (SNP) structure with common complex disease in the genome-wide scale is currently a hot area in human genome research due to the recent development of the Human Genome Project and HapMap Project. Computational science, which includes computational intelligence (CI), has recently become the third method of scientific enquiry besides theory and experimentation. There have been fast growing interests in developing and applying CI in disease mapping using SNP and haplotype data. Some of the recent studies have demonstrated the promise and importance of CI for common complex diseases in genomic association study using SNP/haplotype data, especially for tackling challenges, such as gene-gene and gene-environment interactions, and the notorious "curse of dimensionality" problem. This review provides coverage of recent developments of CI approaches for complex diseases in genetic association study with SNP/haplotype data.

Preterm birth research: from disillusion to the search for new mechanisms.

PubMed

Buekens, P; Klebanoff, M

2001-07-01

No intervention has been shown to decrease the rate of preterm birth. There was thus a need for a new research agenda. The new emphasis is on social and biological mechanisms, including the impact on stress of racism and poverty, and gene-environment interactions. New markers are also under study, and pertain mostly to infection and inflammation. The impact on preterm birth of broad contextual factors, such as universal social protection, will need to be explored further. The recent trends toward increased rates of preterm births deserve much attention. New policies and interventions to decrease medically indicated preterm births should be urgently developed and evaluated. The failure to prevent preterm deliveries has been so disappointing that there is a risk that high rates of preterm births will be seen as unavoidable. The research programme launched by March of Dimes is a timely effort to foster new enthusiasm, to test new ideas and to generate new hypotheses.

Behavioral science and the study of gene-nutrition and gene-physical activity interactions in obesity research.

PubMed

Faith, Myles S

2008-12-01

This report summarizes emerging opportunities for behavioral science to help advance the field of gene-environment and gene-behavior interactions, based on presentations at The National Cancer Institute (NCI) Workshop, "Gene-Nutrition and Gene-Physical Activity Interactions in the Etiology of Obesity." Three opportunities are highlighted: (i) designing potent behavioral "challenges" in experiments, (ii) determining viable behavioral phenotypes for genetics studies, and (iii) identifying specific measures of the environment or environmental exposures. Additional points are underscored, including the need to incorporate novel findings from neuroimaging studies regarding motivation and drive for eating and physical activity. Advances in behavioral science theory and methods can play an important role in advancing understanding of gene-brain-behavior relationships in obesity onset.

The interactive effects of genetic polymorphisms within LFA-1/ICAM-1/GSK-3β pathway and environmental hazards on the development of Graves' opthalmopathy.

PubMed

Yang, Ge; Fu, Yang; Lu, Xiaoyan; Wang, Menghua; Dong, Hongtao; Li, Qiuming

2018-05-22

The purpose of this investigation was to explore the combined effects of single nucleotide polymorphisms (SNPs) within LFA-1/ICAM-1/GSK-3β pathway and environmental hazards on susceptibility to Graves' opthalmopathy (GO) among a Chinese Han population. Altogether 305 GO patients and 283 Graves' disease (GD) subjects were recruited. Information relevant to the participants' age, gender, body mass index (BMI), regular physical activity, smoking history, alcohol intake, stressful work environment, stress at work, family history of thyroid disease and 131 I treatment were summarized, and the participants' related SNPs of LFA-1/ICAM-1/GSK-3β were also detected. Then the gene-gene and gene-environment interactions were evaluated by logistic regression model and multi-factor dimensionality reduction (MDR) modeling. The results exhibited that age, BMI, smoking history, stressful work, stress at home, family history of thyroid disease and 131 I treatment appeared as potential indicators regulating GO risk, when either univariate or multivariate regression analysis was performed (all P < 0.05). Moreover, rs12716977 (T > C) and rs2230433 (G > C) of LFA-1, rs1799969 (G > A) and rs5498 (A > G) of ICAM-1, as well as rs6438552 (T > C) and rs334558 (T > C) of GSK-3β were significantly associated with altered susceptibility to GO under the allelic models (all P < 0.05). Also haplotype TGAATC acted as a protective factor against GO risk (P < 0.05), whereas haplotype CGAACC largely elevated risk of GO (P < 0.05). Besides, logistic regression analysis demonstrated that rs12716927, rs5498 and rs6438552 all would affect the influences exerted by age, BMI, smoking history, stressful work, stress at home, family history of thyroid disease or 131 I treatment on GO susceptibility (all P < 0.05). MDR modeling implied that the combined model of rs12716977, rs2230433 and rs1799969 was the supreme interactive model when BMI was co-assessed, and the interactive model of rs12716977, rs334558 and rs5491 was the most desirable among the smoking population. In conclusion, gene-gene and gene-environment interactions served as a crucial manner in affecting susceptibility to GO, providing solid evidences for screening effective GO-susceptible biomarkers and exploring potential GO treatment strategies. Copyright © 2018. Published by Elsevier Ltd.

A gene-environment interaction analysis of plasma selenium with prevalent and incident diabetes: The Hortega study.

PubMed

Galan-Chilet, Inmaculada; Grau-Perez, Maria; De Marco, Griselda; Guallar, Eliseo; Martin-Escudero, Juan Carlos; Dominguez-Lucas, Alejandro; Gonzalez-Manzano, Isabel; Lopez-Izquierdo, Raul; Briongos-Figuero, Laisa Socorro; Redon, Josep; Chaves, Felipe Javier; Tellez-Plaza, Maria

2017-08-01

Selenium and single-nucleotide-polymorphisms in selenoprotein genes have been associated to diabetes. However, the interaction of selenium with genetic variation in diabetes and oxidative stress-related genes has not been evaluated as a potential determinant of diabetes risk. We evaluated the cross-sectional and prospective associations of plasma selenium concentrations with type 2 diabetes, and the interaction of selenium concentrations with genetic variation in candidate polymorphisms, in a representative sample of 1452 men and women aged 18-85 years from Spain. The geometric mean of plasma selenium levels in the study sample was 84.2µg/L. 120 participants had diabetes at baseline. Among diabetes-free participants who were not lost during the follow-up (N=1234), 75 developed diabetes over time. The multivariable adjusted odds ratios (95% confidence interval) for diabetes prevalence comparing the second and third to the first tertiles of plasma selenium levels were 1.80 (1.03, 3.14) and 1.97 (1.14, 3.41), respectively. The corresponding hazard ratios (95% CI) for diabetes incidence were 1.76 (0.96, 3.22) and 1.80 (0.98, 3.31), respectively. In addition, we observed significant interactions between selenium and polymorphisms in PPARGC1A, and in genes encoding mitochondrial proteins, such as BCS1L and SDHA, and suggestive interactions of selenium with other genes related to selenoproteins and redox metabolism. Plasma selenium was positively associated with prevalent and incident diabetes. While the statistical interactions of selenium with polymorphisms involved in regulation of redox and insulin signaling pathways provide biological plausibility to the positive associations of selenium with diabetes, further research is needed to elucidate the causal pathways underlying these associations. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Disinfection by-products exposure and intra-uterine growth restriction: Do genetic polymorphisms of CYP2E1or deletion of GSTM1 or GSTT1 modify the association?

PubMed

Levallois, Patrick; Giguère, Yves; Nguile-Makao, Molière; Rodriguez, Manuel; Campagna, Céline; Tardif, Robert; Bureau, Alexandre

2016-01-01

Exposure to disinfection by-products (DBPs) during pregnancy was associated with reduced foetal growth. Genetic susceptibility might play a role, especially for genes encoding for the Cytochrome P450 (CYP2E1) and Glutathione S-Transferase (GST) enzymes, involved in metabolism and activation of DBPs. Few epidemiological studies evaluated these gene-environment interactions and their results were never replicated. This study aims to examine interactions between trihalomethanes (THM) or haloacetic acids (HAA) exposure and genetic polymorphisms on small for gestational age (SGA) neonates by investigating single nucleotide polymorphisms (SNPs) in CYP2E1 gene and GSTM1 and GSTT1 deletions in mothers-children pairs. A population-based case-control study of 1549 mothers and 1455 children was conducted on SGA and THM/HAA exposure. DNA was extracted from blood or saliva cells. Targeted SNPs and deletions were genotyped. Statistical interaction between SNPs/deletions and THMs or HAAs in utero exposure with regard to SGA occurrence was evaluated by unconditional logistic regression with control of potential confounders. Previously reported positive modification of the effect of THM uterine exposure by mothers or newborns CYP2E1 rs3813867 C allele or GSTM1 deletion was not replicated. However interactions with CYP2E1 rs117618383 and rs2515641 were observed but were not statistically significant after correction for multiple testing. Previous positive interactions between THMs exposure and CYP2E1 and GSTM1 were not replicated but interactions with other CYP2E1 polymorphisms are reported. Copyright © 2016 Elsevier Ltd. All rights reserved.

Disinfection by-products exposure and intra-uterine growth restriction: do genetic polymorphisms of CYP2E1or deletion of GSTM1 or GSTT1 modify the association?

PubMed Central

Levallois, Patrick; Giguère, Yves; Nguile-Makao, Molière; Rodriguez, Manuel; Campagna, Céline; Tardif, Robert; Bureau, Alexandre

2016-01-01

Background Exposure to disinfection by-products (DBPs) during pregnancy was associated with reduced fetal growth. Genetic susceptibility might play a role, especially for genes encoding for the Cytochrome P450 (CYP2E1) and Glutathione S-Transferase (GST) enzymes, involved in metabolism and activation of DBPs. Few epidemiological studies evaluated these gene-environment interactions and their results were never replicated. Objective This study aims to examine interactions between trihalomethanes (THM) or haloacetic acids (HAA) exposure and genetic polymorphisms on small for gestational age (SGA) neonates by investigating single nucleotide polymorphisms (SNPs) in CYP2E1 gene and GSTM1 and GSTT1 deletions in mothers-children pairs. Methods A population-based case-control study of 1549 mothers and 1455 children was conducted on SGA and THM/HAA exposure. DNA was extracted from blood or saliva cells. Targeted SNPs and deletions were genotyped. Statistical interaction between SNPs/deletions and THMs or HAAs in utero exposure with regard to SGA occurrence was evaluated by unconditional logistic regression with control of potential confounders. Results Previously reported positive modification of the effect of THM uterine exposure by mothers or newborns CYP2E1 rs3813867 C allele or GSTM1 deletion was not replicated. However interactions with CYP2E1 rs117618383 and rs2515641 were observed but were not statistically significant after correction for multiple testing. Conclusions Previous positive interactions between THMs exposure and CYP2E1 and GSTM1 were not replicated but interactions with other CYP2E1 polymorphisms are reported. PMID:27107227

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

Gene-Environment Correlation Underlying the Association between Parental Negativity and Adolescent Externalizing Problems

ERIC Educational Resources Information Center

Marceau, Kristine; Horwitz, Briana N.; Narusyte, Jurgita; Ganiban, Jody M.; Spotts, Erica L.; Reiss, David; Neiderhiser, Jenae M.

2013-01-01

Studies of adolescent or parent-based twins suggest that gene-environment correlation (rGE) is an important mechanism underlying parent-adolescent relationships. However, information on how parents' and children's genes and environments influence correlated parent "and" child behaviors is needed to distinguish types of rGE. The present…

Gene-Environment Interplay in Internalizing Disorders: Consistent Findings across Six Environmental Risk Factors

ERIC Educational Resources Information Center

Hicks, Brian M.; Dirago, Ana C.; Iacono, William G.; McGue, Matt

2009-01-01

Background: Behavior genetic methods can help to elucidate gene-environment (G-E) interplay in the development of internalizing (INT) disorders (i.e., major depression and anxiety disorders). To date, however, no study has conducted a comprehensive analysis examining multiple environmental risk factors with the purpose of delineating general…

Gene-Environment Interaction and Breast Cancer on Long Island, NY

DTIC Science & Technology

2008-05-01

Report on Human Exposure to Environmental Chemicals, 2005; 6–11-year age group, 2001–2002 survey years; 1999–2000 survey years used for 2,4-DCP and 2,5-DCP...Examination Survey (NHANES) conducted between 1999 and 2002 (Centers for Disease Control and Prevention, 2005). NHANES is designed to collect data on the...The CDC has previ- ously reported concentrations in child partici- pants in the National Health and Nutrition Examination Survey (NHANES) for some

Case-only gene-environment interaction between ALAD tagSNPs and occupational lead exposure in prostate cancer.

PubMed

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

2014-05-01

Black men have historically had higher blood lead levels than white men in the U.S. and have the highest incidence of prostate cancer in the world. Inorganic lead has been classified as a probable human carcinogen. Lead (Pb) inhibits delta-aminolevulinic acid dehydratase (ALAD), a gene recently implicated in other genitourinary cancers. The ALAD enzyme is involved in the second step of heme biosynthesis and is an endogenous inhibitor of the 26S proteasome, a master system for protein degradation and a current target of cancer therapy. Using a case-only study design, we assessed potential gene-environment (G × E) interactions between lifetime occupational Pb exposure and 11 tagSNPs within ALAD in black (N = 260) and white (N = 343) prostate cancer cases. Two ALAD tagSNPs in high linkage disequilibrium showed significant interaction with high Pb exposure among black cases (rs818684 interaction odds ratio or IOR = 2.73, 95% CI 1.43-5.22, P = 0.002; rs818689 IOR = 2.20, 95% CI 1.15-4.21, P = 0.017) and an additional tagSNP, rs2761016, showed G × E interaction with low Pb exposure (IOR = 2.08, 95% CI 1.13-3.84, P = 0.019). Further, the variant allele of rs818684 was associated with a higher Gleason grade in those with high Pb exposure among both blacks (OR 3.96, 95% CI 1.01-15.46, P = 0.048) and whites (OR 2.95, 95% CI 1.18-7.39, P = 0.020). Genetic variation in ALAD may modify associations between Pb and prostate cancer. Additional studies of ALAD, Pb, and prostate cancer are warranted and should include black men. Prostate 74:637-646, 2014. © 2014 Wiley Periodicals, Inc. © 2014 Wiley Periodicals, Inc.

Interaction between polygenic risk for cigarette use and environmental exposures in the Detroit Neighborhood Health Study.

PubMed

Meyers, J L; Cerdá, M; Galea, S; Keyes, K M; Aiello, A E; Uddin, M; Wildman, D E; Koenen, K C

2013-08-13

Cigarette smoking is influenced both by genetic and environmental factors. Until this year, all large-scale gene identification studies on smoking were conducted in populations of European ancestry. Consequently, the genetic architecture of smoking is not well described in other populations. Further, despite a rich epidemiologic literature focused on the social determinants of smoking, few studies have examined the moderation of genetic influences (for example, gene-environment interactions) on smoking in African Americans. In the Detroit Neighborhood Health Study (DNHS), a sample of randomly selected majority African American residents of Detroit, we constructed a genetic risk score (GRS), in which we combined top (P-value <5 × 10(-7)) genetic variants from a recent meta-analysis conducted in a large sample of African Americans. Using regression (effective n=399), we first tested for association between the GRS and cigarettes per day, attempting to replicate the findings from the meta-analysis. Second, we examined interactions with three social contexts that may moderate the genetic association with smoking: traumatic events, neighborhood social cohesion and neighborhood physical disorder. Among individuals who had ever smoked cigarettes, the GRS significantly predicted the number of cigarettes smoked per day and accounted for ~3% of the overall variance in the trait. Significant interactions were observed between the GRS and number of traumatic events experienced, as well as between the GRS and average neighborhood social cohesion; the association between genetic risk and smoking was greater among individuals who had experienced an increased number of traumatic events in their lifetimes, and diminished among individuals who lived in a neighborhood characterized by greater social cohesion. This study provides support for the utility of the GRS as an alternative approach to replication of common polygenic variation, and in gene-environment interaction, for smoking behaviors. In addition, this study indicates that environmental determinants have the potential to both exacerbate (traumatic events) and diminish (neighborhood social cohesion) genetic influences on smoking behaviors.

Gene Environment Interactions and Predictors of Colorectal Cancer in Family-Based, Multi-Ethnic Groups.

PubMed

Shiao, S Pamela K; Grayson, James; Yu, Chong Ho; Wasek, Brandi; Bottiglieri, Teodoro

2018-02-16

For the personalization of polygenic/omics-based health care, the purpose of this study was to examine the gene-environment interactions and predictors of colorectal cancer (CRC) by including five key genes in the one-carbon metabolism pathways. In this proof-of-concept study, we included a total of 54 families and 108 participants, 54 CRC cases and 54 matched family friends representing four major racial ethnic groups in southern California (White, Asian, Hispanics, and Black). We used three phases of data analytics, including exploratory, family-based analyses adjusting for the dependence within the family for sharing genetic heritage, the ensemble method, and generalized regression models for predictive modeling with a machine learning validation procedure to validate the results for enhanced prediction and reproducibility. The results revealed that despite the family members sharing genetic heritage, the CRC group had greater combined gene polymorphism rates than the family controls ( p < 0.05), on MTHFR C677T , MTR A2756G , MTRR A66G, and DHFR 19 bp except MTHFR A1298C. Four racial groups presented different polymorphism rates for four genes (all p < 0.05) except MTHFR A1298C. Following the ensemble method, the most influential factors were identified, and the best predictive models were generated by using the generalized regression models, with Akaike's information criterion and leave-one-out cross validation methods. Body mass index (BMI) and gender were consistent predictors of CRC for both models when individual genes versus total polymorphism counts were used, and alcohol use was interactive with BMI status. Body mass index status was also interactive with both gender and MTHFR C677T gene polymorphism, and the exposure to environmental pollutants was an additional predictor. These results point to the important roles of environmental and modifiable factors in relation to gene-environment interactions in the prevention of CRC.

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

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

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

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

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 andmore » 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.« less

Environmental factors as modulators of neurodegeneration: insights from gene-environment interactions in Huntington's disease.

PubMed

Mo, Christina; Hannan, Anthony J; Renoir, Thibault

2015-05-01

Unlike many other neurodegenerative diseases with established gene-environment interactions, Huntington's disease (HD) is viewed as a disorder governed by genetics. The cause of the disease is a highly penetrant tandem repeat expansion encoding an extended polyglutamine tract in the huntingtin protein. In the year 2000, a pioneering study showed that the disease could be delayed in transgenic mice by enriched housing conditions. This review describes subsequent human and preclinical studies identifying environmental modulation of motor, cognitive, affective and other symptoms found in HD. Alongside the behavioral observations we also discuss potential mechanisms and the relevance to other neurodegenerative disorders, including Alzheimer's and Parkinson's disease. In mouse models of HD, increased sensorimotor and cognitive stimulation can delay or ameliorate various endophenotypes. Potential mechanisms include increased trophic support, synaptic plasticity, adult neurogenesis, and other forms of experience-dependent cellular plasticity. Subsequent clinical investigations support a role for lifetime activity levels in modulating the onset and progression of HD. Stress can accelerate memory and olfactory deficits and exacerbate cellular dysfunctions in HD mice. In the absence of effective treatments to slow the course of HD, environmental interventions offer feasible approaches to delay the disease, however further preclinical and human studies are needed in order to generate clinical recommendations. Environmental interventions could be combined with future pharmacological therapies and stimulate the identification of enviromimetics, drugs which mimic or enhance the beneficial effects of cognitive stimulation and physical activity. Copyright © 2015. Published by Elsevier Ltd.

Genotype-Based Association Mapping of Complex Diseases: Gene-Environment Interactions with Multiple Genetic Markers and Measurement Error in Environmental Exposures

PubMed Central

Lobach, Irvna; Fan, Ruzone; Carroll, Raymond T.

2011-01-01

With the advent of dense single nucleotide polymorphism genotyping, population-based association studies have become the major tools for identifying human disease genes and for fine gene mapping of complex traits. We develop a genotype-based approach for association analysis of case-control studies of gene-environment interactions in the case when environmental factors are measured with error and genotype data are available on multiple genetic markers. To directly use the observed genotype data, we propose two genotype-based models: genotype effect and additive effect models. Our approach offers several advantages. First, the proposed risk functions can directly incorporate the observed genotype data while modeling the linkage disequihbrium information in the regression coefficients, thus eliminating the need to infer haplotype phase. Compared with the haplotype-based approach, an estimating procedure based on the proposed methods can be much simpler and significantly faster. In addition, there is no potential risk due to haplotype phase estimation. Further, by fitting the proposed models, it is possible to analyze the risk alleles/variants of complex diseases, including their dominant or additive effects. To model measurement error, we adopt the pseudo-likelihood method by Lobach et al. [2008]. Performance of the proposed method is examined using simulation experiments. An application of our method is illustrated using a population-based case-control study of association between calcium intake with the risk of colorectal adenoma development. PMID:21031455

Environmental stress alters genetic regulation of novelty seeking in vervet monkeys.

PubMed

Fairbanks, L A; Bailey, J N; Breidenthal, S E; Laudenslager, M L; Kaplan, J R; Jorgensen, M J

2011-08-01

Considerable attention has been paid to identifying genetic influences and gene-environment interactions that increase vulnerability to environmental stressors, with promising but inconsistent results. A nonhuman primate model is presented here that allows assessment of genetic influences in response to a stressful life event for a behavioural trait with relevance for psychopathology. Genetic and environmental influences on free-choice novelty seeking behaviour were assessed in a pedigreed colony of vervet monkeys before and after relocation from a low stress to a higher stress environment. Heritability of novelty seeking scores, and genetic correlations within and between environments were conducted using variance components analysis. The results showed that novelty seeking was markedly inhibited in the higher stress environment, with effects persisting across a 2-year period for adults but not for juveniles. There were significant genetic contributions to novelty seeking scores in each year (h(2) = 0.35-0.43), with high genetic correlations within each environment (rhoG > 0.80) and a lower genetic correlation (rhoG = 0.35, non-significant) between environments. There were also significant genetic contributions to individual change scores from before to after the move (h(2) = 0.48). These results indicate that genetic regulation of novelty seeking was modified by the level of environmental stress, and they support a role for gene-environment interactions in a behavioural trait with relevance for mental health. © 2011 The Authors. Genes, Brain and Behavior © 2011 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Childhood problem behavior and parental divorce: evidence for gene-environment interaction.

PubMed

Robbers, Sylvana; van Oort, Floor; Huizink, Anja; Verhulst, Frank; van Beijsterveldt, Catharina; Boomsma, Dorret; Bartels, Meike

2012-10-01

The importance of genetic and environmental influences on children's behavioral and emotional problems may vary as a function of environmental exposure. We previously reported that 12-year-olds with divorced parents showed more internalizing and externalizing problems than children with married parents, and that externalizing problems in girls precede and predict later parental divorce. The aim of the current study was to investigate as to whether genetic and environmental influences on internalizing and externalizing problems were different for children from divorced versus non-divorced families. Maternal ratings on internalizing and externalizing problems were collected with the Child Behavior Checklist in 4,592 twin pairs at ages 3 and 12 years, of whom 367 pairs had experienced a parental divorce between these ages. Variance in internalizing and externalizing problems at ages 3 and 12 was analyzed with biometric models in which additive genetic and environmental effects were allowed to depend on parental divorce and sex. A difference in the contribution of genetic and environmental influences between divorced and non-divorced groups would constitute evidence for gene-environment interaction. For both pre- and post-divorce internalizing and externalizing problems, the total variances were larger for children from divorced families, which was mainly due to higher environmental variances. As a consequence, heritabilities were lower for children from divorced families, and the relative contributions of environmental influences were higher. Environmental influences become more important in explaining variation in children's problem behaviors in the context of parental divorce.

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

PubMed

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

2015-10-01

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 studied (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 dizygotic (DZ) and 803 monozygotic (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.

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

War exposure, 5-HTTLPR genotype and lifetime risk of depression

PubMed Central

Artero, Sylvaine; Touchon, Jacques; Dupuy, Anne-Marie; Malafosse, Alain; Ritchie, Karen

2011-01-01

Background in 1962, during the Algerian war, approximately one and a half million French people living in Algeria were repatriated to France in very poor and often life-threatening conditions. These subjects constitute a cohort for the study of the long term impact of gene-environment interaction on depression. Aims To examine the interaction between a highly stressful life event and subsequent depression, and its modulation by the serotonin transporter gene (5-HTTLPR). Method A community sample of elderly persons aged 65 years and over residing in the Montpellier region of the South of France was randomly recruited from electoral rolls. Genotyping was performed on 248 repatriated persons and 632 controls. Current and lifetime major and minor depressions were assessed according to DSM-IV criteria. Results A significant relationship was observed between exposure to repatriation and subsequent depression (p<0.002), but there was no significant effect of gene alone (p=0.62). After controlling for age, gender, education, disability, recent life events and cognitive function, the gene-environment interaction (Repatriation X 5-HTTLPR) was globally significant (p<0.002; OR= 3.21 [2.48–5.12]). Subjects carrying the two short ( S ) alleles of 5-HTTLPR were observed to be at higher risk (p<0.005; OR=2.34 [1.24–4.32]) and particularly when the repatriation occurred before the age of 35 (p<0.002; OR=2.91 [1.44–5.88]) but did not reach significance in subjects who were older at the time of the event (p=0.067). Conclusion The association between depression and war repatriation is significantly modulated by 5-HTTLPR genotype but this appears to occur only in persons who were younger at the time of exposure. PMID:21593514

War exposure, 5-HTTLPR genotype and lifetime risk of depression.

PubMed

Artero, Sylvaine; Touchon, Jacques; Dupuy, Anne-Marie; Malafosse, Alain; Ritchie, Karen

2011-07-01

In 1962 approximately 1.5 million French people living in Algeria were repatriated to France in very poor and often life-threatening conditions. These people constitute a cohort for the study of the long-term impact of gene-environment interaction on depression. To examine the interaction between a highly stressful life event and subsequent depression, and its modulation by a length polymorphism of the serotonin transporter gene (5-HTTLPR). A community sample of people aged 65 years and over residing in the Montpellier region of the south of France was randomly recruited from electoral rolls. Genotyping was performed on 248 repatriated persons and 632 controls. Current and lifetime major and minor depressive disorders were assessed according to DSM-IV criteria. A significant relationship was observed between exposure to repatriation and subsequent depression (P<0.002), but there was no significant effect of gene alone (P = 0.62). After controlling for age, gender, education, disability, recent life events and cognitive function, the gene-environment interaction (repatriation × 5-HTTLPR) was globally significant (P<0.002; OR = 3.21, 95% CI 2.48-5.12). Individuals carrying the two short (s) alleles of 5-HTTLPR were observed to be at higher risk (P<0.005; OR = 2.34, 95% CI 1.24-4.32), particularly when repatriation occurred before age 35 years (P<0.002; OR = 2.91, 95% CI 1.44-5.88), but this did not reach significance in those who were older at the time of the event (P = 0.067). The association between depression and war repatriation was significantly modulated by 5-HTTLPR genotype but this appeared to occur only in people who were younger at the time of exposure.

Vulnerability or Sensitivity to the Environment? Methodological Issues, Trends, and Recommendations in Gene-Environment Interactions Research in Human Behavior.

PubMed

Leighton, Caroline; Botto, Alberto; Silva, Jaime R; Jiménez, Juan Pablo; Luyten, Patrick

2017-01-01

Research on the potential role of gene-environment interactions (GxE) in explaining vulnerability to psychopathology in humans has witnessed a shift from a diathesis-stress perspective to differential susceptibility approaches. This paper critically reviews methodological issues and trends in this body of research. Databases were screened for studies of GxE in the prediction of personality traits, behavior, and mental health disorders in humans published between January 2002 and January 2015. In total, 315 papers were included. Results showed that 34 candidate genes have been included in GxE studies. Independent of the type of environment studied (early or recent life events, positive or negative environments), about 67-83% of studies have reported significant GxE interactions, which is consistent with a social susceptibility model. The percentage of positive results does not seem to differ depending on the gene studied, although publication bias might be involved. However, the number of positive findings differs depending on the population studied (i.e., young adults vs. older adults). Methodological considerations limit the ability to draw strong conclusions, particularly as almost 90% ( n  = 283/315) of published papers are based on samples from North America and Europe, and about 70% of published studies (219/315) are based on samples that were also used in other reports. At the same time, there are clear indications of methodological improvements over time, as is shown by a significant increase in longitudinal and experimental studies as well as in improved minimum genotyping. Recommendations for future research, such as minimum quality assessment of genes and environmental factors, specifying theoretical models guiding the study, and taking into account of cultural, ethnic, and lifetime perspectives, are formulated.

Family conflict interacts with genetic liability in predicting childhood and adolescent depression.

PubMed

Rice, Frances; Harold, Gordon T; Shelton, Katherine H; Thapar, Anita

2006-07-01

To test for gene-environment interaction with depressive symptoms and family conflict. Specifically, to first examine whether the influence of family conflict in predicting depressive symptoms is increased in individuals at genetic risk of depression. Second, to test whether the genetic component of variance in depressive symptoms increases as levels of family conflict increase. A longitudinal twin design was used. Children ages 5 to 16 were reassessed approximately 3 years later to test whether the influence of family conflict in predicting depressive symptoms varied according to genetic liability. The conflict subscale of the Family Environment Scale was used to assess family conflict and the Mood and Feelings Questionnaire was used to assess depressive symptoms. The response rate to the questionnaire at time 1 was 73% and 65% at time 2. Controlling for initial symptoms levels (i.e., internalizing at time 1), primary analyses were conducted using ordinary least-squares multiple regression. Structural equation models, using raw score maximum likelihood estimation, were also fit to the data for the purpose of model fit comparison. Results suggested significant gene-environment interaction specifically with depressive symptoms and family conflict. Genetic factors were of greater importance in the etiology of depressive symptoms where levels of family conflict were high. The effects of family conflict on depressive symptoms were greater in children and adolescents at genetic risk of depression. The present results suggest that children with a family history of depression may be at an increased risk of developing depressive symptoms in response to family conflict. Intervention programs that incorporate one or more family systems may be of benefit in alleviating the adverse effect of negative family factors on children.

Interaction effects between the 5-hydroxy tryptamine transporter-linked polymorphic region (5-HTTLPR) genotype and family conflict on adolescent alcohol use and misuse.

PubMed

Kim, Jueun; Park, Aesoon; Glatt, Stephen J; Eckert, Tanya L; Vanable, Peter A; Scott-Sheldon, Lori A J; Carey, Kate B; Ewart, Craig K; Carey, Michael P

2015-02-01

To investigate whether the effects of family conflict on adolescent drinking differed as a function of 5-hydroxy tryptamine transporter-linked polymorphic region (5-HTTLPR) genotype cross-sectionally and prospectively in two independent samples of adolescents. Path analysis and multi-group analysis of two prospective datasets were conducted. United States and United Kingdom. Sample 1 was 175 adolescents in the United States (mean age = 15 at times 1 and 2 with a 6-month interval); Sample 2 was 4916 adolescents in the United Kingdon (mean age = 12 at time 1 and 15 at time 2). In both samples, demographics, tri-allelic 5-HTTLPR genotype and perceived family conflict were assessed at time 1. Alcohol use (frequency of drinking) and alcohol misuse (frequency of intoxication, frequency of drinking three or more drinks, maximum number of drinks) were assessed at times 1 and 2. A significant gene-environment interaction on alcohol misuse at time 1 was found in both sample 1 (β = 0.57, P = 0.001) and sample 2 (β = 0.19, P = 0.01), indicating that the 5-HTTLPR low-activity allele carriers exposed to higher levels of family conflict were more likely to engage in alcohol misuse than non-carriers. A significant gene-environment interaction effect on change in alcohol misuse over time was found only in sample 1 (β = 0.48, P = 0.04) but not in sample 2. Compared with non-carriers, adolescents carrying the 5-HTTLPR low-activity allele are more susceptible to the effects of family conflict on alcohol misuse. © 2014 Society for the Study of Addiction.

Impact of sample collection participation on the validity of estimated measures of association in the National Birth Defects Prevention Study when assessing gene-environment interactions.

PubMed

Jenkins, Mary M; Reefhuis, Jennita; Herring, Amy H; Honein, Margaret A

2017-12-01

To better understand the impact that nonresponse for specimen collection has on the validity of estimates of association, we examined associations between self-reported maternal periconceptional smoking, folic acid use, or pregestational diabetes mellitus and six birth defects among families who did and did not submit buccal cell samples for DNA following a telephone interview as part of the National Birth Defects Prevention Study (NBDPS). Analyses included control families with live born infants who had no birth defects (N = 9,465), families of infants with anorectal atresia or stenosis (N = 873), limb reduction defects (N = 1,037), gastroschisis (N = 1,090), neural tube defects (N = 1,764), orofacial clefts (N = 3,836), or septal heart defects (N = 4,157). Estimated dates of delivery were between 1997 and 2009. For each exposure and birth defect, odds ratios and 95% confidence intervals were calculated using logistic regression stratified by race-ethnicity and sample collection status. Tests for interaction were applied to identify potential differences between estimated measures of association based on sample collection status. Significant differences in estimated measures of association were observed in only four of 48 analyses with sufficient sample sizes. Despite lower than desired participation rates in buccal cell sample collection, this validation provides some reassurance that the estimates obtained for sample collectors and noncollectors are comparable. These findings support the validity of observed associations in gene-environment interaction studies for the selected exposures and birth defects among NBDPS participants who submitted DNA samples. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Sleep quality and diurnal preference in a sample of young adults: associations with 5HTTLPR, PER3, and CLOCK 3111.

PubMed

Barclay, Nicola L; Eley, Thalia C; Mill, Jonathan; Wong, Chloe C Y; Zavos, Helena M S; Archer, Simon N; Gregory, Alice M

2011-09-01

Research investigating associations between specific genes and individual differences with regards to the quality and timing of sleep has primarily focussed on serotonin-related and clock genes. However, there are only a few studies of this type and most of those to date have not considered the possibility of gene-environment interaction. Here, we describe associations between sleep quality and diurnal preference and three functional polymorphisms: 5HTTLPR, PERIOD3, and CLOCK 3111. Furthermore, we assessed whether associations between genotypes and sleep phenotypes were moderated by negative life events-a test of gene-environment interaction. DNA from buccal swabs was collected from 947 individuals [mean age = 20.3 years (SD = 1.77), age range = 18-27 years; 61.8% female] and genotyped for the three polymorphisms. Participants completed the Pittsburgh Sleep Quality Index and the Morningness-Eveningness Questionnaire. There was a significant main effect of 5HTTLPR on sleep quality, indicating that "long-long" homozygotes experienced significantly poorer sleep quality (mean = 6.35, SD = 3.36) than carriers of at least one "short" allele (mean = 5.67, SD = 2.96; β = -0.34, P = 0.005). There were no main effects of 5HTTLPR on diurnal preference; no main effects of PERIOD3 or CLOCK on sleep quality or diurnal preference; and no significant interactions with negative life events. The main effect of the "long" 5HTTLPR allele contradicts previous research, suggesting that perhaps the effects of this gene are heterogeneous in different populations. Failure to replicate previous research in relation to PERIOD3 and CLOCK concurs with previous research suggesting that the effects of these genes are small and may be related to population composition. Copyright © 2011 Wiley-Liss, Inc.

Interactive effect of genetic susceptibility with height, body mass index, and hormone replacement therapy on the risk of breast cancer.

PubMed

Harlid, Sophia; Butt, Salma; Ivarsson, Malin I L; Eyfjörd, Jorunn Erla; Lenner, Per; Manjer, Jonas; Dillner, Joakim; Carlson, Joyce

2012-06-22

Breast cancer today has many established risk factors, both genetic and environmental, but these risk factors by themselves explain only part of the total cancer incidence. We have investigated potential interactions between certain known genetic and phenotypic risk factors, specifically nine single nucleotide polymorphisms (SNPs) and height, body mass index (BMI) and hormone replacement therapy (HRT). We analyzed samples from three different study populations: two prospectively followed Swedish cohorts and one Icelandic case-control study. Totally 2884 invasive breast cancer cases and 4508 controls were analysed in the study. Genotypes were determined using Mass spectrometry-Maldi-TOF and phenotypic variables were derived from measurements and/or questionnaires. Odds Ratios and 95% confidence intervals were calculated using unconditional logistic regression with the inclusion of an interaction term in the logistic regression model. One SNP (rs851987 in ESR1) tended to interact with height, with an increasingly protective effect of the major allele in taller women (p = 0.007) and rs13281615 (on 8q24) tended to confer risk only in non users of HRT (p-for interaction = 0.03). There were no significant interactions after correction for multiple testing. We conclude that much larger sample sets would be necessary to demonstrate interactions between low-risk genetic polymorphisms and the phenotypic variables height, BMI and HRT on the risk for breast cancer. However the present hypothesis-generating study has identified tendencies that would be of interest to evaluate for gene-environment interactions in independent materials.

Gene × environment interaction on intergroup bias: the role of 5-HTTLPR and perceived outgroup threat.

PubMed

Cheon, Bobby K; Livingston, Robert W; Hong, Ying-Yi; Chiao, Joan Y

2014-09-01

Perceived threat from outgroups is a consistent social-environmental antecedent of intergroup bias (i.e. prejudice, ingroup favoritism). The serotonin transporter gene polymorphism (5-HTTLPR) has been associated with individual variations in sensitivity to context, particularly stressful and threatening situations. Here, we examined how 5-HTTLPR and environmental factors signaling potential outgroup threat dynamically interact to shape intergroup bias. Across two studies, we provide novel evidence for a gene-environment interaction on the acquisition of intergroup bias and prejudice. Greater exposure to signals of outgroup threat, such as negative prior contact with outgroups and perceived danger from the social environment, were more predictive of intergroup bias among participants possessing at least one short allele (vs two long alleles) of 5-HTTLPR. Furthermore, this gene x environment interaction was observed for biases directed at diverse ethnic and arbitrarily-defined outgroups across measures reflecting intergroup biases in evaluation and discriminatory behavior. These findings reveal a candidate genetic mechanism for the acquisition of intergroup bias, and suggest that intergroup bias is dually inherited and transmitted through the interplay of social (i.e. contextual cues of outgroup threat) and biological mechanisms (i.e. genetic sensitivity toward threatening contexts) that regulate perceived intergroup threats. © The Author (2013). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

A mechanistic explanation of popularity: genes, rule breaking, and evocative gene-environment correlations.

PubMed

Burt, Alexandra

2009-04-01

Previous work has suggested that the serotonergic system plays a key role in "popularity" or likeability. A polymorphism within the 5HT-sub(2A) serotonin receptor gene (-G1438A) has also been associated with popularity, suggesting that genes may predispose individuals to particular social experiences. However, because genes cannot code directly for others' reactions, any legitimate association should be mediated via the individual's behavior (i.e., genes-->behaviors-->social consequences), a phenomenon referred to as an evocative gene-environment correlation (rGE). The current study aimed to identify one such mediating behavior. The author focused on rule breaking given its prior links to both the serotonergic system and to increased popularity during adolescence. Two samples of previously unacquainted late-adolescent boys completed a peer-based interaction paradigm designed to assess their popularity. Analyses revealed that rule breaking partially mediated the genetic effect on popularity, thereby furthering our understanding of the biological mechanisms that underlie popularity. Moreover, the present results represent the first meaningfully explicated evidence that genes predispose individuals not only to particular behaviors but also to the social consequences of those behaviors. (c) 2009 APA, all rights reserved.

Early warm-rewarding parenting moderates the genetic contributions to callous-unemotional traits in childhood.

PubMed

Henry, Jeffrey; Dionne, Ginette; Viding, Essi; Vitaro, Frank; Brendgen, Mara; Tremblay, Richard E; Boivin, Michel

2018-04-23

Previous gene-environment interaction studies of CU traits have relied on the candidate gene approach, which does not account for the entire genetic load of complex phenotypes. Moreover, these studies have not examined the role of positive environmental factors such as warm/rewarding parenting. The aim of the present study was to determine whether early warm/rewarding parenting moderates the genetic contributions (i.e., heritability) to callous-unemotional (CU) traits at school age. Data were collected in a population sample of 662 twin pairs (Quebec Newborn Twin Study - QNTS). Mothers reported on their warm/rewarding parenting. Teachers assessed children's CU traits. These reports were subjected to twin modeling. Callous-unemotional traits were highly heritable, with the remaining variance accounted for by nonshared environmental factors. Warm/rewarding parenting significantly moderated the role of genes in CU traits; heritability was lower when children received high warm/rewarding parenting than when they were exposed to low warm/rewarding parenting. High warm/rewarding parenting may partly impede the genetic expression of CU traits. Developmental models of CU traits need to account for such gene-environment processes. © 2018 Association for Child and Adolescent Mental Health.

Gene-based interaction analysis shows GABAergic genes interacting with parenting in adolescent depressive symptoms.

PubMed

Van Assche, Evelien; Moons, Tim; Cinar, Ozan; Viechtbauer, Wolfgang; Oldehinkel, Albertine J; Van Leeuwen, Karla; Verschueren, Karine; Colpin, Hilde; Lambrechts, Diether; Van den Noortgate, Wim; Goossens, Luc; Claes, Stephan; van Winkel, Ruud

2017-12-01

Most gene-environment interaction studies (G × E) have focused on single candidate genes. This approach is criticized for its expectations of large effect sizes and occurrence of spurious results. We describe an approach that accounts for the polygenic nature of most psychiatric phenotypes and reduces the risk of false-positive findings. We apply this method focusing on the role of perceived parental support, psychological control, and harsh punishment in depressive symptoms in adolescence. Analyses were conducted on 982 adolescents of Caucasian origin (M age (SD) = 13.78 (.94) years) genotyped for 4,947 SNPs in 263 genes, selected based on a literature survey. The Leuven Adolescent Perceived Parenting Scale (LAPPS) and the Parental Behavior Scale (PBS) were used to assess perceived parental psychological control, harsh punishment, and support. The Center for Epidemiologic Studies Depression Scale (CES-D) was the outcome. We used gene-based testing taking into account linkage disequilibrium to identify genes containing SNPs exhibiting an interaction with environmental factors yielding a p-value per single gene. Significant results at the corrected p-value of p < 1.90 × 10 -4 were examined in an independent replication sample of Dutch adolescents (N = 1354). Two genes showed evidence for interaction with perceived support: GABRR1 (p = 4.62 × 10 -5 ) and GABRR2 (p = 9.05 × 10 -6 ). No genes interacted significantly with psychological control or harsh punishment. Gene-based analysis was unable to confirm the interaction of GABRR1 or GABRR2 with support in the replication sample. However, for GABRR2, but not GABRR1, the correlation of the estimates between the two datasets was significant (r (46) = .32; p = .027) and a gene-based analysis of the combined datasets supported GABRR2 × support interaction (p = 1.63 × 10 -4 ). We present a gene-based method for gene-environment interactions in a polygenic context and show that genes interact differently with particular aspects of parenting. This accentuates the importance of polygenic approaches and the need to accurately assess environmental exposure in G × E. © 2017 Association for Child and Adolescent Mental Health.

Links between Friends' Physical Aggression and Adolescents' Physical Aggression: What Happens If Gene-Environment Correlations are Controlled?

ERIC Educational Resources Information Center

Vitaro, Frank; Brendgen, Mara; Girard, Alain; Dionne, Ginette; Tremblay, Richard E.; Boivin, Michel

2016-01-01

Exposure to deviant friends has been found to be a powerful source of influence on children's and adolescents' aggressive behavior. However, the contribution of deviant friends may have been overestimated because of a possible non-accounted gene-environment correlation (rGE). In this study, we used a cross-lagged design to test whether friends'…

Cat exposure in early life decreases asthma risk from the 17q21 high-risk variant.

PubMed

Stokholm, Jakob; Chawes, Bo L; Vissing, Nadja; Bønnelykke, Klaus; Bisgaard, Hans

2018-05-01

Early-life exposure to cats and dogs has shown diverging associations with childhood asthma risk, and gene-environment interaction is one possible explanation. We investigated interactions between cat and dog exposure and single nucleotide polymorphism rs7216389 variants in the chromosome 17q21 locus, the strongest known genetic risk factor for childhood asthma. Genotyping was performed in 377 children from the at-risk Copenhagen Prospective Studies on Asthma in Childhood 2000 . The primary end point was the development of asthma until age 12 years. The secondary end point was the number of episodes with pneumonia and bronchiolitis from 0 to 3 years of age. Exposures included cat and dog ownership from birth and cat and dog allergen levels in bedding at age 1 year. Replication was performed in the unselected COPSAC 2010 cohort with follow-up until 5 years of age. Cat and/or dog exposure from birth was associated with a lower prevalence of asthma among children with the rs7216389 high-risk TT genotype (adjusted hazard ratio, 0.16; 95% CI, 0.04-0.71; P = .015), with no effect in those with the CC/CT genotype (adjusted P = .283), demonstrating interaction between cat and dog exposure and the rs7216389 genotype (adjusted P = .044). Cat allergen levels were inversely associated with asthma development in children with the TT genotype (adjusted hazard ratio, 0.83; 95% CI, 0.71-0.97; P = .022), supporting the cat-rs7216389 genotype interaction (adjusted P = .008). Dog allergen exposure did not show such interaction. Furthermore, the TT genotype was associated with higher risk of pneumonia and bronchiolitis, and this increased risk was likewise decreased in children exposed to cat. Replication showed similar effects on asthma risk. The observed gene-environment interaction suggests a role of early-life exposure, especially to cat, for attenuating the risk of childhood asthma, pneumonia, and bronchiolitis in genetically susceptible subjects. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Design of a Family Study Among High-Risk Caribbean Hispanics: The Northern Manhattan Family Study

PubMed Central

Sacco, Ralph L.; Sabala, Edison A.; Rundek, Tanja; Juo, Suh-Hang Hank; Huang, Jinaping Sam; DiTullio, Marco; Homma, Shunichi; Almonte, Katihurka; Lithgow, Carlos García; Boden-Albala, Bernadette

2008-01-01

Stroke continues to kill disproportionately more Blacks and Hispanics than Whites in the United States. Racial/ethnic variations in the incidence of stroke and prevalence of stroke risk factors are probably explained by both genetic and environmental influences. Family studies can help identify genetic predisposition to stroke and potential stroke precursors. Few studies have evaluated the heritability of these stroke risk factors among non-White populations, and none have focused on Caribbean Hispanic populations. The aim of the Northern Manhattan Family Study (NOMAFS) is to investigate the gene-environment interaction of stroke risk factors among Caribbean Hispanics. The unique recruitment and methodologic approaches used in this study are relevant to the design and conduct of genetic aggregation studies to investigate complex genetic disorders in non-White populations. The aim of this paper is to describe the NOMAFS and report enrollment and characteristics of the participants. The NO-MAFS will provide a data resource for the exploration of the genetic determinants of highly heritable stroke precursor phenotypes that are less complex than the stroke phenotype. Understanding the gene environment interaction is the critical next step toward the development of new and unique approaches to disease prevention and interventions. PMID:17682370

Genomic and Epigenomic Insights into Nutrition and Brain Disorders

PubMed Central

Dauncey, Margaret Joy

2013-01-01

Considerable evidence links many neuropsychiatric, neurodevelopmental and neurodegenerative disorders with multiple complex interactions between genetics and environmental factors such as nutrition. Mental health problems, autism, eating disorders, Alzheimer’s disease, schizophrenia, Parkinson’s disease and brain tumours are related to individual variability in numerous protein-coding and non-coding regions of the genome. However, genotype does not necessarily determine neurological phenotype because the epigenome modulates gene expression in response to endogenous and exogenous regulators, throughout the life-cycle. Studies using both genome-wide analysis of multiple genes and comprehensive analysis of specific genes are providing new insights into genetic and epigenetic mechanisms underlying nutrition and neuroscience. This review provides a critical evaluation of the following related areas: (1) recent advances in genomic and epigenomic technologies, and their relevance to brain disorders; (2) the emerging role of non-coding RNAs as key regulators of transcription, epigenetic processes and gene silencing; (3) novel approaches to nutrition, epigenetics and neuroscience; (4) gene-environment interactions, especially in the serotonergic system, as a paradigm of the multiple signalling pathways affected in neuropsychiatric and neurological disorders. Current and future advances in these four areas should contribute significantly to the prevention, amelioration and treatment of multiple devastating brain disorders. PMID:23503168

Effects of circadian clock genes and environmental factors on cognitive aging in old adults in a Taiwanese population.

PubMed

Lin, Eugene; Kuo, Po-Hsiu; Liu, Yu-Li; Yang, Albert C; Kao, Chung-Feng; Tsai, Shih-Jen

2017-04-11

Previous animal studies have indicated associations between circadian clock genes and cognitive impairment . In this study, we assessed whether 11 circadian clockgenes are associated with cognitive aging independently and/or through complex interactions in an old Taiwanese population. We also analyzed the interactions between environmental factors and these genes in influencing cognitive aging. A total of 634 Taiwanese subjects aged over 60 years from the Taiwan Biobank were analyzed. Mini-Mental State Examinations (MMSE) were administered to all subjects, and MMSE scores were used to evaluate cognitive function. Our data showed associations between cognitive aging and single nucleotide polymorphisms (SNPs) in 4 key circadian clock genes, CLOCK rs3749473 (p = 0.0017), NPAS2 rs17655330 (p = 0.0013), RORA rs13329238 (p = 0.0009), and RORB rs10781247 (p = 7.9 x 10-5). We also found that interactions between CLOCK rs3749473, NPAS2 rs17655330, RORA rs13329238, and RORB rs10781247 affected cognitive aging (p = 0.007). Finally, we investigated the influence of interactions between CLOCK rs3749473, RORA rs13329238, and RORB rs10781247 with environmental factors such as alcohol consumption, smoking status, physical activity, and social support on cognitive aging (p = 0.002 ~ 0.01). Our study indicates that circadian clock genes such as the CLOCK, NPAS2, RORA, and RORB genes may contribute to the risk of cognitive aging independently as well as through gene-gene and gene-environment interactions.

High-Risk Populations: The Pimas of Arizona and Mexico.

PubMed

Schulz, Leslie O; Chaudhari, Lisa S

2015-03-01

The purpose of this review is first, to broadly summarize the long-term commitment that began in 1965 to studying type 2 diabetes and obesity through the cooperation of the Pima Indians of Arizona, and second, to discuss the investigations with the Pima Indians of Mexico that started in 1991. The later studies emphasize gene-environment interactions in the pathogenesis of these metabolic disorders. Through the participation of both groups of Pimas, the researchers made key findings with regard to the epidemiology, physiology, clinical assessment and genetics of type 2 diabetes and obesity.

Association of Polyaminergic Loci With Anxiety, Mood Disorders, and Attempted Suicide

PubMed Central

Fiori, Laura M.; Wanner, Brigitte; Jomphe, Valérie; Croteau, Jordie; Vitaro, Frank

2010-01-01

Background The polyamine system has been implicated in a number of psychiatric conditions, which display both alterations in polyamine levels and altered expression of genes related to polyamine metabolism. Studies have identified associations between genetic variants in spermidine/spermine N1-acetyltransferase (SAT1) and both anxiety and suicide, and several polymorphisms appear to play important roles in determining gene expression. Methodology/Principal Findings We genotyped 63 polymorphisms, spread across four polyaminergic genes (SAT1, spermine synthase (SMS), spermine oxidase (SMOX), and ornithine aminotransferase like-1 (OATL1)), in 1255 French-Canadian individuals who have been followed longitudinally for 22 years. We assessed univariate associations with anxiety, mood disorders, and attempted suicide, as assessed during early adulthood. We also investigated the involvement of gene-environment interactions in terms of childhood abuse, and assessed internalizing and externalizing symptoms as endophenotypes mediating these interactions. Overall, each gene was associated with at least one main outcome: anxiety (SAT1, SMS), mood disorders (SAT1, SMOX), and suicide attempts (SAT1, OATL1). Several SAT1 polymorphisms displayed disease-specific risk alleles, and polymorphisms in this gene were involved in gene-gene interactions with SMS to confer risk for anxiety disorders, as well as gene-environment interactions between childhood physical abuse and mood disorders. Externalizing behaviors demonstrated significant mediation with regards to the association between OATL1 and attempted suicide, however there was no evidence that externalizing or internalizing behaviors were appropriate endophenotypes to explain the associations with mood or anxiety disorders. Finally, childhood sexual abuse did not demonstrate mediating influences on any of our outcomes. Conclusions/Significance These results demonstrate that genetic variants in polyaminergic genes are associated with psychiatric conditions, each of which involves a set of separate and distinct risk alleles. As several of these polymorphisms are associated with gene expression, these findings may provide mechanisms to explain the alterations in polyamine metabolism which have been observed in psychiatric disorders. PMID:21152090

Association of polyaminergic loci with anxiety, mood disorders, and attempted suicide.

PubMed

Fiori, Laura M; Wanner, Brigitte; Jomphe, Valérie; Croteau, Jordie; Vitaro, Frank; Tremblay, Richard E; Bureau, Alexandre; Turecki, Gustavo

2010-11-30

The polyamine system has been implicated in a number of psychiatric conditions, which display both alterations in polyamine levels and altered expression of genes related to polyamine metabolism. Studies have identified associations between genetic variants in spermidine/spermine N1-acetyltransferase (SAT1) and both anxiety and suicide, and several polymorphisms appear to play important roles in determining gene expression. We genotyped 63 polymorphisms, spread across four polyaminergic genes (SAT1, spermine synthase (SMS), spermine oxidase (SMOX), and ornithine aminotransferase like-1 (OATL1)), in 1255 French-Canadian individuals who have been followed longitudinally for 22 years. We assessed univariate associations with anxiety, mood disorders, and attempted suicide, as assessed during early adulthood. We also investigated the involvement of gene-environment interactions in terms of childhood abuse, and assessed internalizing and externalizing symptoms as endophenotypes mediating these interactions. Overall, each gene was associated with at least one main outcome: anxiety (SAT1, SMS), mood disorders (SAT1, SMOX), and suicide attempts (SAT1, OATL1). Several SAT1 polymorphisms displayed disease-specific risk alleles, and polymorphisms in this gene were involved in gene-gene interactions with SMS to confer risk for anxiety disorders, as well as gene-environment interactions between childhood physical abuse and mood disorders. Externalizing behaviors demonstrated significant mediation with regards to the association between OATL1 and attempted suicide, however there was no evidence that externalizing or internalizing behaviors were appropriate endophenotypes to explain the associations with mood or anxiety disorders. Finally, childhood sexual abuse did not demonstrate mediating influences on any of our outcomes. These results demonstrate that genetic variants in polyaminergic genes are associated with psychiatric conditions, each of which involves a set of separate and distinct risk alleles. As several of these polymorphisms are associated with gene expression, these findings may provide mechanisms to explain the alterations in polyamine metabolism which have been observed in psychiatric disorders.

The combined effects of the 5-HTTLPR and 5-HTR1A genes modulates the relationship between negative life events and major depressive disorder in a Chinese population.

PubMed

Zhang, Kerang; Xu, Qi; Xu, Yong; Yang, Hong; Luo, Jinxiu; Sun, Yan; Sun, Ning; Wang, Shan; Shen, Yan

2009-04-01

Serotonin transporter (5-HTT) and 5-HT receptor (5-HTR) involved in the neurotransmission of 5-HT may play an important role in the development of major depression disorder (MDD). Several lines of evidence suggested that the gene-environment interaction may confer susceptibility to depression. The aim of this study is to analyze the combined effect of four serotonin-related genes and two environmental factors on MDD in a Chinese population. This study recruited a total of 401 patients with MDD and 391 age- and gender-matched control subjects. They were all Chinese Han origin. Negative life events and objective social supports were assessed using standard rating scales. Six polymorphisms in the four serotonin-related genes (5-HTT, 5-HTR1A, 5-HTR1B and 5-HTR2A) were selected to detect. The analyses of the gene-environment interactions were performed by the Multifactor Dimensionality Reduction (MDR). Allelic associations between patients with MDD and controls were observed for the polymorphism of 5-HTTLPR and for rs6295 at the 5-HTR1A locus. The 5-HTTLPR polymorphism was associated with negative life events on MDD. A three-way interaction between the 5-HTTLPR polymorphism, rs6295 and negative life events on MDD was found in the individuals aged from 20 years to 29 years. In addition, the individuals carrying the L/L genotype of 5-HTTLPR could be susceptible to MDD when exposed to negative life events. The 5-HTTLPR polymorphism may modify the interaction between negative life events and MDD in the Chinese population. To our knowledge, this is the first report on the combined effect for the 5-HTTLPR polymorphism and 5-HTR1A genes on modifying the response to negative life events conferring susceptibility to MDD in the 20-29 year group.

In Black South Africans from Rural and Urban Communities, the 4G/5G PAI-1 Polymorphism Influences PAI-1 Activity, but Not Plasma Clot Lysis Time

PubMed Central

de Lange, Zelda; Rijken, Dingeman C.; Hoekstra, Tiny; Conradie, Karin R.; Jerling, Johann C.; Pieters, Marlien

2013-01-01

Data on genetic and environmental factors influencing PAI-1 levels and their consequent effect on clot lysis in black African populations are limited. We identified polymorphisms in the promoter area of the PAI-1 gene and determined their influence on PAI-1act levels and plasma clot lysis time (CLT). We also describe gene-environment interactions and the effect of urbanisation. Data from 2010 apparently healthy urban and rural black participants from the South African arm of the PURE study were cross-sectionally analysed. The 5G allele frequency of the 4G/5G polymorphism was 0.85. PAI-1act increased across genotypes in the urban subgroup (p = 0.009) but not significantly in the rural subgroup, while CLT did not differ across genotypes. Significant interaction terms were found between the 4G/5G polymorphism and BMI, waist circumference and triglycerides in determining PAI-1act, and between the 4G/5G polymorphism and fibrinogen and fibrinogen gamma prime in determining CLT. The C428T and G429A polymorphisms did not show direct relationships with PAI-1act or CLT but they did influence the association of other environmental factors with PAI-1act and CLT. Several of these interactions differed significantly between rural and urban subgroups, particularly in individuals harbouring the mutant alleles. In conclusion, although the 4G/5G polymorphism significantly affected PAI-1act, it contributed less than 1% to the PAI-1act variance. (Central) obesity was the biggest contributor to PAI-1act variance (12.5%). Urbanisation significantly influenced the effect of the 4G/5G polymorphism on PAI-1act as well as gene-environment interactions for the C428T and G429A genotypes in determining PAI-1act and CLT. PMID:24386152

In black South Africans from rural and urban communities, the 4G/5G PAI-1 polymorphism influences PAI-1 activity, but not plasma clot lysis time.

PubMed

de Lange, Zelda; Rijken, Dingeman C; Hoekstra, Tiny; Conradie, Karin R; Jerling, Johann C; Pieters, Marlien

2013-01-01

Data on genetic and environmental factors influencing PAI-1 levels and their consequent effect on clot lysis in black African populations are limited. We identified polymorphisms in the promoter area of the PAI-1 gene and determined their influence on PAI-1act levels and plasma clot lysis time (CLT). We also describe gene-environment interactions and the effect of urbanisation. Data from 2010 apparently healthy urban and rural black participants from the South African arm of the PURE study were cross-sectionally analysed. The 5G allele frequency of the 4G/5G polymorphism was 0.85. PAI-1act increased across genotypes in the urban subgroup (p = 0.009) but not significantly in the rural subgroup, while CLT did not differ across genotypes. Significant interaction terms were found between the 4G/5G polymorphism and BMI, waist circumference and triglycerides in determining PAI-1act, and between the 4G/5G polymorphism and fibrinogen and fibrinogen gamma prime in determining CLT. The C428T and G429A polymorphisms did not show direct relationships with PAI-1act or CLT but they did influence the association of other environmental factors with PAI-1act and CLT. Several of these interactions differed significantly between rural and urban subgroups, particularly in individuals harbouring the mutant alleles. In conclusion, although the 4G/5G polymorphism significantly affected PAI-1act, it contributed less than 1% to the PAI-1act variance. (Central) obesity was the biggest contributor to PAI-1act variance (12.5%). Urbanisation significantly influenced the effect of the 4G/5G polymorphism on PAI-1act as well as gene-environment interactions for the C428T and G429A genotypes in determining PAI-1act and CLT.

The interactions among organophosphate pesticide exposure, oxidative stress, and genetic polymorphisms of dopamine receptor D4 increase the risk of attention deficit/hyperactivity disorder in children.

PubMed

Chang, Chia-Huang; Yu, Ching-Jung; Du, Jung-Chieh; Chiou, Hsien-Chih; Chen, Hsin-Chang; Yang, Winnie; Chung, Ming-Yi; Chen, Ying-Sheue; Hwang, Betau; Mao, I-Fang; Chen, Mei-Lien

2018-01-01

The aim of this study was to clarify the association between organophosphate pesticides (OPs) and attention-deficit/hyperactivity disorder (ADHD) related to oxidative stress and genetic polymorphisms. This case-control study enrolled 93 children with ADHD and 112 control children in north Taiwan. Six dialkyl phosphate (DAP) metabolites of OPs and oxidative stress biomarkers were analyzed. Polymorphisms of the dopamine receptor D4 gene (DRD4) were identified. Children with ADHD had significantly higher dimethylphosphate (DMP, 236.69nmol/g cre. vs. 186.84nmol/g cre., p value = 0.01) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA, 28.95µg/g cre. vs. 16.55µg/g cre., p value<0.01) concentrations than control children. Children who carried DRD4 GA/AA genotypes (rs752306) were less likely than those who carried the DRD4 GG genotype to have ADHD (odds ratio [OR]: 0.45, 95% CI: 0.24-0.84). The estimated value of the AP (attributable proportion due to interaction) was 0.59 (95% CI: 0.13-1.05), indicating that 59% of ADHD cases in DMP-exposed children with the DRD4 GG genotype were due to the gene-environment interaction. After adjustment for other covariates, children who carried the DRD4 GG genotype, had been exposed to high DMP levels (more than the median), and had high HNE-MA levels had a significantly increased risk for developing ADHD (OR = 11.74, 95% CI: 2.12-65.04). This study indicated a gene-environment interaction in the risk of ADHD in children. The association between DMP and ADHD in children might relate to the mechanism of lipid peroxidation. Dose-response relationships and the combined effects of OPs, oxidative stress, and genetic polymorphism on ADHD should not be neglected. Copyright © 2017 Elsevier Inc. All rights reserved.

Gene-environment interactions controlling energy and glucose homeostasis and the developmental origins of obesity.

PubMed

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. Copyright © 2015 the American Physiological Society.

Modeling Gene-Environment Interactions With Quasi-Natural Experiments.

PubMed

Schmitz, Lauren; Conley, Dalton

2017-02-01

This overview develops new empirical models that can effectively document Gene × Environment (G×E) interactions in observational data. Current G×E studies are often unable to support causal inference because they use endogenous measures of the environment or fail to adequately address the nonrandom distribution of genes across environments, confounding estimates. Comprehensive measures of genetic variation are incorporated into quasi-natural experimental designs to exploit exogenous environmental shocks or isolate variation in environmental exposure to avoid potential confounders. In addition, we offer insights from population genetics that improve upon extant approaches to address problems from population stratification. Together, these tools offer a powerful way forward for G×E research on the origin and development of social inequality across the life course. © 2015 Wiley Periodicals, Inc.

Advances in asthma and allergy genetics in 2007.

PubMed

Vercelli, Donata

2008-08-01

This review discusses the main advances in the genetics of asthma and allergy published in the Journal in 2007. The association studies discussed herein addressed 3 main topics: the effect of the environment and gene-environment interactions on asthma/allergy susceptibility, the contribution of T(H)2 immunity gene variants to allergic inflammation, and the role of filaggrin mutations in atopic dermatitis and associated phenotypes. Other articles revealed novel, potentially important candidate genes or confirmed known ones. Collectively, the works published in 2007 reiterate that allergy and asthma are typical complex diseases; that is, they are disorders in which intricate interactions among environmental and genetic factors modify disease susceptibility by altering the fundamental structural and functional properties of target organs at critical developmental windows.

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. Copyright © 2014 Elsevier Inc. All rights reserved.

The death(s) of close friends and family moderate genetic influences on symptoms of major depressive disorder in adolescents.

PubMed

Gheyara, S; Klump, K L; McGue, M; Iacono, W G; Burt, S A

2011-04-01

Prior work has suggested that genetic influences on major depressive disorder (MDD) may be activated by the experience of negative life events. However, it is unclear whether these results persist when controlling for the possibility of confounding active gene-environment correlations (rGE). We examined a sample of 1230 adopted and biological siblings between the ages of 10 and 20 years from the Sibling Interaction and Behavior Study. MDD was measured via a lifetime DSM-IV symptom count. Number of deaths experienced served as our environmental risk experience. Because this variable is largely independent of the individual's choices/behaviors, we were able to examine gene-environment interactions while circumventing possible rGE confounds. Biometric analyses revealed pronounced linear increases in the magnitude of genetic influences on symptoms of MDD with the number of deaths experienced, such that genetic influences were estimated to be near-zero for those who had experienced no deaths but were quite large in those who had experienced two or more deaths (i.e. accounting for roughly two-thirds of the phenotypic variance). By contrast, shared and non-shared environmental influences on symptoms of MDD were not meaningfully moderated by the number of deaths experienced. Such results constructively replicate prior findings of genetic moderation of depressive symptoms by negative life events, thereby suggesting that this effect is not a function of active rGE confounds. Our findings are thus consistent with the notion that exposure to specific negative life events may serve to activate genetic risk for depression during adolescence.

Gene-environment interaction in atopic diseases: a population-based twin study of early-life exposures.

PubMed

Kahr, Niklas; Naeser, Vibeke; Stensballe, Lone Graff; Kyvik, Kirsten Ohm; Skytthe, Axel; Backer, Vibeke; Bønnelykke, Klaus; Thomsen, Simon Francis

2015-01-01

The development of atopic diseases early in life suggests an important role of perinatal risk factors. To study whether early-life exposures modify the genetic influence on atopic diseases in a twin population. Questionnaire data on atopic diseases from 850 monozygotic and 2279 like-sex dizygotic twin pairs, 3-9 years of age, from the Danish Twin Registry were cross-linked with data on prematurity, Cesarean section, maternal age at birth, parental cohabitation, season of birth and maternal smoking during pregnancy, from the Danish National Birth Registry. Significant predictors of atopic diseases were identified with logistic regression and subsequently tested for genetic effect modification using variance components analysis. After multivariable adjustment, prematurity (gestational age below 32 weeks) [odds ratio (OR) = 1.93, confidence interval (CI) = 1.45-2.56], Cesarean section (OR = 1.25, CI = 1.05-1.49) and maternal smoking during pregnancy (OR = 1.70, CI = 1.42-2.04) significantly influenced the risk of asthma, whereas none of the factors were significantly associated with atopic dermatitis and hay fever. Variance components analysis stratified by exposure status showed no significant change in the heritability of asthma according to the identified risk factors. In this population-based study of children, there was no evidence of genetic effect modification of atopic diseases by several identified early-life risk factors. The causal relationship between these risk factors and atopic diseases may therefore be mediated via mechanisms different from gene-environment interaction. © 2014 John Wiley & Sons Ltd.

Enacting the molecular imperative: How gene-environment interaction research links bodies and environments in the Post-Genomic Age

PubMed Central

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

2016-01-01

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

Semiparametric Bayesian analysis of gene-environment interactions with error in measurement of environmental covariates and missing genetic data.

PubMed

Lobach, Iryna; Mallick, Bani; Carroll, Raymond J

2011-01-01

Case-control studies are widely used to detect gene-environment interactions in the etiology of complex diseases. Many variables that are of interest to biomedical researchers are difficult to measure on an individual level, e.g. nutrient intake, cigarette smoking exposure, long-term toxic exposure. Measurement error causes bias in parameter estimates, thus masking key features of data and leading to loss of power and spurious/masked associations. We develop a Bayesian methodology for analysis of case-control studies for the case when measurement error is present in an environmental covariate and the genetic variable has missing data. This approach offers several advantages. It allows prior information to enter the model to make estimation and inference more precise. The environmental covariates measured exactly are modeled completely nonparametrically. Further, information about the probability of disease can be incorporated in the estimation procedure to improve quality of parameter estimates, what cannot be done in conventional case-control studies. A unique feature of the procedure under investigation is that the analysis is based on a pseudo-likelihood function therefore conventional Bayesian techniques may not be technically correct. We propose an approach using Markov Chain Monte Carlo sampling as well as a computationally simple method based on an asymptotic posterior distribution. 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 population-based case-control study of the association between calcium intake with the risk of colorectal adenoma development.

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. © 2014 The British Pharmacological Society.

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. Copyright © 2016 Elsevier Ltd. All rights reserved.

Advances in cancer epidemiology in Japan.

PubMed

Tanaka, Hideo

2014-02-15

Epidemiologists in Japan have been performing calculations to estimate nationwide cancer incidence rates as well as 5-year survival rates using population-based cancer registry data. There have been remarkable changes in cancer incidence and/or mortality in cancers of the lung, liver and stomach, which were thought to be attributed to the changing impact of exposure to cigarette smoking, chronic hepatitis C virus infection and Helicobacter pylori infection, respectively. In systematic reviews providing evidence in risk/protective factors for cancer sites using case-control and cohort studies of the Japanese population, there were associations between cancer sites (esophagus, stomach, colo-rectum, liver, pancreas, lung and breast) and various lifestyle factors. In the past 10 years, a hospital-based case-control study at Aichi Cancer Center provided valuable evidence of gene-environment interaction on the development of cancer [i.e., the effects of aldehyde dehydrogenase-2 (ALDH2) polymorphism and heavy alcohol drinking on esophageal cancer, ALDH2 polymorphism and smoking on lung cancer, methylenetetrahydrofolate reductase polymorphism and heavy alcohol drinking on pancreatic cancer]. The database with stored DNA was also used and identified seven loci containing significant but low-penetrance polymorphisms associated with the development of breast cancer. These findings together with established risk factors are likely to be useful to predict personalized breast cancer risk in East Asian women. In 2005, the Japan Multi-Institution Collaborative Cohort (J-MICC) study was launched to elucidate gene-environment interactions as well as to confirm preclinical diagnostic biomarkers of cancer. J-MICC, which has recruited 92,000 healthy individuals by the end of 2012, will follow the individuals until 2025. © 2013 UICC.

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. © 2011 Murdoch Childrens Research Institute.

Microsatellite polymorphisms associated with human behavioural and psychological phenotypes including a gene-environment interaction.

PubMed

Bagshaw, Andrew T M; Horwood, L John; Fergusson, David M; Gemmell, Neil J; Kennedy, Martin A

2017-02-03

The genetic and environmental influences on human personality and behaviour are a complex matter of ongoing debate. Accumulating evidence indicates that short tandem repeats (STRs) in regulatory regions are good candidates to explain heritability not accessed by genome-wide association studies. We tested for associations between the genotypes of four selected repeats and 18 traits relating to personality, behaviour, cognitive ability and mental health in a well-studied longitudinal birth cohort (n = 458-589) using one way analysis of variance. The repeats were a highly conserved poly-AC microsatellite in the upstream promoter region of the T-box brain 1 (TBR1) gene and three previously studied STRs in the activating enhancer-binding protein 2-beta (AP2-β) and androgen receptor (AR) genes. Where significance was found we used multiple regression to assess the influence of confounding factors. Carriers of the shorter, most common, allele of the AR gene's GGN microsatellite polymorphism had fewer anxiety-related symptoms, which was consistent with previous studies, but in our study this was not significant following Bonferroni correction. No associations with two repeats in the AP2-β gene withstood this correction. A novel finding was that carriers of the minor allele of the TBR1 AC microsatellite were at higher risk of conduct problems in childhood at age 7-9 (p = 0.0007, which did pass Bonferroni correction). Including maternal smoking during pregnancy (MSDP) in models controlling for potentially confounding influences showed that an interaction between TBR1 genotype and MSDP was a significant predictor of conduct problems in childhood and adolescence (p < 0.001), and of self-reported criminal behaviour up to age 25 years (p ≤ 0.02). This interaction remained significant after controlling for possible confounders including maternal age at birth, socio-economic status and education, and offspring birth weight. The potential functional importance of the TBR1 gene's promoter microsatellite deserves further investigation. Our results suggest that it participates in a gene-environment interaction with MDSP and antisocial behaviour. However, previous evidence that mothers who smoke during pregnancy carry genes for antisocial behaviour suggests that epistasis may influence the interaction.

Youth appraisals of inter-parental conflict and genetic and environmental contributions to attention-deficit hyperactivity disorder: examination of GxE effects in a twin sample.

PubMed

Nikolas, Molly; Klump, Kelly L; Burt, S Alexandra

2012-05-01

Identification of gene x environment interactions (GxE) for attention-deficit hyperactivity disorder (ADHD) is a crucial component to understanding the mechanisms underpinning the disorder, as prior work indicates large genetic influences and numerous environmental risk factors. Building on prior research, children's appraisals of self-blame were examined as a psychosocial moderator of latent etiological influences on ADHD via biometric twin models, which provide an omnibus test of GxE while managing the potential confound of gene-environment correlation. Participants were 246 twin pairs (total n = 492) ages 6-16 years. ADHD behaviors were assessed via mother report on the Child Behavior Checklist. To assess level of self-blame, each twin completed the Children's Perception of Inter-parental Conflict scale. Two biometric GxE models were fit to the data. The first model revealed a significant decrease in genetic effects and a significant increase in unique environmental influences on ADHD with increasing levels of self-blame. These results generally persisted even after controlling for confounding effects due to gene-environment correlation in the second model. Results suggest that appraisals of self-blame in relation to inter-parental conflict may act as a key moderator of etiological contributions to ADHD.

Youth Appraisals of Inter-parental Conflict and Genetic and Environmental Contributions to Attention-Deficit Hyperactivity Disorder: Examination of G×E Effects in a Twin Sample

PubMed Central

Klump, Kelly L.; Burt, S. Alexandra

2012-01-01

Identification of gene × environment interactions (GxE) for attention-deficit hyperactivity disorder (ADHD) is a crucial component to understanding the mechanisms underpinning the disorder, as prior work indicates large genetic influences and numerous environmental risk factors. Building on prior research, children's appraisals of self-blame were examined as a psychosocial moderator of latent etiological influences on ADHD via biometric twin models, which provide an omnibus test of GxE while managing the potential confound of gene-environment correlation. Participants were 246 twin pairs (total n=492) ages 6–16 years. ADHD behaviors were assessed via mother report on the Child Behavior Checklist. To assess level of self-blame, each twin completed the Children's Perception of Inter-parental Conflict scale. Two biometric GxE models were fit to the data. The first model revealed a significant decrease in genetic effects and a significant increase in unique environmental influences on ADHD with increasing levels of self-blame. These results generally persisted even after controlling for confounding effects due to gene-environment correlation in the second model. Results suggest that appraisals of self-blame in relation to inter-parental conflict may act as a key moderator of etiological contributions to ADHD. PMID:22006350

Studying Gene and Gene-Environment Effects of Uncommon and Common Variants on Continuous Traits: A Marker-Set Approach Using Gene-Trait Similarity Regression

PubMed Central

Tzeng, Jung-Ying; Zhang, Daowen; Pongpanich, Monnat; Smith, Chris; McCarthy, Mark I.; Sale, Michèle M.; Worrall, Bradford B.; Hsu, Fang-Chi; Thomas, Duncan C.; Sullivan, Patrick F.

2011-01-01

Genomic association analyses of complex traits demand statistical tools that are capable of detecting small effects of common and rare variants and modeling complex interaction effects and yet are computationally feasible. In this work, we introduce a similarity-based regression method for assessing the main genetic and interaction effects of a group of markers on quantitative traits. The method uses genetic similarity to aggregate information from multiple polymorphic sites and integrates adaptive weights that depend on allele frequencies to accomodate common and uncommon variants. Collapsing information at the similarity level instead of the genotype level avoids canceling signals that have the opposite etiological effects and is applicable to any class of genetic variants without the need for dichotomizing the allele types. To assess gene-trait associations, we regress trait similarities for pairs of unrelated individuals on their genetic similarities and assess association by using a score test whose limiting distribution is derived in this work. The proposed regression framework allows for covariates, has the capacity to model both main and interaction effects, can be applied to a mixture of different polymorphism types, and is computationally efficient. These features make it an ideal tool for evaluating associations between phenotype and marker sets defined by linkage disequilibrium (LD) blocks, genes, or pathways in whole-genome analysis. PMID:21835306

Advancing the science of environmental exposures during pregnancy and the gene-environment through the National Children's Study.

PubMed

Pak, Victoria; Souders, Margaret C

2012-01-01

In this article we provide nurses with information on the importance of studying environmental exposures during fetal, infant, and childhood development in the National Children's Study. Nurses should be aware of this study to aid in mitigating the complex health problems that arise from environment-health interactions. Nurses may help to educate the public, patients, and caregivers and are in an ideal position to be strong advocates for policy change and regulatory monitoring and enforcement. © 2012 AWHONN, the Association of Women's Health, Obstetric and Neonatal Nurses.

Ecogeographic Genetic Epidemiology

PubMed Central

Sloan, Chantel D.; Duell, Eric J.; Shi, Xun; Irwin, Rebecca; Andrew, Angeline S.; Williams, Scott M.; Moore, Jason H.

2009-01-01

Complex diseases such as cancer and heart disease result from interactions between an individual's genetics and environment, i.e. their human ecology. Rates of complex diseases have consistently demonstrated geographic patterns of incidence, or spatial “clusters” of increased incidence relative to the general population. Likewise, genetic subpopulations and environmental influences are not evenly distributed across space. Merging appropriate methods from genetic epidemiology, ecology and geography will provide a more complete understanding of the spatial interactions between genetics and environment that result in spatial patterning of disease rates. Geographic Information Systems (GIS), which are tools designed specifically for dealing with geographic data and performing spatial analyses to determine their relationship, are key to this kind of data integration. Here the authors introduce a new interdisciplinary paradigm, ecogeographic genetic epidemiology, which uses GIS and spatial statistical analyses to layer genetic subpopulation and environmental data with disease rates and thereby discern the complex gene-environment interactions which result in spatial patterns of incidence. PMID:19025788

Three Approaches to Modeling Gene-Environment Interactions in Longitudinal Family Data: Gene-Smoking Interactions in Blood Pressure.

PubMed

Basson, Jacob; Sung, Yun Ju; de Las Fuentes, Lisa; Schwander, Karen L; Vazquez, Ana; Rao, Dabeeru C

2016-01-01

Blood pressure (BP) has been shown to be substantially heritable, yet identified genetic variants explain only a small fraction of the heritability. Gene-smoking interactions have detected novel BP loci in cross-sectional family data. Longitudinal family data are available and have additional promise to identify BP loci. However, this type of data presents unique analysis challenges. Although several methods for analyzing longitudinal family data are available, which method is the most appropriate and under what conditions has not been fully studied. Using data from three clinic visits from the Framingham Heart Study, we performed association analysis accounting for gene-smoking interactions in BP at 31,203 markers on chromosome 22. We evaluated three different modeling frameworks: generalized estimating equations (GEE), hierarchical linear modeling, and pedigree-based mixed modeling. The three models performed somewhat comparably, with multiple overlaps in the most strongly associated loci from each model. Loci with the greatest significance were more strongly supported in the longitudinal analyses than in any of the component single-visit analyses. The pedigree-based mixed model was more conservative, with less inflation in the variant main effect and greater deflation in the gene-smoking interactions. The GEE, but not the other two models, resulted in substantial inflation in the tail of the distribution when variants with minor allele frequency <1% were included in the analysis. The choice of analysis method should depend on the model and the structure and complexity of the familial and longitudinal data. © 2015 WILEY PERIODICALS, INC.

Role of metabolic phenotyping in understanding obesity and related conditions in Gulf Co-operation Council countries.

PubMed

Ahmad, M S; Ashrafian, H; Alsaleh, M; Holmes, E

2015-12-01

Obesity is a major health concern in the Middle East and the incidence is rising in all sections of the population. Efforts to control obesity through diet and lifestyle interventions, and by surgical means, have had limited effect, and the gene-environment interactions underpinning the development of obesity and related pathologies such as metabolic syndrome, cardiovascular disease and certain cancers are poorly defined. Lifestyle, genetics, inflammation and the interaction between the intestinal bacteria and host metabolism have all been implicated in creating an obesogenic environment. We summarize the role of metabolic and microbial phenotyping in understanding the aetiopathogenesis of obesity and in characterizing the metabolic responses to surgical and non-surgical interventions, and explore the potential for clinical translation of this approach. © 2015 World Obesity.

Dissection of complicate genetic architecture and breeding perspective of cottonseed traits by genome-wide association study.

PubMed

Du, Xiongming; Liu, Shouye; Sun, Junling; Zhang, Gengyun; Jia, Yinhua; Pan, Zhaoe; Xiang, Haitao; He, Shoupu; Xia, Qiuju; Xiao, Songhua; Shi, Weijun; Quan, Zhiwu; Liu, Jianguang; Ma, Jun; Pang, Baoyin; Wang, Liru; Sun, Gaofei; Gong, Wenfang; Jenkins, Johnie N; Lou, Xiangyang; Zhu, Jun; Xu, Haiming

2018-06-13

Cottonseed is one of the most important raw materials for plant protein, oil and alternative biofuel for diesel engines. Understanding the complex genetic basis of cottonseed traits is requisite for achieving efficient genetic improvement of the traits. However, it is not yet clear about their genetic architecture in genomic level. GWAS has been an effective way to explore genetic basis of quantitative traits in human and many crops. This study aims to dissect genetic mechanism seven cottonseed traits by a GWAS for genetic improvement. A genome-wide association study (GWAS) based on a full gene model with gene effects as fixed and gene-environment interaction as random, was conducted for protein, oil and 5 fatty acids using 316 accessions and ~ 390 K SNPs. Totally, 124 significant quantitative trait SNPs (QTSs), consisting of 16, 21, 87 for protein, oil and fatty acids (palmitic, linoleic, oleic, myristic, stearic), respectively, were identified and the broad-sense heritability was estimated from 71.62 to 93.43%; no QTS-environment interaction was detected for the protein, the palmitic and the oleic contents; the protein content was predominantly controlled by epistatic effects accounting for 65.18% of the total variation, but the oil content and the fatty acids except the palmitic were mainly determined by gene main effects and no epistasis was detected for the myristic and the stearic. Prediction of superior pure line and hybrid revealed the potential of the QTSs in the improvement of cottonseed traits, and the hybrid could achieve higher or lower genetic values compared with pure lines. This study revealed complex genetic architecture of seven cottonseed traits at whole genome-wide by mixed linear model approach; the identified genetic variants and estimated genetic component effects of gene, gene-gene and gene-environment interaction provide cotton geneticist or breeders new knowledge on the genetic mechanism of the traits and the potential molecular breeding design strategy.

No Association Between Variant N-acetyltransferase Genes, Cigarette Smoking and Prostate Cancer Susceptibility Among Men of African Descent

PubMed Central

Kidd, La Creis Renee; VanCleave, Tiva T.; Doll, Mark A.; Srivastava, Daya S.; Thacker, Brandon; Komolafe, Oyeyemi; Pihur, Vasyl; Brock, Guy N.; Hein, David W.

2011-01-01

Objective We evaluated the individual and combination effects of NAT1, NAT2 and tobacco smoking in a case-control study of 219 incident prostate cancer (PCa) cases and 555 disease-free men. Methods Allelic discriminations for 15 NAT1 and NAT2 loci were detected in germ-line DNA samples using Taqman polymerase chain reaction (PCR) assays. Single gene, gene-gene and gene-smoking interactions were analyzed using logistic regression models and multi-factor dimensionality reduction (MDR) adjusted for age and subpopulation stratification. MDR involves a rigorous algorithm that has ample statistical power to assess and visualize gene-gene and gene-environment interactions using relatively small samples sizes (i.e., 200 cases and 200 controls). Results Despite the relatively high prevalence of NAT1*10/*10 (40.1%), NAT2 slow (30.6%), and NAT2 very slow acetylator genotypes (10.1%) among our study participants, these putative risk factors did not individually or jointly increase PCa risk among all subjects or a subset analysis restricted to tobacco smokers. Conclusion Our data do not support the use of N-acetyltransferase genetic susceptibilities as PCa risk factors among men of African descent; however, subsequent studies in larger sample populations are needed to confirm this finding. PMID:21709725

Behavioral effects of chronic stress in the Fmr1 mouse model for fragile X syndrome.

PubMed

Lemaire-Mayo, Valerie; Subashi, Enejda; Henkous, Nadia; Beracochea, Daniel; Pietropaolo, Susanna

2017-03-01

Fragile X Syndrome (FXS) is a pervasive developmental disorder due to a mutation in the FMR1 X-linked gene. Despite its clear genetic cause, the expression of FXS symptoms is known to be modulated by environmental factors, including stress. Furthermore, several studies have shown disturbances in stress regulatory systems in FXS patients and Fmr1 mice. These studies have mostly focused on the hormonal responses to stress, using the acute exposure to a single type of stressor. Hence, little is known about the behavioral effects of stress in FXS, and the importance of the nature of the stressing procedure, especially in the context of a repeated exposure that more closely resembles real life conditions. Here we evaluated the effects of chronic exposure to different types of stress (i.e., either repeated restraint or unpredictable stress) on the behavioral phenotype of adult Fmr1 mice. Our results demonstrated that chronic stress induced deficits in social interaction and working memory only in WT mice and the impact of stress depended on the type of stressors and the specific behavior tested. Our data suggest that the behavioral sensitivity to stress is dramatically reduced in FXS, opening new views on the impact of gene-environment interactions in this pathology. Copyright © 2016. Published by Elsevier B.V.

Making medical decisions in dependence of genetic background: estimation of the utility of DNA testing in clinical, pharmaco-epidemiological or genetic studies.

PubMed

Nguyen, Thuy Trang; Schäfer, Helmut; Timmesfeld, Nina

2013-05-01

An index measuring the utility of testing a DNA marker before deciding between two alternative treatments is proposed which can be estimated from pharmaco-epidemiological case-control or cohort studies. In the case-control design, external estimates of the prevalence of the disease and of the frequency of the genetic risk variant are required for estimating the utility index. Formulas for point and interval estimates are derived. Empirical coverage probabilities of the confidence intervals were estimated under different scenarios of disease prevalence, prevalence of drug use, and population frequency of the genetic variant. To illustrate our method, we re-analyse pharmaco-epidemiological case-control data on oral contraceptive intake and venous thrombosis in carriers and non-carriers of the factor V Leiden mutation. We also re-analyse cross-sectional data from the Framingham study on a gene-diet interaction between an APOA2 polymorphism and high saturated fat intake on obesity. We conclude that the utility index may be helpful to evaluate and appraise the potential clinical and public health relevance of gene-environment interaction effects detected in genomic and candidate gene association studies and may be a valuable decision support for designing prospective studies on the clinical utility. © 2013 Wiley Periodicals, Inc.

The association between conduct problems and maltreatment: testing genetic and environmental mediation.

PubMed

Schulz-Heik, R Jay; Rhee, Soo Hyun; Silvern, Louise E; Haberstick, Brett C; Hopfer, Christian; Lessem, Jeffrey M; Hewitt, John K

2010-05-01

It is often assumed that childhood maltreatment causes conduct problems via an environmentally mediated process. However, the association may be due alternatively to either a nonpassive gene-environment correlation, in which parents react to children's genetically-influenced conduct problems by maltreating them, or a passive gene-environment correlation, in which parents' tendency to engage in maltreatment and children's conduct problems are both influenced by a hereditary vulnerability to antisocial behavior (i.e. genetic mediation). The present study estimated the contribution of these processes to the association between maltreatment and conduct problems. Bivariate behavior genetic analyses were conducted on approximately 1,650 twin and sibling pairs drawn from a large longitudinal study of adolescent health (Add Health). The correlation between maltreatment and conduct problems was small; much of the association between maltreatment and conduct problems was due to a nonpassive gene-environment correlation. Results were more consistent with the hypothesis that parents respond to children's genetically-influenced conduct problems by maltreating them than the hypothesis that maltreatment causes conduct problems.

Obesity and type 2 diabetes mellitus in a birth cohort of First Nation children born to mothers with pediatric-onset type 2 diabetes.

PubMed

Mendelson, Michael; Cloutier, Justin; Spence, Louise; Sellers, Elizabeth; Taback, Shayne; Dean, Heather

2011-05-01

Children who are born to mothers with pediatric-onset type 2 diabetes mellitus are exposed to a hyperglycemic intra-uterine environment throughout pregnancy. The growth patterns and risk of type 2 diabetes in these offspring may be influenced by unique gene-environment interactions during intra-uterine and postnatal life. We established a cohort of offspring of First Nation mothers with onset of type 2 diabetes before age 18 years in Manitoba, Canada. We measured height or length and weight at study entry and annually thereafter with fasting blood glucose in offspring aged ≥ 7 years. We collected birth and breastfeeding history and determined the population-specific hepatic nuclear factor-1α (HNF-1α) G319S genotype of offspring at age 7 years. From July 2003 to April 2008, we enrolled 76 offspring of 37 mothers. Sixty-four percent (23/36) of the offspring aged 2-19 years were obese at initial assessment. The rates of obesity remained constant throughout the 5 years. As of April 2008, 7/28 (25%) of the offspring aged 7-19 years have diabetes including 6/14 (43%) aged 10-19 years. Most offspring with diabetes (5/7, 71%) were obese at diagnosis. All of the 7 offspring with diabetes have 1 or 2 copies of the G319S polymorphism. The prevalence of type 2 diabetes in this cohort of offspring of First Nation women with pediatric-onset type 2 diabetes is the highest ever reported. Obesity is an important postnatal risk factor for type 2 diabetes in this population and may result from a unique gene-environment interaction. © 2011 John Wiley & Sons A/S.

Neighborhood alcohol outlet density and genetic influences on alcohol use: evidence for gene-environment interaction.

PubMed

Slutske, Wendy S; Deutsch, Arielle R; Piasecki, Thomas M

2018-05-07

Genetic influences on alcohol involvement are likely to vary as a function of the 'alcohol environment,' given that exposure to alcohol is a necessary precondition for genetic risk to be expressed. However, few gene-environment interaction studies of alcohol involvement have focused on characteristics of the community-level alcohol environment. The goal of this study was to examine whether living in a community with more alcohol outlets would facilitate the expression of the genetic propensity to drink in a genetically-informed national survey of United States young adults. The participants were 2434 18-26-year-old twin, full-, and half-sibling pairs from Wave III of the National Longitudinal Study of Adolescent to Adult Health. Participants completed in-home interviews in which alcohol use was assessed. Alcohol outlet densities were extracted from state-level liquor license databases aggregated at the census tract level to derive the density of outlets. There was evidence that the estimates of genetic and environmental influences on alcohol use varied as a function of the density of alcohol outlets in the community. For example, the heritability of the frequency of alcohol use for those residing in a neighborhood with ten or more outlets was 74% (95% confidence limits = 55-94%), compared with 16% (95% confidence limits = 0-34%) for those in a neighborhood with zero outlets. This moderating effect of alcohol outlet density was not explained by the state of residence, population density, or neighborhood sociodemographic characteristics. The results suggest that living in a neighborhood with many alcohol outlets may be especially high-risk for those individuals who are genetically predisposed to frequently drink.

New Rodent Population Models May Inform Human Health Risk Assessment and Identification of Genetic Susceptibility to Environmental Exposures.

PubMed

Harrill, Alison H; McAllister, Kimberly A

2017-08-15

This paper provides an introduction for environmental health scientists to emerging population-based rodent resources. Mouse reference populations provide an opportunity to model environmental exposures and gene-environment interactions in human disease and to inform human health risk assessment. This review will describe several mouse populations for toxicity assessment, including older models such as the Mouse Diversity Panel (MDP), and newer models that include the Collaborative Cross (CC) and Diversity Outbred (DO) models. This review will outline the features of the MDP, CC, and DO mouse models and will discuss published case studies investigating the use of these mouse population resources in each step of the risk assessment paradigm. These unique resources have the potential to be powerful tools for generating hypotheses related to gene-environment interplay in human disease, performing controlled exposure studies to understand the differential responses in humans for susceptibility or resistance to environmental exposures, and identifying gene variants that influence sensitivity to toxicity and disease states. These new resources offer substantial advances to classical toxicity testing paradigms by including genetically sensitive individuals that may inform toxicity risks for sensitive subpopulations. Both in vivo and complementary in vitro resources provide platforms with which to reduce uncertainty by providing population-level data around biological variability. https://doi.org/10.1289/EHP1274.

Interactions between the vascular endothelial growth factor gene polymorphism and life events in susceptibility to major depressive disorder in a Chinese population.

PubMed

Han, Dong; Qiao, Zhengxue; Chen, Lu; Qiu, Xiaohui; Fang, Deyu; Yang, Xiuxian; Ma, Jingsong; Chen, Mingqi; Yang, Jiarun; Wang, Lin; Zhu, Xiongzhao; Zhang, Congpei; Yang, Yanjie; Pan, Hui

2017-08-01

Recent studies suggest that vascular endothelial growth factor (VEGF) is involved in the development of major depressive disorder. The aim of this study is to investigate the interaction between vascular endothelial growth factor (VEGF) polymorphism (+405G/C, rs2010963) and negative life events in the pathogenesis of major depressive disorder (MDD). DNA genotyping was performed on peripheral blood leukocytes in 274 patients with MDD and 273 age-and sex-matched controls. The frequency and severity of negative life events were assessed by the Life Events Scale (LES). A logistics method was employed to assess the gene-environment interaction (G×E). Differences in rs2010963 genotype distributions were observed between MDD patients and controls. Significant G×E interactions between allelic variation of rs2010963 and negative life events were observed. Individuals carrying the C alleles were susceptible to MDD only when exposed to high-negative life events. These results indicate that interactions between the VEGF rs2010963 polymorphism and environment increases the risk of developing MDD. Copyright © 2017 Elsevier B.V. All rights reserved.

[New perspectives in monitoring of exposures to carcinogens].

PubMed

Pavanello, Sofia; Lotti, Marcello

2011-01-01

Biomonitoring occupational and environmental exposures to carcinogens is a common practice and several biomarkers have been developed for risk assessment. However, in particular, because of the lack of prospective studies, the place of these biomarkers within the complex scenario of the gene-environment interactions leading to cancer cannot be defined. New opportunities and suggestions for biomonitoring exposures to carcinogens could derive from exploring the exposome, from the results of genomewide association and omic studies. Based on these premises it is possible to envisage personalized biomonitoring procedures, as those already actuated in nutrition and clinical oncology, allowing a better predictivity of biomarkers in the preventive settings.

Socioeconomic status and genetic influences on cognitive development.

PubMed

Figlio, David N; Freese, Jeremy; Karbownik, Krzysztof; Roth, Jeffrey

2017-12-19

Accurate understanding of environmental moderation of genetic influences is vital to advancing the science of cognitive development as well as for designing interventions. One widely reported idea is increasing genetic influence on cognition for children raised in higher socioeconomic status (SES) families, including recent proposals that the pattern is a particularly US phenomenon. We used matched birth and school records from Florida siblings and twins born in 1994-2002 to provide the largest, most population-diverse consideration of this hypothesis to date. We found no evidence of SES moderation of genetic influence on test scores, suggesting that articulating gene-environment interactions for cognition is more complex and elusive than previously supposed.

Genetic Dissection of Learning and Memory in Mice

PubMed Central

Mineur, Yann S.; Crusio, Wim E.; Sluyter, Frans

2004-01-01

In this minireview, we discuss different strategies to dissect genetically the keystones of learning and memory. First, we broadly sketch the neurogenetic analysis of complex traits in mice. We then discuss two general strategies to find genes affecting learning and memory: candidate gene studies and whole genome searches. Next, we briefly review more recently developed techniques, such as microarrays and RNA interference. In addition, we focus on gene-environment interactions and endophenotypes. All sections are illustrated with examples from the learning and memory field, including a table summarizing the latest information about genes that have been shown to have effects on learning and memory. PMID:15656270

Genomics, Telomere Length, Epigenetics, and Metabolomics in the Nurses' Health Studies.

PubMed

Townsend, Mary K; Aschard, Hugues; De Vivo, Immaculata; Michels, Karin B; Kraft, Peter

2016-09-01

To review the contribution of the Nurses' Health Study (NHS) and NHS II to genomics, epigenetics, and metabolomics research. We performed a narrative review of the publications of the NHS and NHS II between 1990 and 2016 based on biospecimens, including blood and tumor tissue, collected from participants. The NHS has contributed to the discovery of genetic loci influencing more than 45 complex human phenotypes, including cancers, diabetes, cardiovascular disease, reproductive characteristics, and anthropometric traits. The combination of genomewide genotype data with extensive exposure and lifestyle data has enabled the evaluation of gene-environment interactions. Furthermore, data suggest that longer telomere length increases risk of cancers not related to smoking, and that modifiable factors (e.g., diet) may have an impact on telomere length. "Omics" research in the NHS continues to expand, with epigenetics and metabolomics becoming greater areas of focus. The combination of prospective biomarker data and broad exposure information has enabled the NHS to participate in a variety of "omics" research, contributing to understanding of the epidemiology and biology of multiple complex diseases.

Urinary Polycyclic Aromatic Hydrocarbon (OH-PAH) Metabolite Concentrations and the Effect of GST Polymorphisms Among US Air Force Personnel Exposed to Jet Fuel

PubMed Central

Rodrigues, Ema G.; Smith, Kristen; Maule, Alexis L.; Sjodin, Andreas; Li, Zheng; Romanoff, Lovisa; Kelsey, Karl; Proctor, Susan; McClean, Michael D.

2016-01-01

Objective To evaluate the association between inhalation exposure to jet propulsion fuel 8 (JP-8) and urinary metabolites among US Air Force (USAF) personnel, and investigate the role of glutathione S-transferase polymorphisms. Methods Personal air samples were collected from 37 full-time USAF personnel during 4 consecutive workdays and analyzed for JP-8 constituents and total hydrocarbons. Pre- and postshift urine samples were collected each day and analyzed for polycyclic aromatic hydrocarbon urinary metabolites. Results Work shift exposure to total hydrocarbons was significantly associated with postshift urinary 1-naphthol (β = 0.17; P = <0.0001), 2-naphthol (β = 0.09; P = 0.005), and 2-hydroxyfluorene concentrations (β = 0.08; P = 0.006), and a significant gene-environment interaction was observed with glutathione S-transferase mu-1. Conclusions USAF personnel experience inhalation exposure to JP-8, which is associated with absorption of JP-8 constituents while performing typical job-related tasks, and in our data the glutathione S-transferase mu-1 polymorphism was associated with differential metabolism of naphthalene. PMID:24806557

Urinary polycyclic aromatic hydrocarbon (OH-PAH) metabolite concentrations and the effect of GST polymorphisms among US Air Force personnel exposed to jet fuel.

PubMed

Rodrigues, Ema G; Smith, Kristen; Maule, Alexis L; Sjodin, Andreas; Li, Zheng; Romanoff, Lovisa; Kelsey, Karl; Proctor, Susan; McClean, Michael D

2014-05-01

To evaluate the association between inhalation exposure to jet propulsion fuel 8 (JP-8) and urinary metabolites among US Air Force (USAF) personnel, and investigate the role of glutathione S-transferase polymorphisms. Personal air samples were collected from 37 full-time USAF personnel during 4 consecutive workdays and analyzed for JP-8 constituents and total hydrocarbons. Pre- and postshift urine samples were collected each day and analyzed for polycyclic aromatic hydrocarbon urinary metabolites. Work shift exposure to total hydrocarbons was significantly associated with postshift urinary 1-naphthol (β = 0.17; P = <0.0001), 2-naphthol (β = 0.09; P = 0.005), and 2-hydroxyfluorene concentrations (β = 0.08; P = 0.006), and a significant gene-environment interaction was observed with glutathione S-transferase mu-1. USAF personnel experience inhalation exposure to JP-8, which is associated with absorption of JP-8 constituents while performing typical job-related tasks, and in our data the glutathione S-transferase mu-1 polymorphism was associated with differential metabolism of naphthalene.

Conceptual shifts needed to understand the dynamic interactions of genes, environment, epigenetics, social processes, and behavioral choices.

PubMed

Jackson, Fatimah L C; Niculescu, Mihai D; Jackson, Robert T

2013-10-01

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.

Early identification of atopy in the prediction of persistent asthma in children.

PubMed

Sly, Peter D; Boner, Attilio L; Björksten, Bengt; Bush, Andy; Custovic, Adnan; Eigenmann, Philippe A; Gern, James E; Gerritsen, Jorrit; Hamelmann, Eckard; Helms, Peter J; Lemanske, Robert F; Martinez, Fernando; Pedersen, Soren; Renz, Harald; Sampson, Hugh; von Mutius, Erika; Wahn, Ulrich; Holt, Patrick G

2008-09-20

The long-term solution to the asthma epidemic is thought to be prevention, and not treatment of established disease. Atopic asthma arises from gene-environment interactions, which mainly take place during a short period in prenatal and postnatal development. These interactions are not completely understood, and hence primary prevention remains an elusive goal. We argue that primary-care physicians, paediatricians, and specialists lack knowledge of the role of atopy in early life in the development of persistent asthma in children. In this review, we discuss how early identification of children at high risk is feasible on the basis of available technology and important for potential benefits to the children. Identification of an asthmatic child's atopic status in early life has practical clinical and prognostic implications, and sets the basis for future preventative strategies.

[Predictive factors of anxiety disorders].

PubMed

Domschke, K

2014-10-01

Anxiety disorders are among the most frequent mental disorders in Europe (12-month prevalence 14%) and impose a high socioeconomic burden. The pathogenesis of anxiety disorders is complex with an interaction of biological, environmental and psychosocial factors contributing to the overall disease risk (diathesis-stress model). In this article, risk factors for anxiety disorders will be presented on several levels, e.g. genetic factors, environmental factors, gene-environment interactions, epigenetic mechanisms, neuronal networks ("brain fear circuit"), psychophysiological factors (e.g. startle response and CO2 sensitivity) and dimensional/subclinical phenotypes of anxiety (e.g. anxiety sensitivity and behavioral inhibition), and critically discussed regarding their potential predictive value. The identification of factors predictive of anxiety disorders will possibly allow for effective preventive measures or early treatment interventions, respectively, and reduce the individual patient's suffering as well as the overall socioeconomic burden of anxiety disorders.

Autism risk factors: genes, environment, and gene-environment interactions

PubMed Central

Chaste, Pauline; Leboyer, Marion

2012-01-01

The aim of this review is to summarize the key findings from genetic and epidemiological research, which show that autism is a complex disorder resulting from the combination of genetic and environmental factors. Remarkable advances in the knowledge of genetic causes of autism have resulted from the great efforts made in the field of genetics. The identification of specific alleles contributing to the autism spectrum has supplied important pieces for the autism puzzle. However, many questions remain unanswered, and new questions are raised by recent results. Moreover, given the amount of evidence supporting a significant contribution of environmental factors to autism risk, it is now clear that the search for environmental factors should be reinforced. One aspect of this search that has been neglected so far is the study of interactions between genes and environmental factors. PMID:23226953

Genetic Mechanisms Leading to Sex Differences Across Common Diseases and Anthropometric Traits.

PubMed

Traglia, Michela; Bseiso, Dina; Gusev, Alexander; Adviento, Brigid; Park, Daniel S; Mefford, Joel A; Zaitlen, Noah; Weiss, Lauren A

2017-02-01

Common diseases often show sex differences in prevalence, onset, symptomology, treatment, or prognosis. Although studies have been performed to evaluate sex differences at specific SNP associations, this work aims to comprehensively survey a number of complex heritable diseases and anthropometric traits. Potential genetically encoded sex differences we investigated include differential genetic liability thresholds or distributions, gene-sex interaction at autosomal loci, major contribution of the X-chromosome, or gene-environment interactions reflected in genes responsive to androgens or estrogens. Finally, we tested the overlap between sex-differential association with anthropometric traits and disease risk. We utilized complementary approaches of assessing GWAS association enrichment and SNP-based heritability estimation to explore explicit sex differences, as well as enrichment in sex-implicated functional categories. We do not find consistent increased genetic load in the lower-prevalence sex, or a disproportionate role for the X-chromosome in disease risk, despite sex-heterogeneity on the X for several traits. We find that all anthropometric traits show less than complete correlation between the genetic contribution to males and females, and find a convincing example of autosome-wide genome-sex interaction in multiple sclerosis (P = 1 × 10 -9 ). We also find some evidence for hormone-responsive gene enrichment, and striking evidence of the contribution of sex-differential anthropometric associations to common disease risk, implying that general mechanisms of sexual dimorphism determining secondary sex characteristics have shared effects on disease risk. Copyright © 2017 by the Genetics Society of America.

Boys' serotonin transporter genotype affects maternal behavior through self-control: a case of evocative gene-environment correlation.

PubMed

Pener-Tessler, Roni; Avinun, Reut; Uzefovsky, Florina; Edelman, Shany; Ebstein, Richard P; Knafo, Ariel

2013-02-01

Self-control, involving processes such as delaying gratification, concentrating, planning, following instructions, and adapting emotions and behavior to situational requirements and social norms, may have a profound impact on children's adjustment. The importance of self-control suggests that parents are likely to modify their parenting based on children's ability for self-control. We study the effect of children's self-control, a trait partially molded by genetics, on their mothers' parenting, a process of evocative gene-environment correlation. Israeli 3.5-year-old twins (N = 320) participated in a lab session in which their mothers' parenting was observed. DNA was available from most children (N = 228). Mothers described children's self-control in a questionnaire. Boys were lower in self-control and received less positive parenting from their mothers, in comparison with girls. For boys, and not for girls, the serotonin transporter linked polymorphic region gene predicted mothers' levels of positive parenting, an effect mediated by boys' self-control. The implications of this evocative gene-environment correlation and the observed sex differences are discussed.

Modification of Occupational Exposures on Bladder Cancer Risk by Common Genetic Polymorphisms.

PubMed

Figueroa, Jonine D; Koutros, Stella; Colt, Joanne S; Kogevinas, Manolis; Garcia-Closas, Montserrat; Real, Francisco X; Friesen, Melissa C; Baris, Dalsu; Stewart, Patricia; Schwenn, Molly; Johnson, Alison; Karagas, Margaret R; Armenti, Karla R; Moore, Lee E; Schned, Alan; Lenz, Petra; Prokunina-Olsson, Ludmila; Banday, A Rouf; Paquin, Ashley; Ylaya, Kris; Chung, Joon-Yong; Hewitt, Stephen M; Nickerson, Michael L; Tardón, Adonina; Serra, Consol; Carrato, Alfredo; García-Closas, Reina; Lloreta, Josep; Malats, Núria; Fraumeni, Joseph F; Chanock, Stephen J; Chatterjee, Nilanjan; Rothman, Nathaniel; Silverman, Debra T

2015-11-01

Few studies have demonstrated gene/environment interactions in cancer research. Using data on high-risk occupations for 2258 case patients and 2410 control patients from two bladder cancer studies, we observed that three of 16 known or candidate bladder cancer susceptibility variants displayed statistically significant and consistent evidence of additive interactions; specifically, the GSTM1 deletion polymorphism (P interaction ≤ .001), rs11892031 (UGT1A, P interaction = .01), and rs798766 (TMEM129-TACC3-FGFR3, P interaction = .03). There was limited evidence for multiplicative interactions. When we examined detailed data on a prevalent occupational exposure associated with increased bladder cancer risk, straight metalworking fluids, we also observed statistically significant additive interaction for rs798766 (TMEM129-TACC3-FGFR3, P interaction = .02), with the interaction more apparent in patients with tumors positive for FGFR3 expression. All statistical tests were two-sided. The interaction we observed for rs798766 (TMEM129-TACC3-FGFR3) with specific exposure to straight metalworking fluids illustrates the value of integrating germline genetic variation, environmental exposures, and tumor marker data to provide insight into the mechanisms of bladder carcinogenesis. Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Gene-environment interactions in atherosclerosis.

PubMed

Hegele, R A

1991-06-01

It is becoming clear that genetic and environmental factors can interact to varying degrees in a given individual. In some cases, genetically determined resistance to CAD (eg, genetic hyperalpha- or hypobetalipoproteinemia), or genetically determined susceptibility to CAD (eg, high Lp[a] levels) may not be significantly modulated by a prudent lifestyle. Estimates of the prevalence in the general population of these genetic extremes average around 5% (4). In the remaining 95% of cases, nature and nurture interact. For example, a genetic flaw that is usually expressed phenotypically as premature death due to CAD (eg, some cases of FH) can be ameliorated by a prudent diet. There is little doubt that an individual's responsiveness to environmental factors can be determined by many different genes. The exact candidate genes and the nature of most of the genetic changes affecting response to diet still need to be determined. Once identified, they may one day form the basis for early diagnosis of metabolic problems and individually tailored diet and drug treatment programs.

Serotonin transporter gene and childhood trauma--a G × E effect on anxiety sensitivity.

PubMed

Klauke, Benedikt; Deckert, Jürgen; Reif, Andreas; Pauli, Paul; Zwanzger, Peter; Baumann, Christian; Arolt, Volker; Glöckner-Rist, Angelika; Domschke, Katharina

2011-12-21

Genetic factors and environmental factors are assumed to interactively influence the pathogenesis of anxiety disorders. Thus, a gene-environment interaction (G × E) study was conducted with respect to anxiety sensitivity (AS) as a promising intermediate phenotype of anxiety disorders. Healthy subjects (N = 363) were assessed for AS, childhood maltreatment (Childhood Trauma Questionnaire), and genotyped for functional serotonin transporter gene variants (5-HTTLPR/5-HTT rs25531). The influence of genetic and environmental variables on AS and its subdimensions was determined by a step-wise hierarchical regression and a multiple indicator multiple cause (MIMIC) model. A significant G × E effect of the more active 5-HTT genotypes and childhood maltreatment on AS was observed. Furthermore, genotype (LL)-childhood trauma interaction particularly influenced somatic AS subdimensions, whereas cognitive subdimensions were affected by childhood maltreatment only. Results indicate a G × E effect of the more active 5-HTT genotypes and childhood maltreatment on AS, with particular impact on its somatic subcomponent. © 2011 Wiley Periodicals, Inc.

Interactions Between Monoamine Oxidase A and Punitive Discipline in African American and Caucasian Men’s Antisocial Behavior

PubMed Central

Choe, Daniel Ewon; Shaw, Daniel S.; Hyde, Luke W.; Forbes, Erika E.

2016-01-01

Although previous studies have shown that interactions between monoamine oxidase A (MAOA) genotype and childhood maltreatment predict Caucasian boys’ antisocial behavior, the generalizability of this gene-environment interaction to more diverse populations and more common parenting behaviors, such as punitive discipline in early childhood, is not clearly understood. Among 189 low-income men (44% African American, 56% Caucasian) who underwent rigorous assessments of family behavior and social context longitudinally across 20 years, those men with the low activity MAOA allele who experienced more punitive discipline at ages 1.5, 2, and 5 years showed more antisocial behavior from ages 15 through 20 years. Effects of punitive discipline on antisocial behavior differed by caregiver and age at which it occurred, suggesting sensitive periods throughout early childhood in which low MAOA activity elevated boys’ vulnerability to harsh parenting and risk for antisocial behavior. This genetic vulnerability to punitive discipline—and not just extreme, maltreatment experiences—may generalize to other male populations at risk for antisocial behavior. PMID:27014508

Maltreatment, MAOA, and delinquency: sex differences in gene-environment interaction in a large population-based cohort of adolescents.

PubMed

Aslund, C; Nordquist, N; Comasco, E; Leppert, J; Oreland, L; Nilsson, K W

2011-03-01

The present study investigated a possible interaction between a functional polymorphism in the MAOA gene promoter (MAOA-VNTR) and childhood maltreatment in the prediction of adolescent male and female delinquency. A cohort of 1,825 high school students, 17-18 years old, completed an anonymous questionnaire during class hours which included questions on childhood maltreatment, sexual abuse, and delinquency. Saliva samples were collected for DNA isolation, and analyzed for the MAOA-VNTR polymorphism. Self-reported maltreatment was a strong risk factor for adolescent delinquent behavior. The MAOA genotype also showed a significant main effect when controlled for maltreatment. Boys with a short variant and girls with one or two long variants of the polymorphism showed a higher risk for delinquency when exposed to maltreatment. Our results confirm previous findings of an interaction between the MAOA-VNTR polymorphism and self-reported maltreatment. Results for boys and girls differ according to MAOA-VNTR genotype and direction of phenotypic expression.

Interactions Between Monoamine Oxidase A and Punitive Discipline in African American and Caucasian Men's Antisocial Behavior.

PubMed

Choe, Daniel Ewon; Shaw, Daniel S; Hyde, Luke W; Forbes, Erika E

2014-09-01

Although previous studies have shown that interactions between monoamine oxidase A ( MAOA ) genotype and childhood maltreatment predict Caucasian boys' antisocial behavior, the generalizability of this gene-environment interaction to more diverse populations and more common parenting behaviors, such as punitive discipline in early childhood, is not clearly understood. Among 189 low-income men (44% African American, 56% Caucasian) who underwent rigorous assessments of family behavior and social context longitudinally across 20 years, those men with the low activity MAOA allele who experienced more punitive discipline at ages 1.5, 2, and 5 years showed more antisocial behavior from ages 15 through 20 years. Effects of punitive discipline on antisocial behavior differed by caregiver and age at which it occurred, suggesting sensitive periods throughout early childhood in which low MAOA activity elevated boys' vulnerability to harsh parenting and risk for antisocial behavior. This genetic vulnerability to punitive discipline-and not just extreme, maltreatment experiences-may generalize to other male populations at risk for antisocial behavior.

Brain-derived neurotrophic factor as a model system for examining gene by environment interactions across development.

PubMed

Casey, B J; Glatt, C E; Tottenham, N; Soliman, F; Bath, K; Amso, D; Altemus, M; Pattwell, S; Jones, R; Levita, L; McEwen, B; Magariños, A M; Gunnar, M; Thomas, K M; Mezey, J; Clark, A G; Hempstead, B L; Lee, F S

2009-11-24

There has been a dramatic rise in gene x environment studies of human behavior over the past decade that have moved the field beyond simple nature versus nurture debates. These studies offer promise in accounting for more variability in behavioral and biological phenotypes than studies that focus on genetic or experiential factors alone. They also provide clues into mechanisms of modifying genetic risk or resilience in neurodevelopmental disorders. Yet, it is rare that these studies consider how these interactions change over the course of development. In this paper, we describe research that focuses on the impact of a polymorphism in a brain-derived neurotrophic factor (BDNF) gene, known to be involved in learning and development. Specifically we present findings that assess the effects of genotypic and environmental loadings on neuroanatomic and behavioral phenotypes across development. The findings illustrate the use of a genetic mouse model that mimics the human polymorphism, to constrain the interpretation of gene-environment interactions across development in humans.

Gene-Gene-Environment Interactions of Serotonin Transporter, Monoamine Oxidase A and Childhood Maltreatment Predict Aggressive Behavior in Chinese Adolescents

PubMed Central

Zhang, Yun; Ming, Qing-sen; Yi, Jin-yao; Wang, Xiang; Chai, Qiao-lian; Yao, Shu-qiao

2017-01-01

Gene-environment interactions that moderate aggressive behavior have been identified independently in the serotonin transporter (5-HTT) gene and monoamine oxidase A gene (MAOA). The aim of the present study was to investigate epistasis interactions between MAOA-variable number tandem repeat (VNTR), 5-HTTlinked polymorphism (LPR) and child abuse and the effects of these on aggressive tendencies in a group of otherwise healthy adolescents. A group of 546 Chinese male adolescents completed the Child Trauma Questionnaire and Youth self-report of the Child Behavior Checklist. Buccal cells were collected for DNA analysis. The effects of childhood abuse, MAOA-VNTR, 5-HTTLPR genotypes and their interactive gene-gene-environmental effects on aggressive behavior were analyzed using a linear regression model. The effect of child maltreatment was significant, and a three-way interaction among MAOA-VNTR, 5-HTTLPR and sexual abuse (SA) relating to aggressive behaviors was identified. Chinese male adolescents with high expression of the MAOA-VNTR allele and 5-HTTLPR “SS” genotype exhibited the highest aggression tendencies with an increase in SA during childhood. The findings reported support aggression being a complex behavior involving the synergistic effects of gene-gene-environment interactions. PMID:28203149

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. Copyright © 2013 Elsevier Ltd. All rights reserved.

Combining research approaches to advance our understanding of drug addiction.

PubMed

van den Bree, Marianne B M

2005-04-01

Drug addiction is a complex behavior, likely to be influenced by various genes, environmental factors, and gene-gene and gene-environment interactions. Various aspects of addiction are studied by different disciplines. Animal studies are increasing insight into brain regions and genes associated with addiction. Epidemiologic studies are establishing the factors increasing risk for initiation and continuation of substance use. Twin and adoption studies are increasing our understanding of the complex mechanisms involved in substance use, including comorbidity and gene environment interaction. Finally, molecular genetic studies in humans are starting to yield some converging findings. It is argued and illustrated with examples that greater awareness of progress in other disciplines can speed up our understanding of the complex processes involved in addiction. This should help our ability to identify who is at increased risk of becoming addicted and the development of prevention and intervention strategies targeted at an individual's specific needs.

Stress triggers anhedonia in rats bred for learned helplessness.

PubMed

Enkel, Thomas; Spanagel, Rainer; Vollmayr, Barbara; Schneider, Miriam

2010-05-01

Congenitally helpless (cLH) rats, a well-accepted model for depression, show reduced consumption of sweet solutions only under single-housing conditions, indicating anhedonia under stress. We investigated if anhedonic-like behaviour, measured by a reduction of sweetened-condensed milk (SCM) intake and the pleasure-attenuated startle response (PAS), could be induced by an electric foot-shock stress challenge in group-housed rats. After foot-shock stress, reduced SCM intake was observed in cLH rats compared to non-helpless (cNLH) rats. Furthermore, cLH rats also showed a decreased PAS, indicating deficient reward perception. In summary, we demonstrate that a predisposition for learned helplessness interacts with stress to trigger anhedonic-like behaviour in cLH rats. These findings further add to the validity of congenitally learned helplessness as an animal model of depression, since gene-environment interactions are considered to play a role in the etiology of this disorder.

Genetics of Alcoholism.

PubMed

Zhu, Ena C; Soundy, Timothy J; Hu, Yueshan

2017-05-01

Consuming excessive amounts of alcohol has the potential to modify an individual's brain and lead to alcohol dependence. Alcohol use leads to 88,000 deaths every year in the U.S. alone and can lead to other health issues including cancers, such as colorectal cancer, and mental health problems. While drinking behavior varies due to environmental factors, genetic factors also contribute to the risk of alcoholism. Certain genes affecting alcohol metabolism and neurotransmitters have been found to contribute to or inhibit the risk. Geneenvironment interactions may also play a role in the susceptibility of alcoholism. With a better understanding of the different components that can contribute to alcoholism, more personalized treatment could cater to the individual. This review discusses the major genetic factors and some small variants in other genes that contribute to alcoholism, as well as considers the gene-environmental interactions. Copyright© South Dakota State Medical Association.

Environmental Risk Factors for Multiple Sclerosis: A Review with a Focus on Molecular Mechanisms

PubMed Central

O’Gorman, Cullen; Lucas, Robyn; Taylor, Bruce

2012-01-01

Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system commonly affecting young adults. Pathologically, there are patches of inflammation (plaques) with demyelination of axons and oligodendrocyte loss. There is a global latitude gradient in MS prevalence, and incidence of MS is increasing (particularly in females). These changes suggest a major role for environmental factors in causation of disease. We have reviewed the evidence and potential mechanisms of action for three exposures: vitamin D, Epstein Barr virus and cigarette smoking. Recent advances supporting gene-environment interactions are reviewed. Further research is needed to establish mechanisms of causality in humans and to explore preventative strategies. PMID:23109880

Fanconi anaemia: genetics, molecular biology, and cancer – implications for clinical management in children and adults.

PubMed

Schneider, M; Chandler, K; Tischkowitz, M; Meyer, S

2015-07-01

Fanconi anaemia (FA) is an inherited disease with congenital and developmental abnormalities, cross-linker hypersensitivity and extreme cancer predisposition. With better understanding of the genetic and molecular basis of the disease, and improved clinical management, FA has been transformed from a life-limiting paediatric disease to an uncommon chronic condition that needs lifelong multidisciplinary management, and a paradigm condition for the understanding of the gene-environment interaction in the aetiology of congenital anomalies, haematopoiesis and cancer development. Here we review genetic, molecular and clinical aspects of FA, and discuss current controversies and future prospects. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Genetic mouse models relevant to schizophrenia: taking stock and looking forward.

PubMed

Harrison, Paul J; Pritchett, David; Stumpenhorst, Katharina; Betts, Jill F; Nissen, Wiebke; Schweimer, Judith; Lane, Tracy; Burnet, Philip W J; Lamsa, Karri P; Sharp, Trevor; Bannerman, David M; Tunbridge, Elizabeth M

2012-03-01

Genetic mouse models relevant to schizophrenia complement, and have to a large extent supplanted, pharmacological and lesion-based rat models. The main attraction is that they potentially have greater construct validity; however, they share the fundamental limitations of all animal models of psychiatric disorder, and must also be viewed in the context of the uncertain and complex genetic architecture of psychosis. Some of the key issues, including the choice of gene to target, the manner of its manipulation, gene-gene and gene-environment interactions, and phenotypic characterization, are briefly considered in this commentary, illustrated by the relevant papers reported in this special issue. Copyright © 2011 Elsevier Ltd. All rights reserved.

The Heterogeneity of Disruptive Behavior Disorders – Implications for Neurobiological Research and Treatment

PubMed Central

Stadler, Christina; Poustka, Fritz; Sterzer, Philipp

2010-01-01

Disruptive behavior disorders (DBDs) are reflected by a great variety of symptoms ranging from impulsive-hot-tempered quarrels to purposeful and goal-directed acts of cruelty. A growing body of data indicates that there are neurobiological factors that increase the risk for developing DBDs. In this review, we give a broad overview of recent studies investigating physiological, neural, genetic factors, and specific neurotransmitter systems. We also discuss the impact of psychosocial risk and consider the effects of gene-environment interactions. Due to the heterogeneity of DBDs, it is concluded that specific subtypes of disruptive behavior should be considered both in terms their biological basis and in regard to specific treatment needs. PMID:21423432

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

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. © 2014 UICC.

The Folate Pathway and Nonsyndromic Cleft Lip and Palate

PubMed Central

Blanton, Susan H.; Henry, Robin R.; Yuan, Quiping; Mulliken, John B.; Stal, Samuel; Finnell, Richard H.; Hecht, Jacqueline T.

2013-01-01

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth malformation caused by genetic, environmental and gene-environment interactions. Periconceptional supplementation with folic acid, a key component in DNA synthesis and cell division, has reduced the birth prevalence of neural tube defects (NTDs) and may similarly reduce the birth prevalence of other complex birth defects including NSCLP. Past studies investigating the role of two common methylenetetrahydrofolate reductase (MTHFR) SNP polymorphisms, C677T (rs1801133) and A1298C (rs1801131), in NSCLP have produced conflicting results. Most studies of folate pathway genes have been limited in scope, as few genes/SNPs have been interrogated. In this study, we asked whether variations in a more comprehensive group of folate pathway genes were associated with NSCLP and, if so, were there detectable interactions between these genes and environmental exposures. In addition, we evaluated the data for a sex effect. Fourteen folate metabolism related genes were interrogated using eighty-nine SNPs in multiplex and simplex non-Hispanic White (NHW) (317) and Hispanic (128) NSCLP families. Evidence for a risk association between NSCLP and SNPs in nitrous oxide 3 (NOS3) and thymidylate synthetase (TYMS) was detected in the NHW group, whereas associations with methionine synthase (MTR), betaine-homocysteine methyltransferase (BHMT2), MTHFS and SLC19A1 were detected in the Hispanic group. Evidence for over-transmission of haplotypes and gene interactions in the methionine arm was detected. These results suggest that perturbations of the genes in the folate pathway may contribute to NSCLP. There was evidence for an interaction between several SNPs and maternal smoking, and for one SNP with sex of the offspring. These results provide support for other studies that suggest that high maternal homocysteine levels may contribute to NSCLP and should be further investigated. PMID:21254359

Antisocial Peer Affiliation and Externalizing Disorders: Evidence for Gene × Environment × Development Interaction

PubMed Central

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

2016-01-01

Gene × environment interaction contributes to externalizing disorders in adolescence, but little is known about whether such effects are long-lasting or present in adulthood. We examined gene-environment interplay in the concurrent and prospective associations between antisocial peer affiliation and externalizing disorders (antisocial behavior and substance use disorders) at ages 17, 20, 24, and 29. The sample included 1,382 same-sex twin pairs participating in the Minnesota Twin Family Study. We detected a gene × environment interaction at age 17, such that additive genetic influences on antisocial behavior and substance use disorders were greater in the context of greater antisocial peer affiliation. This gene × environment interaction was not present for antisocial behavior symptoms after age 17, but was for substance use disorder symptoms through age 29 (though effect sizes were largest at age 17). Results suggest adolescence is a critical period for the development of externalizing disorders wherein exposure to greater environmental adversity is associated with a greater expression of genetic risk. This form of gene × environment interaction may persist through young adulthood for substance use disorders, but is limited to adolescence for antisocial behavior. PMID:27580681

Antisocial peer affiliation and externalizing disorders: Evidence for Gene × Environment × Development interaction.

PubMed

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

2017-02-01

Gene × Environment interaction contributes to externalizing disorders in childhood and adolescence, but little is known about whether such effects are long lasting or present in adulthood. We examined gene-environment interplay in the concurrent and prospective associations between antisocial peer affiliation and externalizing disorders (antisocial behavior and substance use disorders) at ages 17, 20, 24, and 29. The sample included 1,382 same-sex twin pairs participating in the Minnesota Twin Family Study. We detected a Gene × Environment interaction at age 17, such that additive genetic influences on antisocial behavior and substance use disorders were greater in the context of greater antisocial peer affiliation. This Gene × Environment interaction was not present for antisocial behavior symptoms after age 17, but it was for substance use disorder symptoms through age 29 (though effect sizes were largest at age 17). The results suggest adolescence is a critical period for the development of externalizing disorders wherein exposure to greater environmental adversity is associated with a greater expression of genetic risk. This form of Gene × Environment interaction may persist through young adulthood for substance use disorders, but it appears to be limited to adolescence for antisocial behavior.

Interactions between Early Parenting and a Polymorphism of the Child’s Dopamine Transporter Gene in Predicting Future Child Conduct Disorder Symptoms

PubMed Central

Lahey, Benjamin B.; Rathouz, Paul J.; Lee, Steve S.; Chronis-Tuscano, Andrea; Pelham, William E.; Waldman, Irwin D.; Cook, Edwin H.

2010-01-01

Mounting evidence suggests that genetic risks for mental disorders often interact with the social environment, but most studies still ignore environmental moderation of genetic influences. We tested interactions between maternal parenting and the variable number tandem repeat (VNTR) polymorphism in the 3′ untranslated region (UTR) of the dopamine transporter gene in the child to increase understanding of gene-environment interactions involving early parenting. Participants were part of a 9-year longitudinal study of 4–6-year-old children who met criteria for attention-deficit/hyperactivity disorder (ADHD) and demographically matched controls. Maternal parenting was observed during standard mother-child interactions in wave 1. The child’s conduct disorder (CD) symptoms 5–8 years later were measured using separate structured diagnostic interviews of the mother and youth. Controlling for ADHD symptoms and child disruptive behavior during the mother-child interaction, there was a significant inverse relation between levels of both positive and negative parenting at 4–6 years and the number of later CD symptoms, but primarily among children with two copies of the 9-repeat allele of the VNTR. The significant interaction with negative parenting was replicated in parent and youth reports of CD symptoms separately. PMID:21171728

The genetics of insomnia--evidence for epigenetic mechanisms?

PubMed

Palagini, Laura; Biber, Knut; Riemann, Dieter

2014-06-01

Sleep is a complex physiological process and still remains one of the great mysteries of science. Over the past 10 y, genetic research has provided a new avenue to address the regulation and function of sleep. Gene loci that contribute quantitatively to sleep characteristics and variability have already been identified. However, up to now, a genetic basis has been established only for a few sleep disorders. Little is yet known about the genetic background of insomnia, one of the most common sleep disorders. According to the conceptualisation of the 3P model of insomnia, predisposing, precipitating and perpetuating factors contribute to the development and maintenance of insomnia. Growing evidence from studies of predisposing factors suggests a certain degree of heritability for insomnia and for a reactivity of sleep patterns to stressful events, explaining the emergence of insomnia in response to stressful life events. While a genetic susceptibility may modulate the impact of stress on the brain, this finding does not provide us with a complete understanding of the capacity of stress to produce long-lasting perturbations of brain and behaviour. Epigenetic gene-environment interactions have been identified just recently and may provide a more complex understanding of the genetic control of sleep and its disorders. It was recently hypothesised that stress-response-related brain plasticity might be epigenetically controlled and, moreover, several epigenetic mechanisms have been assumed to be involved in the regulation of sleep. Hence, it might be postulated that insomnia may be influenced by an epigenetic control process of both sleep mechanisms and stress-response-related gene-environment interactions having an impact on brain plasticity. This paper reviews the evidence for the genetic basis of insomnia and recent theories about epigenetic mechanisms involved in both sleep regulation and brain-stress response, leading to the hypothesis of an involvement of epigenetic mechanisms in the development and maintenance of insomnia. Copyright © 2013 Elsevier Ltd. All rights reserved.

Interactions of central obesity with rs3918242 on risk of non-alcoholic fat liver disease: a preliminary case-control study.

PubMed

Wu, Pengbo; Hua, Yonglong; Tan, Shiyun; Li, Ming; Shu, Yongxiang; Fang, Guo

2015-01-01

NAFLD is a complex disease characterized by inflammation and insulin resistance which is determined by an interaction of genetics and environmental factors. MMP gene has been implicated in relation to inflammation and insulin resistance. The preliminary case-control study aimed to investigate the association between Matrix metalloproteinase (MMP)-9-1562C/T (rs3918242), MMP-2-1306C/T (rs243865) and risk of NAFLD and to further evaluate the interactions of central obesity with rs3918242 and rs243865. Two variants, rs3918242 and rs243865, were genotyped by polymerase chain reaction -restriction fragment length polymorphism. Gene-environment interactions on risk of NAFLD was preliminarily investigated by generalized multifactor dimensionality reduction (GMDR) and further confirmed by unconditional logistic regression methods. After adjusting for covariates, increased risk of NAFLD were observed in subjects carrying TT/CT genotypes in rs3918242 ((Adjust)OR=1.64, 95% CI: 1.24, 2.11, P=0.006). However, decreased risk of non-alcoholic fat liver disease was found when MMP-2 rs243865 (TT/CT) genotype carriers compared with CC carrier ((Adjust)OR=0.65, 95% CI: 0.47, 0.72, P=0.000).Interactions of central obesity with rs3918242 was preliminarily found by GMDR, with a maximum prediction accuracy (67.61%) and a maximum Cross-validation Consistency (10/10).The unconditional logistic regression method indicated central obesity-positive subject with genotype TT/CT had 4.54 times risk of NAFLD compared to central obesity-negative subjects with genotype CC (OR(add)(a)=4.54, 95% CI: 2.81, 7.21, P(add)(a)=0.000), which further confirmed the interactions. The results indicate that both rs3918242 and rs243865 is associated with risk of NAFLD. Furthermore, rs3918242 and central obesity have synergistic effects on risk of NAFLD.

Common methodologies in the evaluation of food allergy: pitfalls and prospects of food allergy prevalence studies.

PubMed

Shu, Shang-an; Chang, Christopher; Leung, Patrick S C

2014-06-01

Global and regional studies on the prevalence of food allergies are plagued by inconsistent methodologies, variations in interpretation of results, and non-standardized study design. Hence, it becomes difficult to compare the prevalence of food allergies in different communities. This information would be useful in providing critical data that will enhance research to elucidate the nature of food allergies, and the role of gene-environment interactions in the sensitization of children and adults to foods. Testing methodologies range from questionnaires to objective in vitro and in vivo testing, to the gold standard, double-blind placebo-controlled food challenge (DBPCFC). Although considered the most accurate and reliable method in detecting the prevalence of food allergy, DBPCFC is not always practical in epidemiological studies of food allergy. On the other hand, multiple logistic regression studies have been done to determine predictability of the outcome of food challenges, and it appears that skin prick testing and in vitro-specific serum IgE are the best predictors. Future studies directed towards confirming the validity of these methods as well as developing algorithms to predict the food challenge outcomes are required, as they may someday become accessory tools to complement DBPCFC.

Mapping Quantitative Traits in Unselected Families: Algorithms and Examples

PubMed Central

Dupuis, Josée; Shi, Jianxin; Manning, Alisa K.; Benjamin, Emelia J.; Meigs, James B.; Cupples, L. Adrienne; Siegmund, David

2009-01-01

Linkage analysis has been widely used to identify from family data genetic variants influencing quantitative traits. Common approaches have both strengths and limitations. Likelihood ratio tests typically computed in variance component analysis can accommodate large families but are highly sensitive to departure from normality assumptions. Regression-based approaches are more robust but their use has primarily been restricted to nuclear families. In this paper, we develop methods for mapping quantitative traits in moderately large pedigrees. Our methods are based on the score statistic which in contrast to the likelihood ratio statistic, can use nonparametric estimators of variability to achieve robustness of the false positive rate against departures from the hypothesized phenotypic model. Because the score statistic is easier to calculate than the likelihood ratio statistic, our basic mapping methods utilize relatively simple computer code that performs statistical analysis on output from any program that computes estimates of identity-by-descent. This simplicity also permits development and evaluation of methods to deal with multivariate and ordinal phenotypes, and with gene-gene and gene-environment interaction. We demonstrate our methods on simulated data and on fasting insulin, a quantitative trait measured in the Framingham Heart Study. PMID:19278016

Defining genes using "blueprint" versus "instruction" metaphors: effects for genetic determinism, response efficacy, and perceived control.

PubMed

Parrott, Roxanne; Smith, Rachel A

2014-01-01

Evidence supports mixed attributions aligned with personal and/or clinical control and gene expression for health in this era of genomic science and health care. We consider variance in these attributions and possible relationships to individual mind sets associated with essentialist beliefs that genes determine health versus threat beliefs that genes increase susceptibility for disease and severity linked to gene-environment interactions. Further, we contribute to theory and empirical research to evaluate the use of metaphors to define genes. Participants (N = 324) read a message that varied the introduction by providing a definition of genes that used either an "instruction" metaphor or a "blueprint" metaphor. The "instruction" metaphor compared to the "blueprint" metaphor promoted stronger threat perceptions, which aligned with both belief in the response efficacy of genetic research for health and perceived behavioral control linked to genes and health. The "blueprint" metaphor compared to the "instruction" metaphor promoted stronger essentialist beliefs, which aligned with more intense positive regard for the efficacy of genetic research and human health. Implications for health communicators include societal effects aligned with stigma and discrimination that such findings portend.

Cancer risk and the complexity of the interactions between environmental and host factors: HENVINET interactive diagrams as simple tools for exploring and understanding the scientific evidence.

PubMed

Merlo, Domenico F; Filiberti, Rosangela; Kobernus, Michael; Bartonova, Alena; Gamulin, Marija; Ferencic, Zeljko; Dusinska, Maria; Fucic, Aleksandra

2012-06-28

Development of graphical/visual presentations of cancer etiology caused by environmental stressors is a process that requires combining the complex biological interactions between xenobiotics in living and occupational environment with genes (gene-environment interaction) and genomic and non-genomic based disease specific mechanisms in living organisms. Traditionally, presentation of causal relationships includes the statistical association between exposure to one xenobiotic and the disease corrected for the effect of potential confounders. Within the FP6 project HENVINET, we aimed at considering together all known agents and mechanisms involved in development of selected cancer types. Selection of cancer types for causal diagrams was based on the corpus of available data and reported relative risk (RR). In constructing causal diagrams the complexity of the interactions between xenobiotics was considered a priority in the interpretation of cancer risk. Additionally, gene-environment interactions were incorporated such as polymorphisms in genes for repair and for phase I and II enzymes involved in metabolism of xenobiotics and their elimination. Information on possible age or gender susceptibility is also included. Diagrams are user friendly thanks to multistep access to information packages and the possibility of referring to related literature and a glossary of terms. Diagrams cover both chemical and physical agents (ionizing and non-ionizing radiation) and provide basic information on the strength of the association between type of exposure and cancer risk reported by human studies and supported by mechanistic studies. Causal diagrams developed within HENVINET project represent a valuable source of information for professionals working in the field of environmental health and epidemiology, and as educational material for students. Cancer risk results from a complex interaction of environmental exposures with inherited gene polymorphisms, genetic burden collected during development and non genomic capacity of response to environmental insults. In order to adopt effective preventive measures and the associated regulatory actions, a comprehensive investigation of cancer etiology is crucial. Variations and fluctuations of cancer incidence in human populations do not necessarily reflect environmental pollution policies or population distribution of polymorphisms of genes known to be associated with increased cancer risk. Tools which may be used in such a comprehensive research, including molecular biology applied to field studies, require a methodological shift from the reductionism that has been used until recently as a basic axiom in interpretation of data. The complexity of the interactions between cells, genes and the environment, i.e. the resonance of the living matter with the environment, can be synthesized by systems biology. Within the HENVINET project such philosophy was followed in order to develop interactive causal diagrams for the investigation of cancers with possible etiology in environmental exposure. Causal diagrams represent integrated knowledge and seed tool for their future development and development of similar diagrams for other environmentally related diseases such as asthma or sterility. In this paper development and application of causal diagrams for cancer are presented and discussed.

Physical punishment and childhood aggression: the role of gender and gene-environment interplay.

PubMed

Boutwell, Brian B; Franklin, Cortney A; Barnes, J C; Beaver, Kevin M

2011-01-01

A large body of research has linked spanking with a range of adverse outcomes in children, including aggression, psychopathology, and criminal involvement. Despite evidence concerning the association of spanking with antisocial behavior, not all children who are spanked develop antisocial traits. Given the heterogeneous effects of spanking on behavior, it is possible that a third variable may condition the influence of corporal punishment on child development. We test this possibility using data drawn from a nationally representative dataset of twin siblings. Our findings suggest that genetic risk factors condition the effects of spanking on antisocial behavior. Moreover, our results provide evidence that the interaction between genetic risk factors and corporal punishment may be particularly salient for males. © 2011 Wiley Periodicals, Inc.

Genetics in population health science: strategies and opportunities.

PubMed

Belsky, Daniel W; Moffitt, Terrie E; Caspi, Avshalom

2013-10-01

Translational research is needed to leverage discoveries from the frontiers of genome science to improve public health. So far, public health researchers have largely ignored genetic discoveries, and geneticists have ignored important aspects of population health science. This mutual neglect should end. In this article, we discuss 3 areas where public health researchers can help to advance translation: (1) risk assessment: investigate genetic profiles as components in composite risk assessments; (2) targeted intervention: conduct life-course longitudinal studies to understand when genetic risks manifest in development and whether intervention during sensitive periods can have lasting effects; and (3) improved understanding of environmental causation: collaborate with geneticists on gene-environment interaction research. We illustrate with examples from our own research on obesity and smoking.

The role of interindividual variation in human carcinogenesis.

PubMed

Lai, C; Shields, P G

1999-02-01

The process of chemical carcinogenesis is a complex multistage process initiated by DNA damage in growth control genes. Carcinogens enter the body from a variety of sources, but most require metabolic activation before they can damage DNA. There are multiple protective processes that include detoxification and conjugation, DNA repair and programmed cell death. Most of these functions exhibit wide interindividual variation in the population and thus are thought to affect cancer risk. The role of gene-environment interactions is being explored, and current data indicate that genetic susceptibilities can modify carcinogen exposures from the diet and tobacco smoking, although much more data exist for the latter. This review addresses the relationships of human carcinogenesis to these interindividual differences of phase I, phase II and DNA repair enzymes.

Genes for normal sleep and sleep disorders.

PubMed

Tafti, Mehdi; Maret, Stéphanie; Dauvilliers, Yves

2005-01-01

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

Geospatial technology and the "exposome": new perspectives on addiction.

PubMed

Stahler, Gerald J; Mennis, Jeremy; Baron, David A

2013-08-01

Addiction represents one of the greatest public health problems facing the United States. Advances in addiction research have focused on the neurobiology of this disease. We discuss potential new breakthroughs in understanding the other side of gene-environment interactions-the environmental context or "exposome" of addiction. Such research has recently been made possible by advances in geospatial technologies together with new mobile and sensor computing platforms. These advances have fostered interdisciplinary collaborations focusing on the intersection of environment and behavior in addiction research. Although issues of privacy protection for study participants remain, these advances could potentially improve our understanding of initiation of drug use and relapse and help develop innovative technology-based interventions to improve treatment and continuing care services.

The exposome concept in a human nutrigenomics study: evaluating the impact of exposure to a complex mixture of phytochemicals using transcriptomics signatures.

PubMed

van Breda, Simone G J; Wilms, Lonneke C; Gaj, Stan; Jennen, Danyel G J; Briedé, Jacob J; Kleinjans, Jos C S; de Kok, Theo M C M

2015-11-01

The application of transcriptome analyses in molecular epidemiology studies has become a promising tool in order to evaluate the impact of environmental exposures. These analyses have a great value in establishing the exposome, the totality of human exposures, both by identifying the chemical nature of the exposures and the induced molecular responses. Transcriptomic signatures can be regarded as biomarker of exposure as well as markers of effect which reflect the interaction between individual genetic background and exposure levels. However, the biological interpretation of modulated gene expression profiles is a challenging task and translating affected molecular pathways into risk assessment, for instance in terms of cancer promoting or disease preventing responses, is a far from standardised process. Here, we describe the in-depth analyses of the gene expression responses in a human dietary intervention in which the interaction between genotype and exposure to a blueberry-apple juice containing a complex mixture of phytochemicals is investigated. We also describe how data on differences in genetic background combined with different effect markers can provide a better understanding of gene-environment interactions. Pathway analyses of differentially expressed genes in combination with gene were used to identify complex but strong changes in several biological processes like immune response, cell adhesion, lipid metabolism and apoptosis. These observed changes may lead to upgraded growth control, induced immunity, reduced platelet aggregation and activation, diminished production of reactive oxidative species by platelets, blood glucose homeostasis, regulation of blood lipid levels and increased apoptosis. Our findings demonstrate that applying transcriptomics to well-controlled human dietary intervention studies can provide insight into mechanistic pathways involved in disease prevention by dietary factors. © The Author 2015. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

rs1495741 as a tag single nucleotide polymorphism of N-acetyltransferase 2 acetylator phenotype associates bladder cancer risk and interacts with smoking: A systematic review and meta-analysis.

PubMed

Ma, Chong; Gu, Liyan; Yang, Mingyuan; Zhang, Zhensheng; Zeng, Shuxiong; Song, Ruixiang; Xu, Chuanliang; Sun, Yinghao

2016-08-01

Rs1495741 has been identified to infer N-acetyltransferase 2 (NAT2) acetylator phenotype, and to decrease the risk of bladder cancer. However, a number of studies conducted in various regions showed controversial results. To quantify the association between rs1495741 and the risk of bladder cancer and to estimate the interaction effect of this genetic variant with smoking, we performed a systematic literature review and meta-analysis involving 14,815 cases and 58,282 controls from 29 studies. Our results indicates rs1495741 significantly associated with bladder cancer risk (OR = 0.85, 95% CI = 0.82-0.89, test for heterogeneity P = 0.36, I = 7.0%). And we verified this association in populations from Europe, America, and Asia. Further, our stratified meta-analysis showed rs1495741's role is typically evident only in ever smokers, which suggests its interaction with smoking. This study may provide new insight into gene-environment study on bladder cancer.

Interactive effects of 5-HTTLPR genotype and rearing environment on affective attitude towards own infant in Japanese mothers.

PubMed

Sawano, Erika; Doi, Hirokazu; Nagai, Tomoko; Ikeda, Satoko; Shinohara, Kauyuki

2017-05-15

Maternal positive attitude towards one's own infant is the cornerstone of effective parenting. Previous research has revealed an influence of both genetic and environmental factors on maternal parenting behavior, but little is known of the potential gene-environment interaction in shaping a mother's affective attitude. To address this gap, we investigated the effect of a mother's childhood rearing environment and a serotonin transporter gene polymorphism (5-HTTLPR) on affective attitude towards her infant. Our analyses found an interactive effect between rearing environment and 5-HTTLPR genotype on maternal attitude. Specifically, a poor rearing environment (characterized by low maternal care and high paternal overprotection) decreased positive attitude towards one's own infant in mothers with homozygous short allele genotype. In contrast, this detrimental effect was almost eliminated in long allele carriers. Altogether, our results indicate that the 5-HTTLPR gene moderates the influence of experienced rearing environment on maternal parental behavior in a manner consistent with the notion that the short 5-HTTLPR allele amplifies environmental influence. Copyright © 2016 Elsevier B.V. All rights reserved.

Child-evoked maternal negativity from 9 to 27 months: evidence of gene-environment correlation and its moderation by marital distress

PubMed Central

Fearon, R.M. Pasco; Reiss, David; Leve, Leslie D.; Shaw, Daniel S.; Scaramella, Laura V.; Ganiban, Jody M.; Neiderhiser, Jenae M.

2014-01-01

Past research has documented pervasive genetic influences on emotional and behavioral disturbance across the lifespan and on liability to adult psychiatric disorder. Increasingly, interest is turning to mechanisms of gene-environment interplay in attempting to understand the earliest manifestations of genetic risk. We report findings from a prospective adoption study, which aimed to test the role of evocative gene-environment correlation in early development. 561 infants adopted at birth were studied between 9 and 27 months with their adoptive parents and birth mothers. Birth mother psychiatric diagnoses and symptoms scales were used as indicators of genetic influence, and multiple self-report measures were used to index adoptive mother parental negativity. We hypothesized that birth parent psychopathology would be associated with greater adoptive parent negativity, and that such evocative effects would be amplified under conditions of high family adversity. The findings suggested that genetic factors linked to birth mother externalizing psychopathology may evoke negative reactions in adoptive mothers in the first year of life, but primarily when the adoptive family environment was characterized by marital problems. The observed maternal negativity mediated the effects of genetic risk on child adjustment at 27 months. The results underline the importance of genetically-influenced evocative processes in early development. PMID:25216383

Child-evoked maternal negativity from 9 to 27 months: Evidence of gene-environment correlation and its moderation by marital distress.

PubMed

Fearon, R M Pasco; Reiss, David; Leve, Leslie D; Shaw, Daniel S; Scaramella, Laura V; Ganiban, Jody M; Neiderhiser, Jenae M

2015-11-01

Past research has documented pervasive genetic influences on emotional and behavioral disturbance across the life span and on liability to adult psychiatric disorder. Increasingly, interest is turning to mechanisms of gene-environment interplay in attempting to understand the earliest manifestations of genetic risk. We report findings from a prospective adoption study, which aimed to test the role of evocative gene-environment correlation in early development. Included in the study were 561 infants adopted at birth and studied between 9 and 27 months, along with their adoptive parents and birth mothers. Birth mother psychiatric diagnoses and symptoms scales were used as indicators of genetic influence, and multiple self-report measures were used to index adoptive mother parental negativity. We hypothesized that birth mother psychopathology would be associated with greater adoptive parent negativity and that such evocative effects would be amplified under conditions of high adoptive family adversity. The findings suggested that genetic factors associated with birth mother externalizing psychopathology may evoke negative reactions in adoptive mothers in the first year of life, but only when the adoptive family environment is characterized by marital problems. Maternal negativity mediated the effects of genetic risk on child adjustment at 27 months. The results underscore the importance of genetically influenced evocative processes in early development.

Evidence that the association of childhood trauma with psychosis and related psychopathology is not explained by gene-environment correlation: A monozygotic twin differences approach.

PubMed

Lecei, Aleksandra; Decoster, Jeroen; De Hert, Marc; Derom, Catherine; Jacobs, Nele; Menne-Lothmann, Claudia; van Os, Jim; Thiery, Evert; Rutten, Bart P F; Wichers, Marieke; van Winkel, Ruud

2018-05-21

Converging evidence supports childhood trauma as possible causal risk for psychosis and related psychopathology. However, studies have shown that baseline psychotic symptoms may actually increase risk for subsequent victimization, suggesting that exposure to CT is not random but may result from pre-existing vulnerability. Therefore, studies testing whether the association between CT and psychopathology persists when accounting for gene-environment correlation are much needed. A monozygotic (MZ) twin differences approach was used to examine whether differences in CT exposure among MZ twin pairs would be associated with MZ differences in symptoms. As MZ twins are genetically identical, within-pair correlations between CT exposure and psychopathology rule out the possibility that the association is solely attributable to gene-environment correlation. 266 monozygotic twins (133 pairs) from a larger general population study were available for analysis. CT was associated with symptoms of psychosis (B = 0.62; SE = 0.08, p < .001) and overall psychopathology (B = 43.13; SE = 6.27; p < .001). There were measurable differences within pairs in CT exposure and symptoms, allowing for meaningful within-pair differences. Within-pair differences in CT exposure were associated with within-pair differences in symptoms of psychosis (B = 0.35; SE = 0.16; p = .024), as well as with overall psychopathology (B = 29.22; SE = 12.24; p = .018), anxiety (B = 0.65; SE = 0.21; p = .002) and depression (B = 0.37; SE = 0.18; p = .043). While it is not unlikely that pre-existing vulnerability may increase the risk for traumatic exposures, such gene-environment correlation does not explain away the association between CT and psychopathology. The present findings thus suggest that at least part of the association between CT and psychopathology may be causal. Copyright © 2018. Published by Elsevier B.V.

Integrating genetic and toxicogenomic information for determining underlying susceptibility to developmental disorders.

PubMed

Robinson, Joshua F; Port, Jesse A; Yu, Xiaozhong; Faustman, Elaine M

2010-10-01

To understand the complex etiology of developmental disorders, an understanding of both genetic and environmental risk factors is needed. Human and rodent genetic studies have identified a multitude of gene candidates for specific developmental disorders such as neural tube defects (NTDs). With the emergence of toxicogenomic-based assessments, scientists now also have the ability to compare and understand the expression of thousands of genes simultaneously across strain, time, and exposure in developmental models. Using a systems-based approach in which we are able to evaluate information from various parts and levels of the developing organism, we propose a framework for integrating genetic information with toxicogenomic-based studies to better understand gene-environmental interactions critical for developmental disorders. This approach has allowed us to characterize candidate genes in the context of variables critical for determining susceptibility such as strain, time, and exposure. Using a combination of toxicogenomic studies and complementary bioinformatic tools, we characterize NTD candidate genes during normal development by function (gene ontology), linked phenotype (disease outcome), location, and expression (temporally and strain-dependent). In addition, we show how environmental exposures (cadmium, methylmercury) can influence expression of these genes in a strain-dependent manner. Using NTDs as an example of developmental disorder, we show how simple integration of genetic information from previous studies into the standard microarray design can enhance analysis of gene-environment interactions to better define environmental exposure-disease pathways in sensitive and resistant mouse strains. © Wiley-Liss, Inc.

Maternal warmth and directiveness jointly moderate the etiology of childhood conduct problems.

PubMed

Alexandra Burt, S; Klahr, Ashlea M; Neale, Michael C; Klump, Kelly L

2013-10-01

Prior studies exploring gene-environment interactions (GxE) in the development of youth conduct problems (CP) have focused almost exclusively on single-risk experiences, despite research indicating that the presence of other risk factors and or the absence of protective factors can accentuate the influence of a given risk factor on CP. The goal of the current study was to fill this gap in the literature, evaluating whether risky and protective aspects of parenting might combine to jointly moderate the etiology of CP. The sample consisted of 500 child twin pairs from the Michigan State University Twin Registry (MSUTR). Child CP was assessed using multiple informant reports. Maternal warmth and directiveness were assessed via videotaped dyadic interactions between mothers and each of their twins. Biometric GxE analyses revealed that directiveness and warmth did appear to jointly moderate the etiology of CP. In particular, shared environmental influences were accentuated by colder, less directive or 'less engaged' mothering, whereas genetic influences were strongest when the child was experiencing warmer, more directive or 'more authoritative' mothering. Such findings serve to highlight the synergistic effects of risky and protective experiences on child outcomes. They also provide additional empirical support for the bioecological form of GxE, which postulates that, in some cases, genetic influences may be most strongly expressed in the presence of low-risk environments. © 2013 The Authors. Journal of Child Psychology and Psychiatry © 2013 Association for Child and Adolescent Mental Health.

Differential Parenting and Risk for Psychopathology: A Monozygotic Twin Difference Approach

PubMed Central

Long, E.C.; Aggen, S. H.; Gardner, C.; Kendler, K. S.

2015-01-01

Purpose Consistent and non-specific associations have been found between parenting style and major depression, anxiety disorders, and externalizing behavior. Although often considered part of twins’ shared environment, parenting can also be conceptualized as non-shared environment. Non-shared environmental influences have important effects on development but are difficult to test and sort out because of the possible confounding effects of gene-environment interactions and evocative gene-environment correlations. The MZ differences approach is one way to analytically investigate non-shared environment. Methods The aim of the present study is to use the MZ differences approach to investigate the relationship between differential parenting among 1,303 twin pairs (mean age 36.69 +/− 8.56) and differences in total symptom counts of major depression (MD), generalized anxiety disorder (GAD), conduct disorder (CD), and anti-social behavior (ASB) during adulthood. Results Although effect sizes tended to be small, a number of results were significantly different from zero. Perceived differences in parental coldness was positively associated with internalizing disorders. Differences in protectiveness were negatively associated with MD, GAD, and ASB. Differences in authoritarianism were positively associated with MD and CD, but negatively associated with ASB. Conclusions Perceived differences in parenting style are associated with differences in MD, GAD, CD, and ASB outcomes in a sample of MZ twins. Despite the lack of a basis for making causal inferences about parenting style and psychopathology, these results are suggestive of such a relationship and show that non-shared environmental influence of parenting does in some cases significantly predict adult psychopathology. PMID:25940788

Genetic influences on adolescent sexual behavior: Why genes matter for environmentally oriented researchers.

PubMed

Harden, K Paige

2014-03-01

There are dramatic individual differences among adolescents in how and when they become sexually active adults, and early sexual activity is frequently cited as a cause of concern for scientists, policymakers, and the general public. Understanding the causes and developmental impact of adolescent sexual activity can be furthered by considering genes as a source of individual differences. Quantitative behavioral genetics (i.e., twin and family studies) and candidate gene association studies now provide clear evidence for the genetic underpinnings of individual differences in adolescent sexual behavior and related phenotypes. Genetic influences on sexual behavior may operate through a variety of direct and indirect mechanisms, including pubertal development, testosterone levels, and dopaminergic systems. Genetic differences may be systematically associated with exposure to environments that are commonly treated as causes of sexual behavior (gene-environment correlation). Possible gene-environment correlations pose a serious challenge for interpreting the results of much behavioral research. Multivariate, genetically informed research on adolescent sexual behavior compares twins and family members as a form of quasi experiment: How do twins who differ in their sexual experiences differ in their later development? The small but growing body of genetically informed research has already challenged dominant assumptions regarding the etiology and sequelae of adolescent sexual behavior, with some studies indicating possible positive effects of teenage sexuality. Studies of Gene × Environment interaction may further elucidate the mechanisms by which genes and environments combine to shape the development of sexual behavior and its psychosocial consequences. Overall, the existence of heritable variation in adolescent sexual behavior has profound implications for environmentally oriented theory and research.

Effects of interactions between common genetic variants and alcohol consumption on colorectal cancer risk

PubMed Central

Song, Nan; Shin, Aesun; Oh, Jae Hwan; Kim, Jeongseon

2018-01-01

Background Genome-wide association studies (GWAS) have identified approximately 40 common genetic loci associated with colorectal cancer risk. To investigate possible gene-environment interactions (GEIs) between GWAS-identified single-nucleotide polymorphisms (SNPs) and alcohol consumption with respect to colorectal cancer, a hospital-based case-control study was conducted. Results Higher levels of alcohol consumption as calculated based on a standardized definition of a drink (1 drink=12.5g of ethanol) were associated with increased risk of colorectal cancer (OR=2.47, 95% CI=1.62-3.76 for heavy drinkers [>50g/day] compared to never drinkers; ptrend<0.01). SNP rs6687758 near the DUSP10 gene at 1q41 had a statistically significant interaction with alcohol consumption in analyses of standardized drinks (p=4.6×10-3), although this did not surpass the corrected threshold for multiple testing. When stratified by alcohol consumption levels, in an additive model the risk of colorectal cancer associated with the G allele of rs6687758 tended to increase among individuals in the heavier alcohol consumption strata. A statistically significant association between rs6687758 and colorectal cancer risk was observed among moderate alcohol drinkers who consumed between >12.5 and ≤50g of alcohol per day (OR=1.46, 95% CI=1.01-2.11). Methods A total of 2,109 subjects (703 colorectal cancer patients and 1,406 healthy controls) were recruited from the Korean National Cancer Center. For genotyping, 30 GWAS-identified SNPs were selected. A logistic regression model was used to evaluate associations of SNPs and alcohol consumption with colorectal cancer risk. We also tested GEIs between SNPs and alcohol consumption using a logistic model with multiplicative interaction terms. Conclusions Our results suggest that SNP rs6687758 at 1q41 may interact with alcohol consumption in the etiology of colorectal cancer. PMID:29464080

Effects of interactions between common genetic variants and alcohol consumption on colorectal cancer risk.

PubMed

Song, Nan; Shin, Aesun; Oh, Jae Hwan; Kim, Jeongseon

2018-01-19

Genome-wide association studies (GWAS) have identified approximately 40 common genetic loci associated with colorectal cancer risk. To investigate possible gene-environment interactions (GEIs) between GWAS-identified single-nucleotide polymorphisms (SNPs) and alcohol consumption with respect to colorectal cancer, a hospital-based case-control study was conducted. Higher levels of alcohol consumption as calculated based on a standardized definition of a drink (1 drink=12.5g of ethanol) were associated with increased risk of colorectal cancer (OR=2.47, 95% CI=1.62-3.76 for heavy drinkers [>50g/day] compared to never drinkers; p trend <0.01). SNP rs6687758 near the DUSP10 gene at 1q41 had a statistically significant interaction with alcohol consumption in analyses of standardized drinks ( p =4.6×10 -3 ), although this did not surpass the corrected threshold for multiple testing. When stratified by alcohol consumption levels, in an additive model the risk of colorectal cancer associated with the G allele of rs6687758 tended to increase among individuals in the heavier alcohol consumption strata. A statistically significant association between rs6687758 and colorectal cancer risk was observed among moderate alcohol drinkers who consumed between >12.5 and ≤50g of alcohol per day (OR=1.46, 95% CI=1.01-2.11). A total of 2,109 subjects (703 colorectal cancer patients and 1,406 healthy controls) were recruited from the Korean National Cancer Center. For genotyping, 30 GWAS-identified SNPs were selected. A logistic regression model was used to evaluate associations of SNPs and alcohol consumption with colorectal cancer risk. We also tested GEIs between SNPs and alcohol consumption using a logistic model with multiplicative interaction terms. Our results suggest that SNP rs6687758 at 1q41 may interact with alcohol consumption in the etiology of colorectal cancer.

Serotonin transporter 5-HTTLPR genotype is associated with intrusion and avoidance symptoms of DSM-5 posttraumatic stress disorder (PTSD) in Chinese earthquake survivors.

PubMed

Liu, Luobing; Wang, Li; Cao, Chengqi; Cao, Xing; Zhu, Ye; Liu, Ping; Luo, Shu; Zhang, Jianxin

2018-05-01

Prior studies have found that the serotonin transporter gene-linked polymorphic region (5-HTTLPR) interacts with trauma exposure to increase general risk for Posttraumatic Stress Disorder (PTSD). However, there is little knowledge about the effects of the interaction on distinct symptom clusters of PTSD. This study aimed to investigate the relation between the interaction of 5-HTTLPR and earthquake-related exposures and a contemporary phenotypic model of DSM-5 PTSD symptoms in a traumatised adult sample from China. A cross-sectional design with gene-environment interaction (G × E) approach was adopted. Participants were 1131 survivors who experienced 2008 Wenchuan earthquake. PTSD symptoms were assessed with the PTSD Checklist for DSM-5 (PCL-5). The 5-HTTLPR polymorphism was genotyped with capillary electrophoresis (CE) in ABI 3730xl genetic Analyzer. Although there was no significant interaction between 5-HTTLPR and traumatic exposure on total PTSD symptoms, respondents with the LL genotype of 5-HTTLPR who were highly exposed to the earthquake experienced lower intrusion and avoidance symptoms than those with the S-allele carriers. The findings suggest that the 5-HTTLPR may have an important impact on the development of PTSD and add to the extant knowledge on understanding and treating of posttraumatic psychopathology.

Differential susceptibility in longitudinal models of gene-environment interaction for adolescent depression.

PubMed

Li, James J; Berk, Michele S; Lee, Steve S

2013-11-01

Although family support reliably predicts the development of adolescent depression and suicidal behaviors, relatively little is known about the interplay of family support with potential genetic factors. We tested the association of the 44 base pair polymorphism in the serotonin transporter linked promoter region gene (5-HTTLPR), family support (i.e., cohesion, communication, and warmth), and their interaction with self-reported depression symptoms and risk for suicide in 1,030 Caucasian adolescents and young adults from the National Longitudinal Study of Adolescent Health. High-quality family support predicted fewer symptoms of depression and reduced risk for suicidality. There was also a significant interaction between 5-HTTLPR and family support for boys and a marginally significant interaction for girls. Among boys with poor family support, youth with at least one short allele had more symptoms of depression and a higher risk for suicide attempts relative to boys homozygous for the long allele. However, in the presence of high family support, boys with the short allele had the fewest depression symptoms (but not suicide attempts). Results suggest that the short allele may increase reactivity to both negative and positive family influences in the development of depression. We discuss the potential role of interactive exchanges between family support and offspring genotype in the development of adolescent depression and suicidal behaviors.

Interaction of CD38 Variant and Chronic Interpersonal Stress Prospectively Predicts Social Anxiety and Depression Symptoms Over Six Years

PubMed Central

Tabak, Benjamin A.; Vrshek-Schallhorn, Suzanne; Zinbarg, Richard E.; Prenoveau, Jason M.; Mineka, Susan; Redei, Eva E.; Adam, Emma K.; Craske, Michelle G.

2015-01-01

Variation in the CD38 gene, which regulates secretion of the neuropeptide oxytocin, has been associated with several social phenotypes. Specifically, rs3796863 A allele carriers have demonstrated increased social sensitivity. In 400 older adolescents, we used trait-state-occasion modeling to investigate how rs3796863 genotype, baseline ratings of chronic interpersonal stress, and their gene-environment (GxE) interaction predicted trait social anxiety and depression symptoms over six years. We found significant GxE effects for CD38 A-carrier genotypes and chronic interpersonal stress at baseline predicting greater social anxiety and depression symptoms. A significant GxE effect of smaller magnitude was also found for C/C genotype and chronic interpersonal stress predicting greater depression; however, this effect was small compared to the main effect of chronic interpersonal stress. Thus, in the context of chronic interpersonal stress, heightened social sensitivity associated with the rs3796863 A allele may prospectively predict risk for social anxiety and (to a lesser extent) depression. PMID:26958455

Religion priming differentially increases prosocial behavior among variants of the dopamine D4 receptor (DRD4) gene.

PubMed

Sasaki, Joni Y; Kim, Heejung S; Mojaverian, Taraneh; Kelley, Lauren D S; Park, In Young; Janusonis, Skirmantas

2013-02-01

Building on gene-environment interaction (G × E) research, this study examines how the dopamine D4 receptor (DRD4) gene interacts with a situational prime of religion to influence prosocial behavior. Some DRD4 variants tend to be more susceptible to environmental influences, whereas other variants are less susceptible. Thus, certain life environments may be associated with acts of prosociality for some DRD4 variants but not others. Given that religion can act as an environmental influence that increases prosocial behavior, environmental input in the form of religion priming may have G × E effects. Results showed that participants with DRD4 susceptibility variants were more prosocial when implicitly primed with religion than not primed with religion, whereas participants without DRD4 susceptibility variants were not impacted by priming. This research has implications for understanding why different people may behave prosocially for different reasons and also integrates G × E research with experimental psychology.

Of Pesticides and Men: A California Story of Genes and Environment in Parkinson’s Disease

PubMed Central

Ritz, BR; Paul, KC; Bronstein, JM

2018-01-01

At the start of the post-genomics era, most Parkinson’s disease (PD) etiology cannot be explained by our knowledge of genetic or environmental factors alone. For more than a decade, we have explored gene-environment (GxE) interactions possibly responsible for the heterogeneity of genetic as well as environmental results across populations. We developed three pesticide exposure measures (ambient due to agricultural applications, home and garden use, occupational use) in a large population-based case-control study of incident PD in central California. Specifically, we assessed interactions with genes responsible for pesticide metabolism (PON1); transport across the blood brain barrier (ABCB1); pesticides interfering with or depending on dopamine transporter activity (DAT) and dopamine metabolism (ALDH2); impacting mitochondrial function via oxidative/nitrosative stress (NOS1) or proteasome inhibition (SKP1); and contributing to immune dysregulation (HLA-DR). These studies established some specificity for pesticides’ neurodegenerative actions, contributed biologic plausibility to epidemiologic findings, and identified genetically susceptible populations. PMID:26857251

Gene by Social-Context Interactions for Number of Sexual Partners Among White Male Youths: Genetics-informed Sociology

PubMed Central

Guo, Guang; Tong, Yuying; Cai, Tianji

2010-01-01

In this study, we set out to investigate whether introducing molecular genetic measures into an analysis of sexual partner variety will yield novel sociological insights. The data source is the white male DNA sample in the National Longitudinal Study of Adolescent Health. Our empirical analysis has produced a robust protective effect of the 9R/9R genotype relative to the Any10R genotype in the dopamine transporter gene (DAT1). The gene-environment interaction analysis demonstrates that the protective effect of 9R/9R tends to be lost in schools in which higher proportions of students start having sex early or among those with relatively low levels of cognitive ability. Our genetics-informed sociological analysis suggests that the “one size” of a single social theory may not fit all. Explaining a human trait or behavior may require a theory that accommodates the complex interplay between social contextual and individual influences and genetic predispositions. PMID:19569400

Vitamin D and Colorectal Cancer: Molecular, Epidemiological, and Clinical Evidence

PubMed Central

Dou, Ruoxu; Ng, Kimmie; Giovannucci, Edward L.; Manson, JoAnn E.; Qian, Zhi Rong; Ogino, Shuji

2016-01-01

In many cells throughout the body, vitamin D is converted into its active form calcitriol, and binds to vitamin D receptor (VDR), which functions as a transcription factor to regulate various biological processes including cellular differentiation and immune response. Vitamin D metabolizing enzymes (including CYP24A1 and CYP27B1) and VDR play major roles in exerting and regulating effects of vitamin D. Preclinical and epidemiological studies provide evidence for anticancer effects of vitamin D (in particular, against colorectal cancer), though clinical trials have yet to prove its benefit. Additionally, molecular pathological epidemiology research can provide insights into the interaction of vitamin D with tumour molecular and immunity status. Other future research directions include genome-wide research on VDR transcriptional targets, gene-environment interaction analyses, and clinical trials on vitamin D efficacy in colorectal cancer patients. Here we review the literature on vitamin D and colorectal cancer from both mechanistic and population studies, and discuss the links and controversies within and between the two parts of evidence. PMID:27245104

Exploring the Genetic Etiology of Trust in Adolescents: Combined Twin and DNA Analyses.

PubMed

Wootton, Robyn E; Davis, Oliver S P; Mottershaw, Abigail L; Wang, R Adele H; Haworth, Claire M A

2016-12-01

Behavioral traits generally show moderate to strong genetic influence, with heritability estimates of around 50%. Some recent research has suggested that trust may be an exception because it is more strongly influenced by social interactions. In a sample of over 7,000 adolescent twins from the United Kingdom's Twins Early Development Study, we found broad sense heritability estimates of 57% for generalized trust and 51% for trust in friends. Genomic-relatedness-matrix restricted maximum likelihood (GREML) estimates in the same sample indicate that 21% of the narrow sense genetic variance can be explained by common single nucleotide polymorphisms for generalized trust and 43% for trust in friends. As expected, this implies a large amount of unexplained heritability, although power is low for estimating DNA-based heritability. The missing heritability may be accounted for by interactions between DNA and the social environment during development or via gene-environment correlations with rare variants. How these genes and environments correlate seem especially important for the development of trust.

General and specific predictors of nicotine and alcohol dependence in early adulthood: genetic and environmental influences.

PubMed

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

2014-07-01

This study builds on previous work delineating a hierarchical model of family environmental risk in relation to a hierarchical model of externalizing disorders (EXTs) by evaluating for gene-environment interplay in these relationships. The associations between parent-child relationship quality (conflict, bonding, and management) and substance-specific adolescent family environments (parental/sibling tobacco/alcohol use) in relation to young adult EXTs (age ∼22 years nicotine, alcohol, and other drug dependence; antisocial and risky sexual behavior) were evaluated. The sample included 533 adopted offspring and 323 biological offspring. Because adopted youth do not share genes with their parents, a significant association between parent-child relationship quality and EXTs would provide evidence against passive gene-environment correlation (rGE). Significant associations between parental tobacco/alcohol use in relation to offspring nicotine/alcohol dependence in the adopted offspring support common environmental influence. Significant associations detected for the biological offspring only suggest common genetic influence. For both adoptive and biological offspring, there was a significant association between parent-child relationship quality and EXTs. Parental tobacco/alcohol use was unrelated to EXTs. Sibling tobacco/alcohol use was related to EXTs, but only for the biological siblings. Parental tobacco use was associated with the residual variance in nicotine dependence in adopted offspring. Findings replicate a long-term influence of adolescent parent-child relationship quality on adult EXTs. Findings extend previous research by providing evidence against passive rGE in this association. The association between parental tobacco use and adult nicotine dependence appears to be environmentally mediated, but caution is warranted as we found this relationship only for adopted youth.

Cannabinoid Receptor 1 Gene Polymorphisms and Marijuana Misuse Interactions On White Matter and Cognitive Deficits in Schizophrenia

PubMed Central

Ho, Beng-Choon; Wassink, Thomas H.; Ziebell, Steven; Andreasen, Nancy C.

2011-01-01

Marijuana exposure during the critical period of adolescent brain maturation may disrupt neuro-modulatory influences of endocannabinoids and increase schizophrenia susceptibility. Cannabinoid receptor 1 (CB1/CNR1) is the principal brain receptor mediating marijuana effects. No study to-date has systematically investigated the impact of CNR1 on quantitative phenotypic features in schizophrenia and inter-relationships with marijuana misuse. We genotyped 235 schizophrenia patients using 12 tag single nucleotide polymorphisms (tSNPs) that account for most of CB1 coding region genetic variability. Patients underwent a high-resolution anatomic brain magnetic resonance scan and cognitive assessment. Almost a quarter of the sample met DSM marijuana abuse (14%) or dependence (8%) criteria. Effects of CNR1 tSNPs and marijuana abuse/dependence on brain volumes and neurocognition were assessed using ANCOVA, including co-morbid alcohol/non-marijuana illicit drug misuse as covariates. Significant main effects of CNR1 tSNPs (rs7766029, rs12720071, and rs9450898) were found in white matter (WM) volumes. Patients with marijuana abuse/dependence had smaller fronto-temporal WM volumes than patients without heavy marijuana use. More interestingly, there were significant rs12720071 genotype-by-marijuana use interaction effects on WM volumes and neurocognitive impairment; suggestive of gene-environment interactions for conferring phenotypic abnormalities in schizophrenia. In this comprehensive evaluation of genetic variants distributed across the CB1 locus, CNR1 genetic polymorphisms were associated with WM brain volume variation among schizophrenia patients. Our findings suggest that heavy cannabis use in the context of specific CNR1 genotypes may contribute to greater WM volume deficits and cognitive impairment, which could in turn increase schizophrenia risk. PMID:21420833

Therapygenetics: Using genetic markers to predict response to psychological treatment for mood and anxiety disorders

PubMed Central

2013-01-01

Considerable variation is evident in response to psychological therapies for mood and anxiety disorders. Genetic factors alongside environmental variables and gene-environment interactions are implicated in the etiology of these disorders and it is plausible that these same factors may also be important in predicting individual differences in response to psychological treatment. In this article, we review the evidence that genetic variation influences psychological treatment outcomes with a primary focus on mood and anxiety disorders. Unlike most past work, which has considered prediction of response to pharmacotherapy, this article reviews recent work in the field of therapygenetics, namely the role of genes in predicting psychological treatment response. As this is a field in its infancy, methodological recommendations are made and opportunities for future research are identified. PMID:23388219

Critical need for family-based, quasi-experimental designs in integrating genetic and social science research.

PubMed

D'Onofrio, Brian M; Lahey, Benjamin B; Turkheimer, Eric; Lichtenstein, Paul

2013-10-01

Researchers have identified environmental risks that predict subsequent psychological and medical problems. Based on these correlational findings, researchers have developed and tested complex developmental models and have examined biological moderating factors (e.g., gene-environment interactions). In this context, we stress the critical need for researchers to use family-based, quasi-experimental designs when trying to integrate genetic and social science research involving environmental variables because these designs rigorously examine causal inferences by testing competing hypotheses. We argue that sibling comparison, offspring of twins or siblings, in vitro fertilization designs, and other genetically informed approaches play a unique role in bridging gaps between basic biological and social science research. We use studies on maternal smoking during pregnancy to exemplify these principles.

The role of epigenetics in genetic and environmental epidemiology.

PubMed

Ladd-Acosta, Christine; Fallin, M Daniele

2016-02-01

Epidemiology is the branch of science that investigates the causes and distribution of disease in populations in order to provide preventative measures and promote human health. The fields of genetic and environmental epidemiology primarily seek to identify genetic and environmental risk factors for disease, respectively. Epigenetics is emerging as an important piece of molecular data to include in these studies because it can provide mechanistic insights into genetic and environmental risk factors for disease, identify potential intervention targets, provide biomarkers of exposure, illuminate gene-environment interactions and help localize disease-relevant genomic regions. Here, we describe the importance of including epigenetics in genetic and environmental epidemiology studies, provide a conceptual framework when considering epigenetic data in population-based studies and touch upon the many challenges that lie ahead.

Smoking and diabetes. Epigenetics involvement in osseointegration.

PubMed

Razzouk, Sleiman; Sarkis, Rami

2013-03-01

Bone quality is a poorly defined parameter for successful implant placement, which largely depends upon many environmental and genetic factors unique to every individual. Smoking and diabetes are among the environmental factors that most impact osseointegration. However, there is an inter-individual variability of bone response in smokers and diabetic patients. Recent data on gene-environment interactions highlight the major role of epigenetic changes to induce a specific phenotype. Histone acetylation and DNA methylation are the main events that occur and modulate the gene expression. In this paper, we emphasize the impact of epigenetics on diabetes and smoking and describe their significance in bone healing. Also, we underscore the importance of adopting a new approach in clinical management for implant placement by customizing the treatment according to the patient's specific characteristics.

Observed positive parenting behaviors and youth genotype: evidence for gene-environment correlations and moderation by parent personality traits.

PubMed

Oppenheimer, Caroline W; Hankin, Benjamin L; Jenness, Jessica L; Young, Jami F; Smolen, Andrew

2013-02-01

Gene-environment correlations (rGE) have been demonstrated in behavioral genetic studies, but rGE have proven elusive in molecular genetic research. Significant gene-environment correlations may be difficult to detect because potential moderators could reduce correlations between measured genetic variants and the environment. Molecular genetic studies investigating moderated rGE are lacking. This study examined associations between child catechol-O-methyltransferase genotype and aspects of positive parenting (responsiveness and warmth), and whether these associations were moderated by parental personality traits (neuroticism and extraversion) among a general community sample of third, sixth, and ninth graders (N = 263) and their parents. Results showed that parent personality traits moderated the rGE association between youths' genotype and coded observations of positive parenting. Parents with low levels of neuroticism and high levels of extraversion exhibited greater sensitive responsiveness and warmth, respectively, to youth with the valine/valine genotype. Moreover, youth with this genotype exhibited lower levels of observed anger. There was no association between the catechol-O-methyltransferase genotype and parenting behaviors for parents high on neuroticism and low on extraversion. Findings highlight the importance of considering moderating variables that may influence child genetic effects on the rearing environment. Implications for developmental models of maladaptive and adaptive child outcomes, and interventions for psychopathology, are discussed within a developmental psychopathology framework.

Moderation of Genetic Influences on Alcohol Involvement by Rural Residency among Adolescents: Results from the 1962 National Merit Twin Study.

PubMed

Davis, Christal N; Natta, Shanaliz S; Slutske, Wendy S

2017-11-01

Adolescents in rural and urban areas may experience different levels of environmental restrictions on alcohol use, with those in rural areas experiencing greater monitoring and less access to alcohol. Such restrictions may limit expression of genetic vulnerability for alcohol use, resulting in a gene-environment interaction (G × E). This phenomenon has previously been reported in Finnish and Minnesota adolescents. The current study used data from 839 same-sex twin pairs from the 1962 National Merit Scholarship Qualifying Test to determine whether the G × E interaction would be evident in this earlier time period. We also assessed whether the G × E interaction would be moderated by sex, and whether family socioeconomic status (SES; income and parental education) may mediate the G × E interaction. Findings showed the expected interaction among females, with a weaker contribution of genes (2 vs. 44%) and greater contribution of shared environment (62 vs. 29%) to variation in alcohol involvement among rural as compared to urban residents. The G × E interaction was not observed among males, and operated independently from differences in family SES among rural and urban adolescents. This study represents a partial replication in a novel setting of the moderation of the genetic contribution to alcohol use by rural/urban residency, and suggests that SES differences may not explain this effect.

Gene-environment interaction: Does fluoride influence the reproductive hormones in male farmers modified by ERα gene polymorphisms?

PubMed

Ma, Qiang; Huang, Hui; Sun, Long; Zhou, Tong; Zhu, Jingyuan; Cheng, Xuemin; Duan, Lijv; Li, Zhiyuan; Cui, Liuxin; Ba, Yue

2017-12-01

The occurrence of endemic fluorosis is derived from high fluoride levels in drinking water and industrial fumes or dust. Reproductive disruption is also a major harm caused by fluoride exposure besides dental and skeletal lesions. However, few studies focus on the mechanism of fluoride exposure on male reproductive function, especially the possible interaction of fluoride exposure and gene polymorphism on male reproductive hormones. Therefore, we conducted a cross-sectional study in rural areas of Henan province in China to explore the interaction between the estrogen receptor alpha (ERα) gene and fluoride exposure on reproductive hormone levels in male farmers living in the endemic fluorosis villages. The results showed that fluoride exposure significantly increased the serum level of estradiol in the hypothalamic-pituitary-testicular (HPT) axis in male farmers. Moreover, the observations indicated that fluoride exposure and genetic markers had an interaction on serum concentration of follicle-stimulating hormone and estradiol, and the interaction among different loci of the ERα gene could impact the serum testosterone level. Findings in the present work suggest that chronic fluoride exposure in drinking water could modulate the levels of reproductive hormones in males living in endemic fluorosis areas, and the interaction between fluoride exposure and ERα polymorphisms might affect the serum levels of hormones in the HPT axis in male farmers. Copyright © 2017 Elsevier Ltd. All rights reserved.

Monoamine Oxidase A (MAOA) and Catechol-O-Methyltransferase (COMT) Gene Polymorphisms Interact with Maternal Parenting in Association with Adolescent Reactive Aggression but not Proactive Aggression: Evidence of Differential Susceptibility.

PubMed

Zhang, Wenxin; Cao, Cong; Wang, Meiping; Ji, Linqin; Cao, Yanmiao

2016-04-01

To date, whether and how gene-environment (G × E) interactions operate differently across distinct subtypes of aggression remains untested. More recently, in contrast with the diathesis-stress hypothesis, an alternative hypothesis of differential susceptibility proposes that individuals could be differentially susceptible to environments depending on their genotypes in a "for better and for worse" manner. The current study examined interactions between monoamine oxidase A (MAOA) T941G and catechol-O-methyltransferase (COMT) Val158Met polymorphisms with maternal parenting on two types of aggression: reactive and proactive. Moreover, whether these potential G × E interactions would be consistent with the diathesis-stress versus the differential susceptibility hypothesis was tested. Within the sample of 1399 Chinese Han adolescents (47.2 % girls, M age = 12.32 years, SD = 0.50), MAOA and COMT genes both interacted with positive parenting in their associations with reactive but not proactive aggression. Adolescents with T alleles/TT homozygotes of MAOA gene or Met alleles of COMT gene exhibited more reactive aggression when exposed to low positive parenting, but less reactive aggression when exposed to high positive parenting. These findings provide the first evidence for distinct G × E interaction effects on reactive versus proactive aggression and lend further support for the differential susceptibility hypothesis.

Next Generation Analytic Tools for Large Scale Genetic Epidemiology Studies of Complex Diseases

PubMed Central

Mechanic, Leah E.; Chen, Huann-Sheng; Amos, Christopher I.; Chatterjee, Nilanjan; Cox, Nancy J.; Divi, Rao L.; Fan, Ruzong; Harris, Emily L.; Jacobs, Kevin; Kraft, Peter; Leal, Suzanne M.; McAllister, Kimberly; Moore, Jason H.; Paltoo, Dina N.; Province, Michael A.; Ramos, Erin M.; Ritchie, Marylyn D.; Roeder, Kathryn; Schaid, Daniel J.; Stephens, Matthew; Thomas, Duncan C.; Weinberg, Clarice R.; Witte, John S.; Zhang, Shunpu; Zöllner, Sebastian; Feuer, Eric J.; Gillanders, Elizabeth M.

2012-01-01

Over the past several years, genome-wide association studies (GWAS) have succeeded in identifying hundreds of genetic markers associated with common diseases. However, most of these markers confer relatively small increments of risk and explain only a small proportion of familial clustering. To identify obstacles to future progress in genetic epidemiology research and provide recommendations to NIH for overcoming these barriers, the National Cancer Institute sponsored a workshop entitled “Next Generation Analytic Tools for Large-Scale Genetic Epidemiology Studies of Complex Diseases” on September 15–16, 2010. The goal of the workshop was to facilitate discussions on (1) statistical strategies and methods to efficiently identify genetic and environmental factors contributing to the risk of complex disease; and (2) how to develop, apply, and evaluate these strategies for the design, analysis, and interpretation of large-scale complex disease association studies in order to guide NIH in setting the future agenda in this area of research. The workshop was organized as a series of short presentations covering scientific (gene-gene and gene-environment interaction, complex phenotypes, and rare variants and next generation sequencing) and methodological (simulation modeling and computational resources and data management) topic areas. Specific needs to advance the field were identified during each session and are summarized. PMID:22147673

Genetics of preeclampsia: what are the challenges?

PubMed

Bernard, Nathalie; Giguère, Yves

2003-07-01

Despite recent efforts to identify susceptibility genes of preeclampsia, the genetic determinants of the condition remain ill-defined, as is the situation for most disorders of complex inheritance patterns. The angiotensinogen, factor V, and methylenetetrahydrofolate reductase genes have been investigated in different populations, as have other genes involved in blood pressure, vascular volume control, thrombophilia, lipid metabolism, oxidative stress, and endothelial dysfunction. The study of the genetics of complex traits is faced with both methodological and genetic issues; these include adequate sample size to allow for the identification of modest genetic effects, of gene-gene and gene-environment interactions, the study of adequate quantitative traits and extreme phenotypes, haplotype analyses, statistical genetics, genome-wide (hypothesis-free) versus candidate-gene (hypothesis-driven) approaches, and the validation of positive associations. The use of genetically well-characterized populations showing a founder effect, such as the French-Canadian population of Quebec, in genetic association studies, may help to unravel the susceptibility genes of disorders showing complex inheritance, such as preeclampsia. It is necessary to better evaluate the role of the fetal genome in the resulting predisposition to preeclampsia and its complications. Eventually, we may be able to integrate genetic information to better identify the women at risk of developing preeclampsia, and to improve the management of those suffering from this condition.

Genetic Influences on Adolescent Sexual Behavior: Why Genes Matter for Environmentally-Oriented Researchers

PubMed Central

Harden, K. Paige

2013-01-01

There are dramatic individual differences among adolescents in how and when they become sexually active adults, and “early” sexual activity is frequently cited as a cause of concern for scientists, policymakers, and the general public. Understanding the causes and developmental impact of adolescent sexual activity can be furthered by considering genes as a source of individual differences. Quantitative behavioral genetics (i.e., twin and family studies) and candidate gene association studies now provide clear evidence for the genetic underpinnings of individual differences in adolescent sexual behavior and related phenotypes. Genetic influences on sexual behavior may operate through a variety of direct and indirect mechanisms, including pubertal development, testosterone levels, and dopaminergic systems. Genetic differences may be systematically associated with exposure to environments that are commonly treated as causes of sexual behavior (gene-environment correlation). Possible gene-environment correlations pose a serious challenge for interpreting the results of much behavioral research. Multivariate, genetically-informed research on adolescent sexual behavior compares twins and family members as a form of “quasi-experiment”: How do twins who differ in their sexual experiences differ in their later development? The small but growing body of genetically-informed research has already challenged dominant assumptions regarding the etiology and sequelae of adolescent sexual behavior, with some studies indicating possible positive effects of teenage sexuality. Studies of gene × environment interaction may further elucidate the mechanisms by which genes and environments combine to shape the development of sexual behavior and its psychosocial consequences. Overall, the existence of heritable variation in adolescent sexual behavior has profound implications for environmentally-oriented theory and research. PMID:23855958

Impact of variation in the BDNF gene on social stress sensitivity and the buffering impact of positive emotions: replication and extension of a gene-environment interaction.

PubMed

van Winkel, Mark; Peeters, Frenk; van Winkel, Ruud; Kenis, Gunter; Collip, Dina; Geschwind, Nicole; Jacobs, Nele; Derom, Catherine; Thiery, Evert; van Os, Jim; Myin-Germeys, Inez; Wichers, Marieke

2014-06-01

A previous study reported that social stress sensitivity is moderated by the brain-derived-neurotrophic-factor(Val66Met) (BDNF rs6265) genotype. Additionally, positive emotions partially neutralize this moderating effect. The current study aimed to: (i) replicate in a new independent sample of subjects with residual depressive symptoms the moderating effect of BDNF(Val66Met) genotype on social stress sensitivity, (ii) replicate the neutralizing impact of positive emotions, (iii) extend these analyses to other variations in the BDNF gene in the new independent sample and the original sample of non-depressed individuals. Previous findings were replicated in an experience sampling method (ESM) study. Negative Affect (NA) responses to social stress were stronger in "Val/Met" carriers of BDNF(Val66Met) compared to "Val/Val" carriers. Positive emotions neutralized the moderating effect of BDNF(Val66Met) genotype on social stress sensitivity in a dose-response fashion. Finally, two of four additional BDNF SNPs (rs11030101, rs2049046) showed similar moderating effects on social stress-sensitivity across both samples. The neutralizing effect of positive emotions on the moderating effects of these two additional SNPs was found in one sample. In conclusion, ESM has important advantages in gene-environment (GxE) research and may attribute to more consistent findings in future GxE research. This study shows how the impact of BDNF genetic variation on depressive symptoms may be explained by its impact on subtle daily life responses to social stress. Further, it shows that the generation of positive affect (PA) can buffer social stress sensitivity and partially undo the genetic susceptibility. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

[The role of genotype in the intergenerational transmission of experiences of childhood adversity].

PubMed

Reichl, Corinna; Kaess, Michael; Resch, Franz; Brunner, Romuald

2014-09-01

The prevalence of childhood abuse and maltreatment is estimated to lie at about 15% in the overall German population. Previous research suggested that about one third of all individuals who had experienced childhood adversity subsequently maltreated their own children or responded insensitively to their children's needs. Empirical studies imply that interindividual differences in the responsiveness to childhood adversity can partially be explained by gene-environment interactions. This article discusses the potential interplay of genes and environment in the context of transmitting maltreating behavior and (in)sensitive parenting against the background of current challenges in genetic research. Selected studies on gene × environment interactions are presented and relevant gene polymorphisms are identified. Overall, previous studies reported interactions between polymorphisms of the serotonergic, dopaminergic, oxytocin-related, and arginine vasopressin-related systems and childhood experiences of care and abuse in the prediction of social behaviors during mother-child interactions. The results indicate a differential susceptibility toward both negative and positive environments which is dependent on genetic characteristics. Future research should thus investigate the effects of children's presumed risk gene variants toward negative as well as positive parenting. This could contribute to a deeper understanding of the underlying mechanisms of the intergenerational transmission of abusive and beneficial parenting behavior and help to avoid false stigmatizations.

Additive gene-environment effects on hippocampal structure in healthy humans.

PubMed

Rabl, Ulrich; Meyer, Bernhard M; Diers, Kersten; Bartova, Lucie; Berger, Andreas; Mandorfer, Dominik; Popovic, Ana; Scharinger, Christian; Huemer, Julia; Kalcher, Klaudius; Pail, Gerald; Haslacher, Helmuth; Perkmann, Thomas; Windischberger, Christian; Brocke, Burkhard; Sitte, Harald H; Pollak, Daniela D; Dreher, Jean-Claude; Kasper, Siegfried; Praschak-Rieder, Nicole; Moser, Ewald; Esterbauer, Harald; Pezawas, Lukas

2014-07-23

Hippocampal volume loss has been related to chronic stress as well as genetic factors. Although genetic and environmental variables affecting hippocampal volume have extensively been studied and related to mental illness, limited evidence is available with respect to G × E interactions on hippocampal volume. The present MRI study investigated interaction effects on hippocampal volume between three well-studied functional genetic variants (COMT Val158Met, BDNF Val66Met, 5-HTTLPR) associated with hippocampal volume and a measure of environmental adversity (life events questionnaire) in a large sample of healthy humans (n = 153). All three variants showed significant interactions with environmental adversity with respect to hippocampal volume. Observed effects were additive by nature and driven by both recent as well as early life events. A consecutive analysis of hippocampal subfields revealed a spatially distinct profile for each genetic variant suggesting a specific role of 5-HTTLPR for the subiculum, BDNF Val66Met for CA4/dentate gyrus, and COMT Val158Met for CA2/3 volume changes. The present study underscores the importance of G × E interactions as determinants of hippocampal volume, which is crucial for the neurobiological understanding of stress-related conditions, such as mood disorders or post-traumatic stress disorder (PTSD). Copyright © 2014 the authors 0270-6474/14/349917-10$15.00/0.

The interactive effect of the MAOA-VNTR genotype and childhood abuse on aggressive behaviors in Chinese male adolescents.

PubMed

Zhang, Yun; Ming, Qingsen; Wang, Xiang; Yao, Shuqiao

2016-06-01

Gene-environment interactions that moderate aggressive behavior have been identified in association with the MAOA (monoamine oxidase A) gene. The present study examined the moderating effect of MAOA-VNTR (variable number of tandem repeats) on aggression behavior relating to child abuse among Chinese adolescents. A sample of 507 healthy Chinese male adolescents completed the Child Trauma Questionnaire-Short Form (CTQ-SF) and Youth Self-report of the Child Behavior Checklist. The participants' buccal cells were sampled and subjected to DNA analysis. The effects of childhood abuse (CTQ-SF scores), MAOA-VNTR [high-activity allele (H) versus low-activity allele (L)], and their interaction in aggressive behaviors were analyzed by linear regression. Child maltreatment was found to be a significant independent factor in the manifestation of aggressive behavior, whereas MAOA activity was not. There was a significant interaction between MAOA-VNTR and childhood maltreatment in the exhibition of aggressive behaviors. In the context of physical or emotional abuse, boys in the MAOA-L group showed a greater tendency toward aggression than those in the MAOA-H group. Aggressive behavior arising from childhood maltreatment is moderated by MAOA-VNTR, which may be differentially sensitive to the subtype of childhood maltreatment experienced, among Chinese adolescents.

Synergistic Association of Genetic Variants with Environmental Risk Factors in Susceptibility to Essential Hypertension.

PubMed

Sousa, Ana Célia; Mendonça, Maria I; Pereira, Andreia; Gouveia, Sara; Freitas, Ana I; Guerra, Graça; Rodrigues, Mariana; Henriques, Eva; Freitas, Sónia; Borges, Sofia; Pereira, Décio; Brehm, António; Palma Dos Reis, Roberto

2017-10-01

Essential hypertension (EH) is a disease in which both environment and genes have an important role. This study was designed to identify the interaction model between genetic variants and environmental risk factors that most highly potentiates EH development. We performed a case-control study with 1641 participants (mean age 50.6 ± 8.1 years), specifically 848 patients with EH and 793 controls, adjusted for gender and age. Traditional risk factors, biochemical and genetic parameters, including the genotypic discrimination of 14 genetic variants previously associated with EH, were investigated. Multifactorial dimensionality reduction (MDR) software was used to analyze gene-environment interactions. Validation was performed using logistic regression analysis with environmental risk factors, significant genetic variants, and the best MDR model. The best model indicates that the interactions among the ADD1 rs4961 640T allele, diabetes, and obesity (body mass index ≥30) increase approximately four-fold the risk of EH (odds ratio = 3.725; 95% confidence interval: 2.945-4.711; p < 0.0001). This work showed that the interaction between the ADD1 rs4961 variant, obesity, and the presence of diabetes increased the susceptibility to EH four-fold. In these circumstances, lifestyle adjustment and diabetes control should be intensified in patients who carry the ADD1 variant.

CELF4 Variant and Anthracycline-Related Cardiomyopathy: A Children’s Oncology Group Genome-Wide Association Study

PubMed Central

Wang, Xuexia; Sun, Can-Lan; Quiñones-Lombraña, Adolfo; Singh, Purnima; Landier, Wendy; Hageman, Lindsey; Mather, Molly; Rotter, Jerome I.; Taylor, Kent D.; Chen, Yii-Der Ida; Armenian, Saro H.; Winick, Naomi; Ginsberg, Jill P.; Neglia, Joseph P.; Oeffinger, Kevin C.; Castellino, Sharon M.; Dreyer, Zoann E.; Hudson, Melissa M.; Robison, Leslie L.; Blanco, Javier G.

2016-01-01

Purpose Interindividual variability in the dose-dependent association between anthracyclines and cardiomyopathy suggests that genetic susceptibility could play a role. The current study uses an agnostic approach to identify genetic variants that could modify cardiomyopathy risk. Methods A genome-wide association study was conducted in childhood cancer survivors with and without cardiomyopathy (cases and controls, respectively). Single-nucleotide polymorphisms (SNPs) that surpassed a prespecified threshold for statistical significance were independently replicated. The possible mechanistic significance of validated SNP(s) was sought by using healthy heart samples. Results No SNP was marginally associated with cardiomyopathy. However, SNP rs1786814 on the CELF4 gene passed the significance cutoff for gene-environment interaction (Pge = 1.14 × 10−5). Multivariable analyses adjusted for age at cancer diagnosis, sex, anthracycline dose, and chest radiation revealed that, among patients with the A allele, cardiomyopathy was infrequent and not dose related. However, among those exposed to greater than 300 mg/m2 of anthracyclines, the rs1786814 GG genotype conferred a 10.2-fold (95% CI, 3.8- to 27.3-fold; P < .001) increased risk of cardiomyopathy compared with those who had GA/AA genotypes and anthracycline exposure of 300 mg/m2 or less. This gene-environment interaction was successfully replicated in an independent set of anthracycline-related cardiomyopathy. CUG-BP and ETR-3-like factor proteins control developmentally regulated splicing of TNNT2, the gene that encodes for cardiac troponin T (cTnT), a biomarker of myocardial injury. Coexistence of more than one cTnT variant results in a temporally split myofilament response to calcium, which causes decreased contractility. Analysis of TNNT2 splicing variants in healthy human hearts suggested an association between the rs1786814 GG genotype and coexistence of more than one TNNT2 splicing variant (90.5% GG v 41.7% GA/AA; P = .005). Conclusion We report a modifying effect of a polymorphism of CELF4 (rs1786814) on the dose-dependent association between anthracyclines and cardiomyopathy, which possibly occurs through a pathway that involves the expression of abnormally spliced TNNT2 variants. PMID:26811534

Genetic, environmental, and epigenetic factors in the development of personality disturbance.

PubMed

Depue, Richard A

2009-01-01

A dimensional model of personality disturbance is presented that is defined by extreme values on interacting subsets of seven major personality traits. Being at the extreme has marked effects on the threshold for eliciting those traits under stimulus conditions: that is, the extent to which the environment affects the neurobiological functioning underlying the traits. To explore the nature of development of extreme values on these traits, each trait is discussed in terms of three major issues: (a) the neurobiological variables associated with the trait, (b) individual variation in this neurobiology as a function of genetic polymorphisms, and (c) the effects of environmental adversity on these neurobiological variables through the action of epigenetic processes. It is noted that gene-environment interaction appears to be dependent on two main factors: (a) both genetic and environmental variables appear to have the most profound and enduring effects when they exert their effects during early postnatal periods, times when the forebrain is undergoing exuberant experience-expectant dendritic and axonal growth; and (b) environmental effects on neurobiology are strongly modified by individual differences in "traitlike" functioning of neurobiological variables. A model of the nature of the interaction between environmental and neurobiological variables in the development of personality disturbance is presented.

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

PubMed

Abe, Koichiro; Yu, Philipp

2009-02-01

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

Individualized weight management: what can be learned from nutrigenomics and nutrigenetics?

PubMed

Rudkowska, Iwona; Pérusse, Louis

2012-01-01

The rise in the prevalence of obesity observed over the past decades is taken by many as an indication of the predominance of environmental factors (the so-called obesogenic environment) over genetic factors in explaining why obesity has reached epidemic proportions. While a changing environment favoring increased food intake and decreased physical activity levels has clearly contributed to shifting the distribution of body mass index (BMI) at the population level, not everyone is becoming overweight or obese. This suggests that there are genetic factors interacting with environmental factors to predispose some individuals to obesity. This gene-environment interaction is not only important in determining an individual's susceptibility to obesity but can also influence the outcome of weight-loss programs and weight-management strategies in overweight and obese subjects. This chapter reviews the role of gene-nutrient interactions in the context of weight management. The first section reviews the application of transcriptomics in human nutrition intervention studies on the molecular impact of caloric restriction and macronutrient composition. The second section reviews the effects of various obesity candidate gene polymorphisms on the response of body weight or weight-related phenotypes to weight-loss programs which include nutritional interventions. Copyright © 2012 Elsevier Inc. All rights reserved.

Gene-environment interaction between SCN5A-1103Y and hypokalemia influences QT interval prolongation in African Americans: the Jackson Heart Study.

PubMed

Akylbekova, Ermeg L; Payne, John P; Newton-Cheh, Christopher; May, Warren L; Fox, Ervin R; Wilson, James G; Sarpong, Daniel F; Taylor, Herman A; Maher, Joseph F

2014-01-01

African-American ancestry, hypokalemia, and QT interval prolongation on the electrocardiogram are all risk factors for sudden cardiac death (SCD), but their interactions remain to be characterized. SCN5A-1103Y is a common missense variant, of African ancestry, of the cardiac sodium channel gene. SCN5A-1103Y is known to interact with QT-prolonging factors to promote ventricular arrhythmias in persons at high risk for SCD, but its clinical impact in the general African-American population has not been established. We genotyped SCN5A-S1103Y in 4,476 participants of the Jackson Heart Study, a population-based cohort of African Americans. We investigated the effect of SCN5A-1103Y, including interaction with hypokalemia, on QT interval prolongation, a widely-used indicator of prolonged myocardial repolarization and predisposition to SCD. We then evaluated the two sub-components of the QT interval: QRS duration and JT interval. The carrier frequency for SCN5A-1103Y was 15.4%. SCN5A-1103Y was associated with QT interval prolongation (2.7 milliseconds; P < .001) and potentiated the effect of hypokalemia on QT interval prolongation (14.6 milliseconds; P = .02). SCN5A-1103Y had opposing effects on the two sub-components of the QT interval, with shortening of QRS duration (-1.5 milliseconds; P = .001) and prolongation of the JT interval (3.4 milliseconds; P < .001). Hypokalemia was associated with diuretic use (78%; P < .001). SCN5A-1103Y potentiates the effect of hypokalemia on prolonging myocardial repolarization in the general African-American population. These findings have clinical implications for modification of QT prolonging factors, such as hypokalemia, in the 15% of African Americans who are carriers of SCN5A-1103Y. © 2014.

Lung cancer risk associated with Thr495Pro polymorphism of GHR in Chinese population.

PubMed

Cao, Guochun; Lu, Hongna; Feng, Jifeng; Shu, Jian; Zheng, Datong; Hou, Yayi

2008-04-01

The incidence of lung cancer has been increasing over recent decades. Previous studies showed that polymorphisms of the genes involved in carcinogen-detoxication, DNA repair and cell cycle control comprise risk factors for lung cancer. Recent observations revealed that the growth hormone receptor (GHR) might play important roles in carcinogenesis and Rudd et al. found that the Thr495Pro polymorphism of GHR was strongly associated with lung cancer risk in Caucasians living in the UK (OR = 12.98, P = 0.0019, 95% CI: 1.77-infinity). To test whether this variant of GHR would modify the risk of lung cancer in Chinese population, we compared the polymorphism between 778 lung cancer patients and 781 healthy control subjects. Our results indicate that the frequency of 495Thr (2.8%) allele in cases was significantly higher than in controls (OR = 2.04, P = 0.006, 95% CI: 1.21-3.42) which indicated this allele might be a risk factor for lung cancer. Further analyses revealed Thr495Pro variant was associated with lung cancer in the subpopulation with higher risk for lung cancer: male subpopulation, still-smokers subpopulation and the subpopulation with familial history of cancer. In different histological types of lung cancer, Thr495Pro SNP was significantly associated with small cell and squamous cell lung cancer, but not with adenocarcinoma, which suggested a potential interaction between this polymorphism and metabolic pathways related to smoking. The potential gene-environment interaction on lung cancer risk was evaluated using MDR software. A significant redundant interaction between Thr495Pro polymorphism and smoking dose and familial history of cancer was identified and the combination of genetic factors and smoking status or familial history of cancer barely increased the cancer risk prediction accuracy. In conclusion, our results suggested that the Thr495Pro polymorphism of GHR was associated with the risk of lung cancer in a redundant interaction with smoking and familial history of cancer.

The effects of TLR3, TRIF and TRAF3 SNPs and interactions with environmental factors on type 2 diabetes mellitus and vascular complications in a Han Chinese population.

PubMed

Zhou, Zixing; Zeng, Chengli; Nie, Lihong; Huang, Shiqi; Guo, Congcong; Xiao, Di; Han, Yajing; Ye, Xiaohong; Ou, Meiling; Huang, Chuican; Ye, Xingguang; Wen, Zihao; Yang, Guang; Jing, Chunxia

2017-08-30

Toll-like receptor 3 (TLR3) is involved in type I interferon-β (IFN-β) via TIR-domain-containing adapter-inducing interferon-β (TRIF) and Tumor necrosis factor receptor-associated factor 3 (TRAF3), culminating in inflammation and immunity reactions. TLR3 is implicated in insulin resistance and type 2 diabetes mellitus (T2DM). Eight SNPs of these genes were detected in 552 T2DM patients and 552 matched healthy control subjects. Gene-gene and gene-environment interactions and haplotype associations were also evaluated. We identified a 21% increased risk of T2DM for the T allele of rs12435483 in the TRAF3 gene (OR: 1.21; 95% CI: 1.01-1.44; P=0.036). The GA genotype and GA+AA genotype of TRAF3 rs12147254 were found to increase the risk of coronary heart disease (CHD) among T2DM patients (GA vs. GG: OR=4.17, 95% CI: 1.04-16.79, P=0.045; GA+AA vs. GG: OR=3.97, 95% CI: 1.02-15.48, P=0.047). However, the GACGAC haplotype in TRAF3 had a protective effect on T2DM micro-macrovascular complications (OR=0.33, 95% CI: 0.13-0.85, P=0.017). Two-factor (TRAF3 rs12435483 and LDL) and three-factor (TRAF3 rs12435483, BMI and HDL) interactions of the risk of T2DM were identified. In conclusion, the genetic variants in the TLR3-TRIF-TRAF3-INF-β signaling pathway and interactions with some particular environmental factors (LDL, BMI and HDL) may contribute to susceptibility to T2DM and vascular complications in the Han Chinese population. Copyright © 2017. Published by Elsevier B.V.

A systematic review of the neurobiological underpinnings of borderline personality disorder (BPD) in childhood and adolescence.

PubMed

Winsper, Catherine; Marwaha, Steven; Lereya, Suzet Tanya; Thompson, Andrew; Eyden, Julie; Singh, Swaran P

2016-12-01

Contemporary theories for the aetiology of borderline personality disorder (BPD) take a lifespan approach asserting that inborn biological predisposition is potentiated across development by environmental risk factors. In this review, we present and critically evaluate evidence on the neurobiology of BPD in childhood and adolescence, compare this evidence to the adult literature, and contextualise within a neurodevelopmental framework. A systematic review was conducted to identify studies examining the neurobiological (i.e. genetic, structural neuroimaging, neurophysiological, and neuropsychological) correlates of BPD symptoms in children and adolescents aged 19 years or under. We identified, quality assessed, and narratively summarised 34 studies published between 1980 and June 2016. Similar to findings in adult populations, twin studies indicated moderate to high levels of heritability of BPD, and there was some evidence for gene-environment interactions. Also consistent with adult reports is that some adolescents with BPD demonstrated structural (grey and white matter) alterations in frontolimbic regions and neuropsychological abnormalities (i.e. reduced executive function and disturbances in social cognition). These findings suggest that neurobiological abnormalities observed in adult BPD may not solely be the consequence of chronic morbidity or prolonged medication use. They also provide tentative support for neurodevelopmental theories of BPD by demonstrating that neurobiological markers may be observed from childhood onwards and interact with environmental factors to increase risk of BPD in young populations. Prospective studies with a range of repeated measures are now required to elucidate the temporal unfurling of neurobiological features and further delineate the complex pathways to BPD.

MATERNAL INFECTION AND IMMUNE INVOLVEMENT IN AUTISM

PubMed Central

Patterson, Paul H.

2011-01-01

Recent studies have highlighted a connection between infection during pregnancy and increased risk for autism in the offspring. Parallel studies of cerebral spinal fluid, blood, and postmortem brains reveal an ongoing, hyper-responsive inflammatory-like state in many young as well as adult autism subjects. There are also indications of gastrointestinal problems in at least a subset of autistic children. Work with animal models of the maternal infection risk factor indicate that aspects of brain and peripheral immune dysregulation can be begin during fetal development and be maintained through adulthood. The offspring of infected, or immune-activated dams also display cardinal behavioral features of autism, as well as neuropathology consistent with that seen in human autism. These rodent models are proving useful for the study of pathogenesis and gene-environment interaction, as well as for the exploration of potential therapeutic strategies. PMID:21482187

Different implications of paternal and maternal atopy for perinatal IgE production and asthma development.

PubMed

Wu, Chih-Chiang; Chen, Rong-Fu; Kuo, Ho-Chang

2012-01-01

Asthma is a hereditary disease associated with IgE-mediated reaction. Whether maternal atopy and paternal atopy have different impacts on perinatal IgE production and asthma development remains unclear. This paper reviews and summarizes the effects of maternal and paternal atopy on the developmental aspects of IgE production and asthma. Maternal atopy affects both pre- and postnatal IgE production, whereas paternal atopy mainly affects the latter. Maternally transmitted genes GSTP1 and FceRI-beta are associated with lung function and allergic sensitization, respectively. In IgE production and asthma development, the maternal influence on gene-environment interaction is greater than paternal influence. Maternal, paternal, and/or postnatal environmental modulation of allergic responses have been linked to epigenetic mechanisms, which may be good targets for early prevention of asthma.

Different Implications of Paternal and Maternal Atopy for Perinatal IgE Production and Asthma Development

PubMed Central

Wu, Chih-Chiang; Chen, Rong-Fu; Kuo, Ho-Chang

2012-01-01

Asthma is a hereditary disease associated with IgE-mediated reaction. Whether maternal atopy and paternal atopy have different impacts on perinatal IgE production and asthma development remains unclear. This paper reviews and summarizes the effects of maternal and paternal atopy on the developmental aspects of IgE production and asthma. Maternal atopy affects both pre- and postnatal IgE production, whereas paternal atopy mainly affects the latter. Maternally transmitted genes GSTP1 and FceRI-beta are associated with lung function and allergic sensitization, respectively. In IgE production and asthma development, the maternal influence on gene-environment interaction is greater than paternal influence. Maternal, paternal, and/or postnatal environmental modulation of allergic responses have been linked to epigenetic mechanisms, which may be good targets for early prevention of asthma. PMID:22272211

Role of Investigating Thrombophilic Disorders in Young Stroke

PubMed Central

Ng, Kay W. P.; Loh, Pei K.; Sharma, Vijay K.

2011-01-01

Our knowledge about various inherited and acquired causes of thrombophilic disorders has increased significantly during the past decade. Technology for various diagnostic tests for these rare disorders has matched the rapid advances in our understanding about the thrombophilic disorders. Inherited thrombophilic disorders predispose young patients for various venous or arterial thrombotic and thromboembolic episodes. Our understanding has also improved about various gene-gene and gene-environment interactions and their impact on the resultant heterogenous clinical manifestations. We describe various thrombophilic disorders, their diagnostic tests, pathogenic potential in isolation or with other concurrent inherited/acquired defects and possible therapeutic and prophylactic strategies. Better understanding, optimal diagnostic and screening protocols are expected to improve the diagnostic yield and help to reduce morbidity, disability, and mortality in relatively younger patients harbouring these inherited and acquired thrombophilic disorders. PMID:21331344

Comparative analysis of methods for detecting interacting loci

PubMed Central

2011-01-01

Background Interactions among genetic loci are believed to play an important role in disease risk. While many methods have been proposed for detecting such interactions, their relative performance remains largely unclear, mainly because different data sources, detection performance criteria, and experimental protocols were used in the papers introducing these methods and in subsequent studies. Moreover, there have been very few studies strictly focused on comparison of existing methods. Given the importance of detecting gene-gene and gene-environment interactions, a rigorous, comprehensive comparison of performance and limitations of available interaction detection methods is warranted. Results We report a comparison of eight representative methods, of which seven were specifically designed to detect interactions among single nucleotide polymorphisms (SNPs), with the last a popular main-effect testing method used as a baseline for performance evaluation. The selected methods, multifactor dimensionality reduction (MDR), full interaction model (FIM), information gain (IG), Bayesian epistasis association mapping (BEAM), SNP harvester (SH), maximum entropy conditional probability modeling (MECPM), logistic regression with an interaction term (LRIT), and logistic regression (LR) were compared on a large number of simulated data sets, each, consistent with complex disease models, embedding multiple sets of interacting SNPs, under different interaction models. The assessment criteria included several relevant detection power measures, family-wise type I error rate, and computational complexity. There are several important results from this study. First, while some SNPs in interactions with strong effects are successfully detected, most of the methods miss many interacting SNPs at an acceptable rate of false positives. In this study, the best-performing method was MECPM. Second, the statistical significance assessment criteria, used by some of the methods to control the type I error rate, are quite conservative, thereby limiting their power and making it difficult to fairly compare them. Third, as expected, power varies for different models and as a function of penetrance, minor allele frequency, linkage disequilibrium and marginal effects. Fourth, the analytical relationships between power and these factors are derived, aiding in the interpretation of the study results. Fifth, for these methods the magnitude of the main effect influences the power of the tests. Sixth, most methods can detect some ground-truth SNPs but have modest power to detect the whole set of interacting SNPs. Conclusion This comparison study provides new insights into the strengths and limitations of current methods for detecting interacting loci. This study, along with freely available simulation tools we provide, should help support development of improved methods. The simulation tools are available at: http://code.google.com/p/simulation-tool-bmc-ms9169818735220977/downloads/list. PMID:21729295

Comparative analysis of methods for detecting interacting loci.

PubMed

Chen, Li; Yu, Guoqiang; Langefeld, Carl D; Miller, David J; Guy, Richard T; Raghuram, Jayaram; Yuan, Xiguo; Herrington, David M; Wang, Yue

2011-07-05

Interactions among genetic loci are believed to play an important role in disease risk. While many methods have been proposed for detecting such interactions, their relative performance remains largely unclear, mainly because different data sources, detection performance criteria, and experimental protocols were used in the papers introducing these methods and in subsequent studies. Moreover, there have been very few studies strictly focused on comparison of existing methods. Given the importance of detecting gene-gene and gene-environment interactions, a rigorous, comprehensive comparison of performance and limitations of available interaction detection methods is warranted. We report a comparison of eight representative methods, of which seven were specifically designed to detect interactions among single nucleotide polymorphisms (SNPs), with the last a popular main-effect testing method used as a baseline for performance evaluation. The selected methods, multifactor dimensionality reduction (MDR), full interaction model (FIM), information gain (IG), Bayesian epistasis association mapping (BEAM), SNP harvester (SH), maximum entropy conditional probability modeling (MECPM), logistic regression with an interaction term (LRIT), and logistic regression (LR) were compared on a large number of simulated data sets, each, consistent with complex disease models, embedding multiple sets of interacting SNPs, under different interaction models. The assessment criteria included several relevant detection power measures, family-wise type I error rate, and computational complexity. There are several important results from this study. First, while some SNPs in interactions with strong effects are successfully detected, most of the methods miss many interacting SNPs at an acceptable rate of false positives. In this study, the best-performing method was MECPM. Second, the statistical significance assessment criteria, used by some of the methods to control the type I error rate, are quite conservative, thereby limiting their power and making it difficult to fairly compare them. Third, as expected, power varies for different models and as a function of penetrance, minor allele frequency, linkage disequilibrium and marginal effects. Fourth, the analytical relationships between power and these factors are derived, aiding in the interpretation of the study results. Fifth, for these methods the magnitude of the main effect influences the power of the tests. Sixth, most methods can detect some ground-truth SNPs but have modest power to detect the whole set of interacting SNPs. This comparison study provides new insights into the strengths and limitations of current methods for detecting interacting loci. This study, along with freely available simulation tools we provide, should help support development of improved methods. The simulation tools are available at: http://code.google.com/p/simulation-tool-bmc-ms9169818735220977/downloads/list.

Targeting the human genome-microbiome axis for drug discovery: inspirations from global systems biology and traditional Chinese medicine.

PubMed

Zhao, Liping; Nicholson, Jeremy K; Lu, Aiping; Wang, Zhengtao; Tang, Huiru; Holmes, Elaine; Shen, Jian; Zhang, Xu; Li, Jia V; Lindon, John C

2012-07-06

Most chronic diseases impairing current human public health involve not only the human genome but also gene-environment interactions, and in the latter case the gut microbiome is an important factor. This makes the classical single drug-receptor target drug discovery paradigm much less applicable. There is widespread and increasing international interest in understanding the properties of traditional Chinese medicines (TCMs) for their potential utilization as a source of new drugs for Western markets as emerging evidence indicates that most TCM drugs are actually targeting both the host and its symbiotic microbes. In this review, we explore the challenges of and opportunities for harmonizing Eastern-Western drug discovery paradigms by focusing on emergent functions at the whole body level of humans as superorganisms. This could lead to new drug candidate compounds for chronic diseases targeting receptors outside the currently accepted "druggable genome" and shed light on current high interest issues in Western medicine such as drug-drug and drug-diet-gut microbial interactions that will be crucial in the development and delivery of future therapeutic regimes optimized for the individual patient.

Epistasis and Its Implications for Personal Genetics

PubMed Central

Moore, Jason H.; Williams, Scott M.

2009-01-01

The widespread availability of high-throughput genotyping technology has opened the door to the era of personal genetics, which brings to consumers the promise of using genetic variations to predict individual susceptibility to common diseases. Despite easy access to commercial personal genetics services, our knowledge of the genetic architecture of common diseases is still very limited and has not yet fulfilled the promise of accurately predicting most people at risk. This is partly because of the complexity of the mapping relationship between genotype and phenotype that is a consequence of epistasis (gene-gene interaction) and other phenomena such as gene-environment interaction and locus heterogeneity. Unfortunately, these aspects of genetic architecture have not been addressed in most of the genetic association studies that provide the knowledge base for interpreting large-scale genetic association results. We provide here an introductory review of how epistasis can affect human health and disease and how it can be detected in population-based studies. We provide some thoughts on the implications of epistasis for personal genetics and some recommendations for improving personal genetics in light of this complexity. PMID:19733727

Epistasis and its implications for personal genetics.

PubMed

Moore, Jason H; Williams, Scott M

2009-09-01

The widespread availability of high-throughput genotyping technology has opened the door to the era of personal genetics, which brings to consumers the promise of using genetic variations to predict individual susceptibility to common diseases. Despite easy access to commercial personal genetics services, our knowledge of the genetic architecture of common diseases is still very limited and has not yet fulfilled the promise of accurately predicting most people at risk. This is partly because of the complexity of the mapping relationship between genotype and phenotype that is a consequence of epistasis (gene-gene interaction) and other phenomena such as gene-environment interaction and locus heterogeneity. Unfortunately, these aspects of genetic architecture have not been addressed in most of the genetic association studies that provide the knowledge base for interpreting large-scale genetic association results. We provide here an introductory review of how epistasis can affect human health and disease and how it can be detected in population-based studies. We provide some thoughts on the implications of epistasis for personal genetics and some recommendations for improving personal genetics in light of this complexity.

Parent depressive symptomatology moderates the etiology of externalizing behavior in childhood: An examination of gene-environment interaction effects.

PubMed

Clark, D Angus; Klump, Kelly L; Burt, S Alexandra

2018-04-26

Parent depressive symptomatology is robust risk factor for externalizing behavior in childhood (Goodman et al., 2011). Although the precise mechanisms underlying this association have yet to be fully illuminated, there is some evidence that parent depression can impact externalizing behavior via both genetic and environmental pathways. In the current study, we investigated the extent to which genetic and environmental influences on externalizing behavior are moderated by parent depressive symptoms (i.e., genotype-environment interaction) in a sample of 2,060, 6- to 11-year-old twins. Results suggest that genetic influences explain more variance in externalizing behavior as maternal depressive symptoms increase, whereas shared environmental effects decrease. These findings were specific to maternal depressive symptoms, however, and did not extend to not paternal depressive symptoms. Findings are critical for understanding the role of parental depression as a risk factor for problematic child behavior, and informing programs that seek to minimize the impact of this risk factor. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Genetic liability, environment, and the development of fussiness in toddlers: the roles of maternal depression and parental responsiveness.

PubMed

Natsuaki, Misaki N; Ge, Xiaojia; Leve, Leslie D; Neiderhiser, Jenae M; Shaw, Daniel S; Conger, Rand D; Scaramella, Laura V; Reid, John B; Reiss, David

2010-09-01

Using a longitudinal, prospective adoption design, the authors of this study examined the effects of the environment (adoptive parents' depressive symptoms and responsiveness) and genetic liability of maternal depression (inferred by birth mothers' major depressive disorder [MDD]) on the development of fussiness in adopted children between 9 and 18 months old. The sample included 281 families linked through adoption, with each family including 4 individuals (i.e., adopted child, birth mother, adoptive father and mother). Results showed that adoptive mothers' depressive symptoms when their child was 9 months old were positively associated with child fussiness at 18 months. A significant interaction between birth mothers' MDD and adoptive mothers' responsiveness indicated that children of birth mothers with MDD showed higher levels of fussiness at 18 months when adoptive mothers had been less responsive to the children at 9 months. However, in the context of high levels of adoptive mothers' responsiveness, children of birth mothers with MDD did not show elevated fussiness at 18 months. Findings are discussed in terms of gene-environment interactions in the intergenerational risk transmission of depression.

Vitamin D and colorectal cancer: molecular, epidemiological and clinical evidence.

PubMed

Dou, Ruoxu; Ng, Kimmie; Giovannucci, Edward L; Manson, JoAnn E; Qian, Zhi Rong; Ogino, Shuji

2016-05-01

In many cells throughout the body, vitamin D is converted into its active form calcitriol and binds to the vitamin D receptor (VDR), which functions as a transcription factor to regulate various biological processes including cellular differentiation and immune response. Vitamin D-metabolising enzymes (including CYP24A1 and CYP27B1) and VDR play major roles in exerting and regulating the effects of vitamin D. Preclinical and epidemiological studies have provided evidence for anti-cancer effects of vitamin D (particularly against colorectal cancer), although clinical trials have yet to prove its benefit. In addition, molecular pathological epidemiology research can provide insights into the interaction of vitamin D with tumour molecular and immunity status. Other future research directions include genome-wide research on VDR transcriptional targets, gene-environment interaction analyses and clinical trials on vitamin D efficacy in colorectal cancer patients. In this study, we review the literature on vitamin D and colorectal cancer from both mechanistic and population studies and discuss the links and controversies within and between the two parts of evidence.

How much can a large population study on genes, environments, their interactions and common diseases contribute to the health of the American people?

PubMed

Chaufan, Claudia

2007-10-01

I offer a critical perspective on a large-scale population study on gene-environment interactions and common diseases proposed by the US Secretary of Health and Human Services' Advisory Committee on Genetics, Health, and Society (SACGHS). I argue that for scientific and policy reasons this and similar studies have little to add to current knowledge about how to prevent, treat, or decrease inequalities in common diseases, all of which are major claims of the proposal. I use diabetes as an exemplar of the diseases that the study purports to illuminate. I conclude that the question is not whether the study will meet expectations or whether the current emphasis on a genetic paradigm is real or imagined, desirable or not. Rather, the question is why, given the flaws of the science underwriting the study, its assumptions remain unchallenged. Future research should investigate the reasons for this immunity from criticism and for the popularity of this and similar projects among laypersons as well as among intellectuals.

Exposure to Environmental Toxicants and Pathogenesis of Amyotrophic Lateral Sclerosis: State of the Art and Research Perspectives

PubMed Central

Trojsi, Francesca; Monsurrò, Maria Rosaria; Tedeschi, Gioacchino

2013-01-01

There is a broad scientific consensus that amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease, is caused by gene-environment interactions. In fact, given that only about 10% of all ALS diagnosis has a genetic basis, gene-environmental interaction may give account for the remaining percentage of cases. However, relatively little attention has been paid to environmental and lifestyle factors that may trigger the cascade of motor neuron degeneration leading to ALS, although exposure to chemicals—including lead and pesticides—agricultural environments, smoking, intense physical activity, trauma and electromagnetic fields have been associated with an increased risk of ALS. This review provides an overview of our current knowledge of potential toxic etiologies of ALS with emphasis on the role of cyanobacteria, heavy metals and pesticides as potential risk factors for developing ALS. We will summarize the most recent evidence from epidemiological studies and experimental findings from animal and cellular models, revealing that potential causal links between environmental toxicants and ALS pathogenesis have not been fully ascertained, thus justifying the need for further research. PMID:23887652

Interaction of child maltreatment and 5-HTT polymorphisms: suicidal ideation among children from low-SES backgrounds.

PubMed

Cicchetti, Dante; Rogosch, Fred A; Sturge-Apple, Melissa; Toth, Sheree L

2010-06-01

To investigate whether genotypic variation of the serotonin transporter gene-linked promoter region (5-HTTLPR) moderates the effect of maltreatment on suicidal ideation in school-aged children. Eight hundred and fifty low-income children (478 maltreated; 372 non-maltreated) provided DNA samples and self-reported depressive and suicidal symptoms. Genotypes of 5-HTTLPR (s/s or s/l vs. l/l) were determined by fragment analyses. Higher suicidal ideation was found among maltreated than non-maltreated children; the groups did not differ in 5-HTTLPR genotype frequencies. Children with one to two maltreatment subtypes and s/s or s/l genotypes had higher suicidal ideation than those with the l/l genotype; suicidal ideation did not differ in non-maltreated children or children with three to four maltreatment subtypes based on 5-HTTLPR variation. The results were applicable to emotionally maltreated/neglected and to physically/sexually abused children. Gene-environment interaction was not found for depressive symptoms. The protective effect of the 5-HTTLPR l/l genotype on suicidal ideation was limited to maltreated children experiencing fewer subtypes.

Oxytocin Pathways in the Intergenerational Transmission of Maternal Early Life Stress

PubMed Central

Toepfer, Philipp; Heim, Christine; Entringer, Sonja; Binder, Elisabeth; Wadhwa, Pathik; Buss, Claudia

2017-01-01

Severe stress in early life, such as childhood abuse and neglect, constitutes a major risk factor in the etiology of psychiatric disorders and somatic diseases. Importantly, these long-term effects may impact the next generation. The intergenerational transmission of maternal early life stress (ELS) may occur via pre-and postnatal pathways, such as alterations in maternal-fetal-placental stress physiology, maternal depression during pregnancy and postpartum, as well as impaired mother-offspring interactions. The neuropeptide oxytocin (OT) has gained considerable attention for its role in modulating all of these assumed transmission pathways. Moreover, central and peripheral OT signaling pathways are highly sensitive to environmental exposures and may be compromised by ELS with implications for these putative transmission mechanisms. Together, these data suggest that OT pathways play an important role in the intergenerational transmission of maternal ELS in humans. By integrating recent studies on gene-environment interactions and epigenetic modifications in OT pathway genes, the present review aims to develop a conceptual framework of intergenerational transmission of maternal ELS that emphasizes the role of OT. PMID:28027955

Powerful multilocus tests of genetic association in the presence of gene-gene and gene-environment interactions.

PubMed

Chatterjee, Nilanjan; Kalaylioglu, Zeynep; Moslehi, Roxana; Peters, Ulrike; Wacholder, Sholom

2006-12-01

In modern genetic epidemiology studies, the association between the disease and a genomic region, such as a candidate gene, is often investigated using multiple SNPs. We propose a multilocus test of genetic association that can account for genetic effects that might be modified by variants in other genes or by environmental factors. We consider use of the venerable and parsimonious Tukey's 1-degree-of-freedom model of interaction, which is natural when individual SNPs within a gene are associated with disease through a common biological mechanism; in contrast, many standard regression models are designed as if each SNP has unique functional significance. On the basis of Tukey's model, we propose a novel but computationally simple generalized test of association that can simultaneously capture both the main effects of the variants within a genomic region and their interactions with the variants in another region or with an environmental exposure. We compared performance of our method with that of two standard tests of association, one ignoring gene-gene/gene-environment interactions and the other based on a saturated model of interactions. We demonstrate major power advantages of our method both in analysis of data from a case-control study of the association between colorectal adenoma and DNA variants in the NAT2 genomic region, which are well known to be related to a common biological phenotype, and under different models of gene-gene interactions with use of simulated data.

Multiscale Modeling of Gene-Behavior Associations in an Artificial Neural Network Model of Cognitive Development.

PubMed

Thomas, Michael S C; Forrester, Neil A; Ronald, Angelica

2016-01-01

In the multidisciplinary field of developmental cognitive neuroscience, statistical associations between levels of description play an increasingly important role. One example of such associations is the observation of correlations between relatively common gene variants and individual differences in behavior. It is perhaps surprising that such associations can be detected despite the remoteness of these levels of description, and the fact that behavior is the outcome of an extended developmental process involving interaction of the whole organism with a variable environment. Given that they have been detected, how do such associations inform cognitive-level theories? To investigate this question, we employed a multiscale computational model of development, using a sample domain drawn from the field of language acquisition. The model comprised an artificial neural network model of past-tense acquisition trained using the backpropagation learning algorithm, extended to incorporate population modeling and genetic algorithms. It included five levels of description-four internal: genetic, network, neurocomputation, behavior; and one external: environment. Since the mechanistic assumptions of the model were known and its operation was relatively transparent, we could evaluate whether cross-level associations gave an accurate picture of causal processes. We established that associations could be detected between artificial genes and behavioral variation, even under polygenic assumptions of a many-to-one relationship between genes and neurocomputational parameters, and when an experience-dependent developmental process interceded between the action of genes and the emergence of behavior. We evaluated these associations with respect to their specificity (to different behaviors, to function vs. structure), to their developmental stability, and to their replicability, as well as considering issues of missing heritability and gene-environment interactions. We argue that gene-behavior associations can inform cognitive theory with respect to effect size, specificity, and timing. The model demonstrates a means by which researchers can undertake multiscale modeling with respect to cognition and develop highly specific and complex hypotheses across multiple levels of description. Copyright © 2015 Cognitive Science Society, Inc.

Allowing for population stratification in case-only studies of gene-environment interaction, using genomic control.

PubMed

Yadav, Pankaj; Freitag-Wolf, Sandra; Lieb, Wolfgang; Dempfle, Astrid; Krawczak, Michael

2015-10-01

Gene-environment interactions (G × E) have attracted considerable research interest in the past owing to their scientific and public health implications, but powerful statistical methods are required to successfully track down G × E, particularly at a genome-wide level. Previously, a case-only (CO) design has been proposed as a means to identify G × E with greater efficiency than traditional case-control or cohort studies. However, as with genotype-phenotype association studies themselves, hidden population stratification (PS) can impact the validity of G × E studies using a CO design. Since this problem has been subject to little research to date, we used comprehensive simulation to systematically assess the type I error rate, power and effect size bias of CO studies of G × E in the presence of PS. Three types of PS were considered, namely genetic-only (PSG), environment-only (PSE), and joint genetic and environmental stratification (PSGE). Our results reveal that the type I error rate of an unadjusted Wald test, appropriate for the CO design, would be close to its nominal level (0.05 in our study) as long as PS involves only one interaction partner (i.e., either PSG or PSE). In contrast, if the study population is stratified with respect to both G and E (i.e., if there is PSGE), then the type I error rate is seriously inflated and estimates of the underlying G × E interaction are biased. Comparison of CO to a family-based case-parents design confirmed that the latter is more robust against PSGE, as expected. However, case-parent trios may be particularly unsuitable for G × E studies in view of the fact that they require genotype data from parents and that many diseases with an environmental component are likely to be of late onset. An alternative approach to adjusting for PS is principal component analysis (PCA), which has been widely used for this very purpose in past genome-wide association studies (GWAS). However, resolving genetic PS properly by PCA requires genetic data at the population level, the availability of which would conflict with the basic idea of the CO design. Therefore, we explored three modified Wald test statistics, inspired by the genomic control (GC) approach to GWAS, as an alternative means to allow for PSGE. The modified statistics were benchmarked against a stratified Wald test assuming known population affiliation, which should provide maximum power under PS. Our results confirm that GC is capable of successfully and efficiently correcting the PS-induced inflation of the type I error rate in CO studies of G × E.

Early life stress, MAOA, and gene-environment interactions predict behavioral disinhibition in children.

PubMed

Enoch, M-A; Steer, C D; Newman, T K; Gibson, N; Goldman, D

2010-02-01

Several, but not all, studies have shown that the monoamine oxidase A functional promoter polymorphism (MAOA-LPR) interacts with childhood adversity to predict adolescent and adult antisocial behavior. However, it is not known whether MAOA-LPR interacts with early life (pre-birth-3 years) stressors to influence behavior in prepubertal children. The Avon Longitudinal Study of Parents and Children, UK, is a community-representative cohort study of children followed from pre-birth onwards. The impact of family adversity from pre-birth to age 3 years and stressful life events from 6 months to 7 years on behavioral disinhibition was determined in 7500 girls and boys. Behavioral disinhibition measures were: mother-reported hyperactivity and conduct disturbances (Strengths and Difficulties Questionnaire) at ages 4 and 7 years. In both sexes, exposure to family adversity and stressful life events in the first 3 years of life predicted behavioral disinhibition at age 4, persisting until age 7. In girls, MAOA-LPR interacted with stressful life events experienced from 6 months to 3.5 years to influence hyperactivity at ages 4 and 7. In boys, the interaction of MAOA-LPR with stressful life events between 1.5 and 2.5 years predicted hyperactivity at age 7 years. The low activity MAOA-LPR variant was associated with increased hyperactivity in girls and boys exposed to high stress. In contrast, there was no MAOA-LPR interaction with family adversity. In a general population sample of prepubertal children, exposure to common stressors from pre-birth to 3 years predicted behavioral disinhibition, and MAOA-LPR- stressful life event interactions specifically predicted hyperactivity.

A meta-analysis of heritability of cognitive aging: minding the "missing heritability" gap.

PubMed

Reynolds, Chandra A; Finkel, Deborah

2015-03-01

The etiologies underlying variation in adult cognitive performance and cognitive aging have enjoyed much attention in the literature, but much of that attention has focused on broad factors, principally general cognitive ability. The current review provides meta-analyses of age trends in heritability of specific cognitive abilities and considers the profile of genetic and environmental factors contributing to cognitive aging to address the 'missing heritability' issue. Our findings, based upon evaluating 27 reports in the literature, indicate that verbal ability demonstrated declining heritability, after about age 60, as did spatial ability and perceptual speed more modestly. Trends for general memory, working memory, and spatial ability generally indicated stability, or small increases in heritability in mid-life. Equivocal results were found for executive function. A second meta-analysis then considered the gap between twin-based versus SNP-based heritability derived from population-based GWAS studies. Specifically, we considered twin correlation ratios to agnostically re-evaluate biometrical models across age and by cognitive domain. Results modestly suggest that nonadditive genetic variance may become increasingly important with age, especially for verbal ability. If so, this would support arguments that lower SNP-based heritability estimates result in part from uncaptured non-additive influences (e.g., dominance, gene-gene interactions), and possibly gene-environment (GE) correlations. Moreover, consistent with longitudinal twin studies of aging, as rearing environment becomes a distal factor, increasing genetic variance may result in part from nonadditive genetic influences or possible GE correlations. Sensitivity to life course dynamics is crucial to understanding etiological contributions to adult cognitive performance and cognitive aging.

Caffeine, creatine, GRIN2A and Parkinson's disease progression.

PubMed

Simon, David K; Wu, Cai; Tilley, Barbara C; Lohmann, Katja; Klein, Christine; Payami, Haydeh; Wills, Anne-Marie; Aminoff, Michael J; Bainbridge, Jacquelyn; Dewey, Richard; Hauser, Robert A; Schaake, Susen; Schneider, Jay S; Sharma, Saloni; Singer, Carlos; Tanner, Caroline M; Truong, Daniel; Wei, Peng; Wong, Pei Shieen; Yang, Tianzhong

2017-04-15

Caffeine is neuroprotective in animal models of Parkinson's disease (PD) and caffeine intake is inversely associated with the risk of PD. This association may be influenced by the genotype of GRIN2A, which encodes an NMDA-glutamate-receptor subunit. In two placebo-controlled studies, we detected no association of caffeine intake with the rate of clinical progression of PD, except among subjects taking creatine, for whom higher caffeine intake was associated with more rapid progression. We now have analyzed data from 420 subjects for whom DNA samples and caffeine intake data were available from a placebo-controlled study of creatine in PD. The GRIN2A genotype was not associated with the rate of clinical progression of PD in the placebo group. However, there was a 4-way interaction between GRIN2A genotype, caffeine, creatine and the time since baseline. Among subjects in the creatine group with high levels of caffeine intake, but not among those with low caffeine intake, the GRIN2A T allele was associated with more rapid progression (p=0.03). These data indicate that the deleterious interaction between caffeine and creatine with respect to rate of progression of PD is influenced by GRIN2A genotype. This example of a genetic factor interacting with environmental factors illustrates the complexity of gene-environment interactions in the progression of PD. Copyright © 2017 Elsevier B.V. All rights reserved.

BDNF rs6265 methylation and genotype interact on risk for schizophrenia.

PubMed

Ursini, Gianluca; Cavalleri, Tommaso; Fazio, Leonardo; Angrisano, Tiziana; Iacovelli, Luisa; Porcelli, Annamaria; Maddalena, Giancarlo; Punzi, Giovanna; Mancini, Marina; Gelao, Barbara; Romano, Raffaella; Masellis, Rita; Calabrese, Francesca; Rampino, Antonio; Taurisano, Paolo; Di Giorgio, Annabella; Keller, Simona; Tarantini, Letizia; Sinibaldi, Lorenzo; Quarto, Tiziana; Popolizio, Teresa; Caforio, Grazia; Blasi, Giuseppe; Riva, Marco A; De Blasi, Antonio; Chiariotti, Lorenzo; Bollati, Valentina; Bertolino, Alessandro

2016-01-01

Epigenetic mechanisms can mediate gene-environment interactions relevant for complex disorders. The BDNF gene is crucial for development and brain plasticity, is sensitive to environmental stressors, such as hypoxia, and harbors the functional SNP rs6265 (Val(66)Met), which creates or abolishes a CpG dinucleotide for DNA methylation. We found that methylation at the BDNF rs6265 Val allele in peripheral blood of healthy subjects is associated with hypoxia-related early life events (hOCs) and intermediate phenotypes for schizophrenia in a distinctive manner, depending on rs6265 genotype: in ValVal individuals increased methylation is associated with exposure to hOCs and impaired working memory (WM) accuracy, while the opposite is true for ValMet subjects. Also, rs6265 methylation and hOCs interact in modulating WM-related prefrontal activity, another intermediate phenotype for schizophrenia, with an analogous opposite direction in the 2 genotypes. Consistently, rs6265 methylation has a different association with schizophrenia risk in ValVals and ValMets. The relationships of methylation with BDNF levels and of genotype with BHLHB2 binding likely contribute to these opposite effects of methylation. We conclude that BDNF rs6265 methylation interacts with genotype to bridge early environmental exposures to adult phenotypes, relevant for schizophrenia. The study of epigenetic changes in regions containing genetic variation relevant for human diseases may have beneficial implications for the understanding of how genes are actually translated into phenotypes.

The association between adult mortality risk and family history of longevity: the moderating effects of socioeconomic status.

PubMed

Temby, Owen F; Smith, Ken R

2014-11-01

Studies consistently show that increasing levels of socioeconomic status (SES) and having a familial history of longevity reduce the risk of mortality. But do these two variables interact, such that individuals with lower levels of SES, for example, may experience an attenuated longevity penalty by virtue of having long-lived relatives? This article examines this interaction by analysing survival past age 40 based on data from the Utah Population Database on an extinct cohort of men born from the years 1840 to 1909. Cox proportional hazards regression and logistic regression are used to test for the main and interaction mortality effects of SES and familial excess longevity (FEL), a summary measure of an individual's history of longevity among his or her relatives. This research finds that the mortality hazard rate for men in the top 15th percentile of occupational status decreases more as FEL increases than it does among men in the bottom 15th percentile. In addition, the mortality hazard rate among farmers decreases more as FEL increases than it does for non-farmers. With a strong family history of longevity as a proxy for a genetic predisposition, this research suggests that a gene-environment interaction occurs whereby the benefits of familial excess longevity are more available to those who have occupations with more autonomy and greater economic resources and/or opportunities for physical activity.

Nature versus nurture in determining athletic ability.

PubMed

Brutsaert, Tom D; Parra, Esteban J

2009-01-01

This chapter provides an overview of the truism that both nature and nurture determine human athletic ability. The major thesis developed is that environmental effects work through the process of growth and development and interact with an individual's genetic background to produce a specific adult phenotype, i.e. an athletic or nonathletic phenotype. On the nature side (genetics), a brief historical review is provided with emphasis on several areas that are likely to command future attention including the rise of genome-wide association as a mapping strategy, the problem of false positives using association approaches, as well as the relatively unknown effects of gene-gene interaction(epistasis), gene-environment interaction, and genome structure on complex trait variance. On the nurture side (environment), common environmental effects such as training-level and sports nutrition are largely ignored in favor of developmental environmental effects that are channeled through growth and development processes. Developmental effects are difficult to distinguish from genetic effects as phenotypic plasticity in response to early life environmental perturbation can produce lasting effects into adulthood. In this regard, the fetal programming (FP) hypothesis is reviewed in some detail as FP provides an excellent example of how developmental effects work and also interact with genetics. In general, FP has well-documented effects on adult body composition and the risk for adult chronic disease, but there is emerging evidence that FP affects human athletic performance as well. 2009 S. Karger AG, Basel

Genotypic variability-based genome-wide association study identifies non-additive loci HLA-C and IL12B for psoriasis.

PubMed

Wei, Wen-Hua; Massey, Jonathan; Worthington, Jane; Barton, Anne; Warren, Richard B

2018-03-01

Genome-wide association studies (GWASs) have identified a number of loci for psoriasis but largely ignored non-additive effects. We report a genotypic variability-based GWAS (vGWAS) that can prioritize non-additive loci without requiring prior knowledge of interaction types or interacting factors in two steps, using a mixed model to partition dichotomous phenotypes into an additive component and non-additive environmental residuals on the liability scale and then the Levene's (Brown-Forsythe) test to assess equality of the residual variances across genotype groups genome widely. The vGWAS identified two genome-wide significant (P < 5.0e-08) non-additive loci HLA-C and IL12B that were also genome-wide significant in an accompanying GWAS in the discovery cohort. Both loci were statistically replicated in vGWAS of an independent cohort with a small sample size. HLA-C and IL12B were reported in moderate gene-gene and/or gene-environment interactions in several occasions. We found a moderate interaction with age-of-onset of psoriasis, which was replicated indirectly. The vGWAS also revealed five suggestive loci (P < 6.76e-05) including FUT2 that was associated with psoriasis with environmental aspects triggered by virus infection and/or metabolic factors. Replication and functional investigation are needed to validate the suggestive vGWAS loci.

Monoamine Oxidase-A Genetic Variants and Childhood Abuse Predict Impulsiveness in Borderline Personality Disorder.

PubMed

Kolla, Nathan J; Meyer, Jeffrey; Sanches, Marcos; Charbonneau, James

2017-11-30

Impulsivity is a core feature of borderline personality disorder (BPD) and antisocial personality disorder (ASPD) that likely arises from combined genetic and environmental influences. The interaction of the low activity variant of the monoamine oxidase-A (MAOA-L) gene and early childhood adversity has been shown to predict aggression in clinical and non-clinical populations. Although impulsivity is a risk factor for aggression in BPD and ASPD, little research has investigated potential gene-environment (G×E) influences impacting its expression in these conditions. Moreover, G×E interactions may differ by diagnosis. Full factorial analysis of variance was employed to investigate the influence of monoamine oxidase-A (MAO-A) genotype, childhood abuse, and diagnosis on Barratt Impulsiveness Scale-11 (BIS-11) scores in 61 individuals: 20 subjects with BPD, 18 subjects with ASPD, and 23 healthy controls. A group×genotype×abuse interaction was present (F(2,49)=4.4, p =0.018), such that the interaction of MAOA-L and childhood abuse predicted greater BIS-11 motor impulsiveness in BPD. Additionally, BPD subjects reported higher BIS-11 attentional impulsiveness versus ASPD participants (t(1,36)=2.3, p =0.025). These preliminary results suggest that MAOA-L may modulate the impact of childhood abuse on impulsivity in BPD. Results additionally indicate that impulsiveness may be expressed differently in BPD and ASPD.

Changing Concepts and Findings on Autism

ERIC Educational Resources Information Center

Rutter, Michael

2013-01-01

New research findings provide major challenges regarding our understanding of the concept of autism. These are critically discussed in relation to research relevant to classification, genetics, environmental risk factors, gene-environment interplay, animal models, biomarkers, clinical features, neuropathology, pharmacotherapy, behavioral…

Can friends protect genetically vulnerable children from depression?

PubMed

Brendgen, Mara; Vitaro, Frank; Bukowski, William M; Dionne, Ginette; Tremblay, Richard E; Boivin, Michel

2013-05-01

The study examined whether reciprocal friendship quantity or quality can mitigate genetic vulnerability for depression symptoms in children. The sample comprised 168 monozygotic twin pairs and 126 same-sex dizygotic twin pairs assessed in Grade 4 (mean age = 10.04 years). Friendship participation was measured via reciprocal nominations of close friendships within the classroom. Friendship quality was measured through self-reports. Depression symptoms were measured through teacher and peer reports. Genetic vulnerability for depression symptoms was unrelated to friendship participation or the number of reciprocal friends, but it was negatively related to positive friendship quality. In line with gene-environment interaction, genetic risk effects on depression symptoms were mitigated in girls who had at least one close reciprocal friend. In boys, only moderate main effects of genetic vulnerability and friendship participation were found but no interaction between them. However, among boys with at least one reciprocal friend, a greater number of friends was related to fewer depression symptoms whereas no cumulative effect of friendship was found for girls. Finally, positive friendship quality was related to fewer depression symptoms in girls and boys even when controlling for genetic risk. The findings emphasize the importance of teaching social interactional skills that promote high-quality friendship relations to help prevent the development of depression symptoms in children.

Schizophrenia, vitamin D, and brain development.

PubMed

Mackay-Sim, Alan; Féron, François; Eyles, Darryl; Burne, Thomas; McGrath, John

2004-01-01

Schizophrenia research is invigorated at present by the recent discovery of several plausible candidate susceptibility genes identified from genetic linkage and gene expression studies of brains from persons with schizophrenia. It is a current challenge to reconcile this gathering evidence for specific candidate susceptibility genes with the "neurodevelopmental hypothesis," which posits that schizophrenia arises from gene-environment interactions that disrupt brain development. We make the case here that schizophrenia may result not from numerous genes of small effect, but a few genes of transcriptional regulation acting during brain development. In particular we propose that low vitamin D during brain development interacts with susceptibility genes to alter the trajectory of brain development, probably by epigenetic regulation that alters gene expression throughout adult life. Vitamin D is an attractive "environmental" candidate because it appears to explain several key epidemiological features of schizophrenia. Vitamin D is an attractive "genetic" candidate because its nuclear hormone receptor regulates gene expression and nervous system development. The polygenic quality of schizophrenia, with linkage to many genes of small effect, maybe brought together via this "vitamin D hypothesis." We also discuss the possibility of a broader set of environmental and genetic factors interacting via the nuclear hormone receptors to affect the development of the brain leading to schizophrenia.

Protein content and methyl donors in maternal diet interact to influence the proliferation rate and cell fate of neural stem cells in rat hippocampus.

PubMed

Amarger, Valérie; Lecouillard, Angèle; Ancellet, Laure; Grit, Isabelle; Castellano, Blandine; Hulin, Philippe; Parnet, Patricia

2014-10-14

Maternal diet during pregnancy and early postnatal life influences the setting up of normal physiological functions in the offspring. Epigenetic mechanisms regulate cell differentiation during embryonic development and may mediate gene/environment interactions. We showed here that high methyl donors associated with normal protein content in maternal diet increased the in vitro proliferation rate of neural stem/progenitor cells isolated from rat E19 fetuses. Gene expression on whole hippocampi at weaning confirmed this effect as evidenced by the higher expression of the Nestin and Igf2 genes, suggesting a higher amount of undifferentiated precursor cells. Additionally, protein restriction reduced the expression of the insulin receptor gene, which is essential to the action of IGFII. Inhibition of DNA methylation in neural stem/progenitor cells in vitro increased the expression of the astrocyte-specific Gfap gene and decreased the expression of the neuron-specific Dcx gene, suggesting an impact on cell differentiation. Our data suggest a complex interaction between methyl donors and protein content in maternal diet that influence the expression of major growth factors and their receptors and therefore impact the proliferation and differentiation capacities of neural stem cells, either through external hormone signals or internal genomic regulation.

The role of epigenetics in depression and suicide: A platform for gene-environment interactions.

PubMed

Lockwood, Laura E; Su, Shaoyong; Youssef, Nagy A

2015-08-30

Epigenetics involves functional modifications of genes. The aim of this paper is to explore if an association exists between epigenetics and depression and/or suicide. MedLine/PubMed searches were performed using both Medical Subject Heading (MeSH) and Non-MeSH terms. Based on pre-specified terms and inclusion criteria, sixteen studies met inclusion criteria by the 3 independent reviewers. Epigenetic changes seem to be important in both depression and suicide. All of the studies reviewed herein found significant epigenetic changes associated with depression and suicide except for two. Several studies showed that hypermethylation of BDNF is involved in suicide. TrkB hypermethylation was also shown to be associated with suicide by several studies, specifically in Brodmann's Areas (BA) 8 and 9. Future research is needed in a larger sample to further characterize these changes. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Effect of household pet ownership on infant immune response and subsequent sensitization

PubMed Central

Simpson, Angela

2010-01-01

Sensitization to pets is a major risk factor for asthma. There are many reports on the relationship between household pets, sensitization to the pet, and sensitization to other allergens, often with conflicting results. Pet ownership is not random, and household pets are associated with exposures other than pet allergens. We will review some of the evidence regarding the effects of household pets on infant immune responses, focusing on data from birth cohort studies. It remains unclear precisely why some children develop specific sensitizations to pets whilst others do not in the face of equivalent exposures, but it is likely to be due to gene-environment interactions. Further long-term follow-up of children in whom neonatal and infant immune responses have been measured is necessary to understand how these events occur and how they relate to subsequent disease. PMID:21437047

Environmental stressors influencing hormones and systems physiology in cattle

PubMed Central

2014-01-01

Environmental stressors undoubtedly influence organismal biology, specifically the endocrine system that, in turn, impact cattle at the systems physiology level. Despite the significant advances in understanding the genetic determinants of the ideal dairy or beef cow, there is a grave lack of understanding of the systems physiology and effects of the environmental stressors that interfere with the endocrine system. This is a major problem because the lack of such knowledge is preventing advances in understanding gene-environment interactions and developing science-based solutions to these challenges. In this review, we synthesize the current knowledge on the nature of the major environmental stressors, such as climate (heat, cold, wind, and humidity), nutrition (feeds, feeding systems, and endocrine disruptors) and management (housing density and conditions, transportation, weaning practices). We summarize the impact of each one of these factors on cattle at the systems level, and provide solutions for the challenges. PMID:24996419

Marital Satisfaction and Physical Health: Evidence for an Orchid Effect

PubMed Central

South, Susan C.; Krueger, Robert F.

2013-01-01

Marital distress and conflict are linked to poor physical health. Here, we used behavior genetic modeling to determine the etiology of this association. Biometric moderation models were used to estimate gene-by-environment interaction in the presence of gene-environment correlation between marital satisfaction and self-reported health. Using a sample of 347 married twin pairs from the Midlife in the United States study, we found that genetic influences on the variation in self-reported health were greatest at both high (h2 = .30) and low (h2 = .38) levels of marital satisfaction, with the lowest levels of heritability estimated for participants at the average level of marital satisfaction (h2 = .10). These findings are evidence of the orchid effect: the idea that genetic influences on a phenotype such as physical health are enhanced in nonnormative—both unusually positive and unusually negative—environmental contexts. PMID:23359109

Cigarette smoking and the pathogenesis of systemic lupus erythematosus.

PubMed

Speyer, Cameron B; Costenbader, Karen H

2018-06-01

Systemic lupus erythematosus (SLE) is a multi-system inflammatory autoimmune disease of incompletely understood etiology. It is thought that environmental exposures 'trigger' or accelerate the disease in genetically-predisposed individuals. Areas covered: Substantial epidemiological evidence exists to support the association between cigarette smoking and the risk of incident SLE. Recent evidence points to current smoking as the specific risk factor, with decreasing risk 5 years after smoking cessation, and the greatest risk for disease characterized by the presence of SLE-specific autoantibodies. Research has begun to search for possible explanations for the temporal nature of the relationship between current smoking and autoantibody positive-SLE. Here we review potential biologic mechanisms linking smoking and SLE risk, including effects upon T and B cells, inflammatory cytokines, oxidative stress, and the formation of short-lived DNA adducts. Expert commentary: The directions for future research in this field include studies of gene-environment interactions, epigenetics, metabolomics and putative biologic mechanisms.

Beyond genome-wide association studies: genetic heterogeneity and individual predisposition to cancer

PubMed Central

Galvan, Antonella; Ioannidis, John P.A.; Dragani, Tommaso A.

2010-01-01

Genome-wide association studies (GWAS) using population-based designs have identified many genetic loci associated with risk of a range of complex diseases including cancer; however, each locus exerts a very small effect and most heritability remains unexplained. Family-based pedigree studies have also suggested tentative loci linked to increased cancer risk, often characterized by pedigree-specificity. However, a comparison between the results of population-and those of family-based studies shows little concordance. Explanations for this unidentified genetic ‘dark matter’ of cancer include phenotype ascertainment issues, limited power, gene-gene and gene-environment interactions, population heterogeneity, parent-of-origin-specific effects, rare and unexplored variants. Many of these reasons converge towards the concept of genetic heterogeneity that might implicate hundreds of genetic variants in regulating cancer risk. Dissecting the dark matter is a challenging task. Further insights can be gained from both population association and pedigree studies. PMID:20106545

PRENATAL STRESS AND RISK FOR AUTISM

PubMed Central

Kinney, Dennis K.; Munir, Kerim M.; Crowley, David J.; Miller, Andrea M.

2008-01-01

This paper reviews several converging lines of research that suggest that prenatal exposure to environmental stress may increase risk for Autistic Disorder (AD). We first discuss studies finding that prenatal exposure to stressful life events is associated with significantly increased risk of AD, as well as other disorders, such as schizophrenia and depression. We then review evidence from animal and human studies that prenatal stress can produce both (a) abnormal postnatal behaviors that resemble the defining symptoms of AD, and (b) other abnormalities that have elevated rates in AD, such as learning deficits, seizure disorders, perinatal complications, immunologic and neuroinflammatory anomalies, and low postnatal tolerance for stress. We explain why an etiologic role for prenatal stress is compatible with genetic factors in AD, and describe how stress can disrupt fetal brain development. Finally, we discuss implications for understanding underlying processes in AD, including potential gene-environment interactions, and developing new therapies and early prevention programs. PMID:18598714

Ambulatory Assessment

PubMed Central

Trull, Timothy J.; Ebner-Priemer, Ulrich

2014-01-01

Ambulatory assessment (AA) covers a wide range of assessment methods to study people in their natural environment, including self-report, observational, and biological/physiological/behavioral. AA methods minimize retrospective biases while gathering ecologically valid data from patients’ everyday life in real time or near real time. Here, we report on the major characteristics of AA, and we provide examples of applications of AA in clinical psychology (a) to investigate mechanisms and dynamics of symptoms, (b) to predict the future recurrence or onset of symptoms, (c) to monitor treatment effects, (d) to predict treatment success, (e) to prevent relapse, and (f) as interventions. In addition, we present and discuss the most pressing and compelling future AA applications: technological developments (the smartphone), improved ecological validity of laboratory results by combined lab-field studies, and investigating gene-environment interactions. We conclude with a discussion of acceptability, compliance, privacy, and ethical issues. PMID:23157450

Nutrigenomics, the Microbiome, and Gene-Environment Interactions: New Directions in Cardiovascular Disease Research, Prevention, and Treatment: A Scientific Statement From the American Heart Association.

PubMed

Ferguson, Jane F; Allayee, Hooman; Gerszten, Robert E; Ideraabdullah, Folami; Kris-Etherton, Penny M; Ordovás, José M; Rimm, Eric B; Wang, Thomas J; Bennett, Brian J

2016-06-01

Cardiometabolic diseases are the leading cause of death worldwide and are strongly linked to both genetic and nutritional factors. The field of nutrigenomics encompasses multiple approaches aimed at understanding the effects of diet on health or disease development, including nutrigenetic studies investigating the relationship between genetic variants and diet in modulating cardiometabolic risk, as well as the effects of dietary components on multiple "omic" measures, including transcriptomics, metabolomics, proteomics, lipidomics, epigenetic modifications, and the microbiome. Here, we describe the current state of the field of nutrigenomics with respect to cardiometabolic disease research and outline a direction for the integration of multiple omics techniques in future nutrigenomic studies aimed at understanding mechanisms and developing new therapeutic options for cardiometabolic disease treatment and prevention. © 2016 American Heart Association, Inc.

Utility of Small Animal Models of Developmental Programming.

PubMed

Reynolds, Clare M; Vickers, Mark H

2018-01-01

Any effective strategy to tackle the global obesity and rising noncommunicable disease epidemic requires an in-depth understanding of the mechanisms that underlie these conditions that manifest as a consequence of complex gene-environment interactions. In this context, it is now well established that alterations in the early life environment, including suboptimal nutrition, can result in an increased risk for a range of metabolic, cardiovascular, and behavioral disorders in later life, a process preferentially termed developmental programming. To date, most of the mechanistic knowledge around the processes underpinning development programming has been derived from preclinical research performed mostly, but not exclusively, in laboratory mouse and rat strains. This review will cover the utility of small animal models in developmental programming, the limitations of such models, and potential future directions that are required to fully maximize information derived from preclinical models in order to effectively translate to clinical use.

Alkylphenols--potential modulators of the allergic response.

PubMed

Suen, Jau-Ling; Hung, Chih-Hsin; Yu, Hsin-Su; Huang, Shau-Ku

2012-07-01

The prevalence of allergic diseases has increased in recent decades. Allergic diseases, particularly asthma, are complex diseases with strong gene-environment interactions. Epidemiological studies have identified a variety of risk factors for the development of allergic diseases. Among them, endocrine-disrupting chemicals (EDCs) play an important role in triggering or exacerbating these diseases. 4-Nonylphenol (NP) and 4-octylphenol (OP)--two major alkylphenols--have been recognized as common toxic and xenobiotic endocrine disrupters. Due to their low solubility, high hydrophobicity, and low estrogenic activity, they tend to accumulate in the human body and may be associated with the adverse effects of allergic diseases. Recently, new evidence has supported the importance of alkylphenols in the in vitro allergic response. This review focuses on the effects of alkylphenols on several key cell types in the context of allergic inflammation. Copyright © 2012. Published by Elsevier B.V.

Ambient Air Pollution and Asthma-Related Outcomes in Children of Color of the USA: a Scoping Review of Literature Published Between 2013 and 2017.

PubMed

Nardone, Anthony; Neophytou, Andreas M; Balmes, John; Thakur, Neeta

2018-04-16

Given racial disparities in ambient air pollution (AAP) exposure and asthma risk, this review offers an overview of the literature investigating the ambient air pollution-asthma relationship in children of color between 2013 and 2017. AAP is likely a key contributor to the excess burden of asthma in children of color due to pervasive exposure before birth, at home, and in school. Recent findings suggest that psychosocial stressors may modify the relationship between AAP and asthma. The effect of AAP on asthma in children of color is likely modulated by multiple unique psychosocial stressors and gene-environment interactions. Although children of color are being included in asthma studies, more research is still needed on impacts of specific criteria pollutants throughout the life course. Additionally, future studies should consider historical factors when analyzing current exposure profiles.

Breaking barriers in the genomics and pharmacogenetics of drug addiction

PubMed Central

Ho, MK; Goldman, D; Heinz, A; Kaprio, J; Kreek, MJ; Li, MD; Munafò, MR; Tyndale, RF

2013-01-01

Drug addictions remain a substantial health issue, with limited treatment options currently available. Despite considerable advances in the understanding of our genetic architecture, the genetic underpinning of complex disorders remains elusive. Numerous candidate genes have been implicated in the etiology and response to treatment for different addictions based on our current understanding of the neurobiology. Genome-wide association studies have also provided novel targets. However, replication of these studies is often lacking which complicates interpretation; this will improve as issues such as phenotypic characterization, the apparent “missing heritability”, the identification of functional variants, and possible gene-environment interactions are addressed. In addition, there is growing evidence that genetic information can be useful for refining the choice of addiction treatment. As genetic testing becomes more common in the practice of medicine, a variety of ethical and practical challenges, some of which are unique to drug addiction, will also need to be considered. PMID:20981002

The Influence of Nutritional Factors on Verbal Deficits and Psychopathic Personality Traits: Evidence of the Moderating Role of the MAOA Genotype

PubMed Central

Jackson, Dylan B.; Beaver, Kevin M.

2015-01-01

The current study explores whether: (a) nutritional factors among adolescent males predict their risk of exhibiting verbal deficits and psychopathic traits during adulthood and (b) the link between nutritional factors and these outcomes is conditioned by the MAOA genotype. The study analyzes data from the U.S. National Longitudinal Study of Adolescent Health (Add Health), a nationally representative, genetically informative sample. We find evidence that meal deprivation increases the likelihood of both verbal deficits and psychopathic personality traits, whereas poor quality nutrition increases the risk of verbal deficits. We detect the presence of a number of gene-environment interactions between measures of food quality and MAOA genotype, but no evidence of GxE in the case of meal deprivation. Limitations are noted and avenues for future research are discussed. PMID:26690459

Maternal substance use during pregnancy and offspring conduct problems: A meta-analysis.

PubMed

Ruisch, I Hyun; Dietrich, Andrea; Glennon, Jeffrey C; Buitelaar, Jan K; Hoekstra, Pieter J

2018-01-01

We conducted meta-analyses of relationships between highly prevalent substance use during pregnancy and offspring conduct disorder problems. In total 36 studies were included. Odds ratios (ORs) were 2.06 (1.67-2.54, 25 studies) for maternal smoking, 2.11 (1.42-3.15, 9 studies) for alcohol use, and 1.29 (0.93-1.81, 3 studies) for cannabis use, while a single study of caffeine use reported no effects. Our meta-analyses support an association between smoking and alcohol use during pregnancy, and offspring conduct problems, yet do not resolve causality issues given potential confounding by genetic factors, gene-environment interactions, and comorbidity such as with attention deficit hyperactivity disorders. Future studies should use genetically sensitive designs to investigate the role of pregnancy substance use in offspring conduct problems and may consider more broadly defined behavioral problems. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of Antenatal Maternal Depressive Symptoms and Socio-Economic Status on Neonatal Brain Development are Modulated by Genetic Risk.

PubMed

Qiu, Anqi; Shen, Mojun; Buss, Claudia; Chong, Yap-Seng; Kwek, Kenneth; Saw, Seang-Mei; Gluckman, Peter D; Wadhwa, Pathik D; Entringer, Sonja; Styner, Martin; Karnani, Neerja; Heim, Christine M; O'Donnell, Kieran J; Holbrook, Joanna D; Fortier, Marielle V; Meaney, Michael J

2017-05-01

This study included 168 and 85 mother-infant dyads from Asian and United States of America cohorts to examine whether a genomic profile risk score for major depressive disorder (GPRSMDD) moderates the association between antenatal maternal depressive symptoms (or socio-economic status, SES) and fetal neurodevelopment, and to identify candidate biological processes underlying such association. Both cohorts showed a significant interaction between antenatal maternal depressive symptoms and infant GPRSMDD on the right amygdala volume. The Asian cohort also showed such interaction on the right hippocampal volume and shape, thickness of the orbitofrontal and ventromedial prefrontal cortex. Likewise, a significant interaction between SES and infant GPRSMDD was on the right amygdala and hippocampal volumes and shapes. After controlling for each other, the interaction effect of antenatal maternal depressive symptoms and GPRSMDD was mainly shown on the right amygdala, while the interaction effect of SES and GPRSMDD was mainly shown on the right hippocampus. Bioinformatic analyses suggested neurotransmitter/neurotrophic signaling, SNAp REceptor complex, and glutamate receptor activity as common biological processes underlying the influence of antenatal maternal depressive symptoms on fetal cortico-limbic development. These findings suggest gene-environment interdependence in the fetal development of brain regions implicated in cognitive-emotional function. Candidate biological mechanisms involve a range of brain region-specific signaling pathways that converge on common processes of synaptic development. © The Author 2017. Published by Oxford University Press.

Nutrigenomics and nutrigenetics in inflammatory bowel diseases.

PubMed

Gruber, Lisa; Lichti, Pia; Rath, Eva; Haller, Dirk

2012-10-01

Inflammatory bowel diseases (IBD) including ulcerative colitis and Crohn's disease are chronically relapsing, immune-mediated disorders of the gastrointestinal tract. A major challenge in the treatment of IBD is the heterogenous nature of these pathologies. Both, ulcerative colitis and Crohn's disease are of multifactorial etiology and feature a complex interaction of host genetic susceptibility and environmental factors such as diet and gut microbiota. Genome-wide association studies identified disease-relevant single-nucleotide polymorphisms in approximately 100 genes, but at the same time twin studies also clearly indicated a strong environmental impact in disease development. However, attempts to link dietary factors to the risk of developing IBD, based on epidemiological observations showed controversial outcomes. Yet, emerging high-throughput technologies implying complete biological systems might allow taking nutrient-gene interactions into account for a better classification of patient subsets in the future. In this context, 2 new scientific fields, "nutrigenetics" and "nutrigenomics" have been established. "Nutrigenetics," studying the effect of genetic variations on nutrient-gene interactions and "Nutrigenomics," describing the impact of nutrition on physiology and health status on the level of gene transcription, protein expression, and metabolism. It is hoped that the integration of both research areas will promote the understanding of the complex gene-environment interaction in IBD etiology and in the long-term will lead to personalized nutrition for disease prevention and treatment. This review briefly summarizes data on the impact of nutrients on intestinal inflammation, highlights nutrient-gene interactions, and addresses the potential of applying "omic" technologies in the context of IBD.

Polymorphisms in the non-muscle myosin heavy chain 9 gene (MYH9) are strongly associated with end-stage renal disease historically attributed to hypertension in African Americans

PubMed Central

Freedman, Barry I.; Hicks, Pamela J.; Bostrom, Meredith A.; Cunningham, Mary E.; Liu, Yongmei; Divers, Jasmin; Kopp, Jeffrey B.; Winkler, Cheryl A.; Nelson, George W.; Langefeld, Carl D.; Bowden, Donald W.

2009-01-01

African Americans have high incidence rates of end-stage renal disease (ESRD) labeled as due to hypertension. As recent studies showed strong association with idiopathic and HIV-related focal segmental glomerulosclerosis and non-muscle myosin heavy chain 9 (MYH9) gene polymorphisms in this ethnic group, we tested for MYH9 associations in a variety of kidney diseases. Fifteen MYH9 single-nucleotide polymorphisms were evaluated in 175 African Americans with chronic glomerulonephritis-associated ESRD, 696 African Americans reportedly with hypertension-associated ESRD, and 948 control subjects without kidney disease. Significant associations were detected with 14 of the 15 polymorphisms in all 871 non-diabetic patients with ESRD. In hypertension-associated ESRD cases alone, significant associations were found with 13 MYH9 polymorphisms and the previously reported E1 haplotype. Thus, hypertension-associated ESRD in African Americans is substantially related to MYH9 gene polymorphisms and this may explain the poor response to blood pressure control in those diagnosed with hypertensive nephrosclerosis. It is possible that many African Americans classified as having hypertension-associated ESRD have occult MYH9-associated segmental or global glomerulosclerosis. Our study shows that gene-environment and/or gene–gene interactions may initiate kidney disease in genetically susceptible individuals, because African Americans homozygous for MYH9 risk alleles do not universally develop kidney disease. PMID:19177153

The BDNF-Val66Met polymorphism modulates parental rearing effects on adult psychiatric symptoms: a community twin-based study.

PubMed

Ibarra, P; Alemany, S; Fatjó-Vilas, M; Córdova-Palomera, A; Goldberg, X; Arias, B; González-Ortega, I; González-Pinto, A; Nenadic, I; Fañanás, L

2014-06-01

To test whether firstly, different parental rearing components were associated with different dimensions of psychiatric symptoms in adulthood, secondly BDNF-Val66Met polymorphism moderated this association and thirdly, this association was due to genetic confounding. Perceived parental rearing according to Parental Bonding Instrument (PBI), psychiatric symptoms evaluated with the Brief Symptom Inventory (BSI) and the BDNF-Val66Met polymorphism were analyzed in a sample of 232 adult twins from the general population. In the whole sample, paternal care was negatively associated with depression. Maternal overprotection was positively associated with paranoid ideation, obsession-compulsion and somatization. Gene-environment interaction effects were detected between the BDNF-Val66Met polymorphism and maternal care on phobic anxiety, paternal care on hostility, maternal overprotection on somatization and paternal overprotection also in somatization. In the subsample of MZ twins, intrapair differences in maternal care were associated with anxiety, paranoid ideation and somatization. Met carriers were, in general, more sensitive to the effects of parental rearing compared to Val/Val carriers in relation to anxiety and somatization. Contra-intuitively, our findings suggest that high rates of maternal care might be of risk for Met carriers regarding anxiety. Results from analyses controlling for genetic confounding were in line with this finding. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Association between methylation of the glucocorticoid receptor gene, childhood maltreatment, and clinical severity in borderline personality disorder.

PubMed

Martín-Blanco, Ana; Ferrer, Marc; Soler, Joaquim; Salazar, Juliana; Vega, Daniel; Andión, Oscar; Sanchez-Mora, Cristina; Arranz, Maria Jesús; Ribases, Marta; Feliu-Soler, Albert; Pérez, Víctor; Pascual, Juan Carlos

2014-10-01

The hypothalamus-pituitary-adrenal axis (HPA) is essential in the regulation of stress responses. Increased methylation of the promoter region of the glucocorticoid receptor gene (NR3C1) has been described both in subjects with history of childhood trauma and in patients with Borderline Personality Disorder (BPD). However, no data on the possible association between a higher methylation of this gene and clinical severity is available. The aim of this study was to evaluate the association between NR3C1 methylation status, the history of childhood trauma, and current clinical severity in subjects with BPD. A sample of 281 subjects with BPD (diagnosed by SCID-II and DIB-R semi-structured diagnostic interviews) was recruited. Clinical variables included previous hospitalizations, self-injurious behavior, and self-reported history of childhood trauma. DNA was extracted from peripheral blood. The results indicated a significant positive correlation between NR3C1 methylation status and childhood maltreatment (specifically physical abuse). In addition, a positive correlation between methylation status and clinical severity (DIB-R total score and hospitalizations) was observed. These findings suggest that NR3C1 methylation in subjects with BPD may be associated not only with childhood trauma but also with clinical severity, adding new evidence to the involvement of gene-environment interactions in this disorder. Copyright © 2014 Elsevier Ltd. All rights reserved.

Polymorphisms in GEMIN4 and AGO1 Genes Are Associated with the Risk of Lung Cancer: A Case-Control Study in Chinese Female Non-Smokers

PubMed Central

Fang, Xue; Yin, Zhihua; Li, Xuelian; Xia, Lingzi; Zhou, Baosen

2016-01-01

MicroRNA biosynthesis genes can affect the regulatory effect of global microRNAs to target mRNA and hence influence the genesis and development of human cancer. Here, we selected five single nucleotide polymorphisms (SNPs) (rs7813, rs2740349, rs2291778, rs910924, rs595961) in two key microRNA biosynthesis genes (GEMIN4 and AGO1) and systematically evaluated the association between these SNPs, the gene-environment interaction and lung cancer risk. To control the impact of cigarette smoking on lung cancer, we recruited Chinese female non-smokers for the study. The total number of lung cancer cases and cancer-free controls were 473 and 395 in the case-control study. Four SNPs showed statistically significant associations with lung cancer risk. After Bonferroni correction, rs7813 and rs595961 were evidently still associated with lung cancer risk. In the stratified analysis, our results revealed that all five SNPs were associated with the risk of lung adenocarcinoma; after Bonferroni correction, significant association was maintained for rs7813, rs910924 and rs595961. Haplotype analysis showed GEMIN4 haplotype C-A-G-T was a protective haplotype for lung cancer. In the combined unfavorable genotype analysis, with the increasing number of unfavorable genotypes, a progressively increased gene-dose effect was observed in lung adenocarcinoma. We also found that individuals exposed to cooking oil fumes showed a relatively high risk of lung cancer, but no interactions were found between cooking oil fume exposure or passive smoking exposure with these SNPs, either on an additive scale or a multiplicative scale. Overall, this is the first study showing that rs7813 and rs595961 could be meaningful as genetic markers for lung cancer risk. PMID:27669275

AMACR polymorphisms, dietary intake of red meat and dairy and prostate cancer risk.

PubMed

Wright, Jonathan L; Neuhouser, Marian L; Lin, Daniel W; Kwon, Erika M; Feng, Ziding; Ostrander, Elaine A; Stanford, Janet L

2011-04-01

Alpha-methylacyl CoA racemase (AMACR) is an enzyme involved in fatty acids metabolism. One of AMACRs primary substrates, phytanic acid, is principally obtained from dietary red meat/dairy, which are associated with prostate cancer (PCa) risk. AMACR is also a tumor tissue biomarker over-expressed in PCa. In this study, we explored the potential relationship between AMACR polymorphisms, red meat/dairy intake, and PCa risk. Caucasian participants from two population-based PCa case-control studies were included. AMACR single nucleotide polymorphisms (SNPs) were selected to capture variation across the gene and regulatory regions. Red meat and dairy intake was determined from food frequency questionnaires. The odds ratio (OR) of PCa (overall and by disease aggressiveness) was estimated by logistic and polytomous regression. Potential interactions between genotypes and dietary exposures were evaluated. Data from 1,309 cases and 1,267 controls were analyzed. Carriers of the variant T allele (rs2287939) had an OR of 0.81 (95% CI 0.68-0.97) for less aggressive PCa, but no alteration in risk for more aggressive PCa. Red meat consumption was positively associated with PCa risk, and the association was stronger for more aggressive disease (lowest vs. highest tertile OR=1.55, 95% CI 1.10-2.20). No effect modification of AMACR polymorphisms by either dietary red meat or dairy intake on PCa risk was observed. PCa risk varied by level of red meat intake and by one AMACR SNP, but there was no evidence for gene-environment interaction. These findings suggest that the effects of AMACR polymorphisms and red meat and dairy on PCa risk are independent. Copyright © 2010 Wiley-Liss, Inc.

The impact of GPX1 on the association of groundwater selenium and depression: a project FRONTIER study

PubMed Central

2013-01-01

Background Prior animal model and human-based studies have linked selenium concentrations to decreased risk for depression; however, this work has not focused on household groundwater levels or specific depressive symptoms. The current study evaluated the link between groundwater selenium levels and depression. We also sought to determine if a functional polymorphism in the glutathione peroxidase 1 (GPX1) gene impacted this link. Methods We used a cross-sectional design to analyze data from 585 participants (183 men and 402 women) from Project FRONTIER, a study of rural health in West Texas. Residential selenium concentrations were estimated using Geospatial Information System (GIS) analyses. Linear regression models were created using Geriatric Depression Scale (GDS-30) total and subfactor scores as outcome variables and selenium concentrations as predictor variables. Analyses were re-run after stratification of the sample on GPX1 Pro198Leu genotype (rs1050454). Results Selenium levels were significantly and negatively related to all GDS and subfactor scores accounting for up to 17% of the variance beyond covariates. Selenium was most strongly protective against depression among homozygous carriers of the C allele at the Pro198Leu polymorphism of the GPX1 gene. Analyses also point towards a gene-environmental interaction between selenium exposure and GPX1 polymorphism. Conclusion Our results support the link between groundwater selenium levels and decreased depression symptoms. These findings also highlight the need to consider the genetics of the glutathione peroxidase system when examining this relationship, as variation in the GPX1 gene is related to depression risk and significantly influences the protective impact of selenium, which is indicative of a gene-environment interaction. PMID:23289525

The GP problem: quantifying gene-to-phenotype relationships.

PubMed

Cooper, Mark; Chapman, Scott C; Podlich, Dean W; Hammer, Graeme L

2002-01-01

In this paper we refer to the gene-to-phenotype modeling challenge as the GP problem. Integrating information across levels of organization within a genotype-environment system is a major challenge in computational biology. However, resolving the GP problem is a fundamental requirement if we are to understand and predict phenotypes given knowledge of the genome and model dynamic properties of biological systems. Organisms are consequences of this integration, and it is a major property of biological systems that underlies the responses we observe. We discuss the E(NK) model as a framework for investigation of the GP problem and the prediction of system properties at different levels of organization. We apply this quantitative framework to an investigation of the processes involved in genetic improvement of plants for agriculture. In our analysis, N genes determine the genetic variation for a set of traits that are responsible for plant adaptation to E environment-types within a target population of environments. The N genes can interact in epistatic NK gene-networks through the way that they influence plant growth and development processes within a dynamic crop growth model. We use a sorghum crop growth model, available within the APSIM agricultural production systems simulation model, to integrate the gene-environment interactions that occur during growth and development and to predict genotype-to-phenotype relationships for a given E(NK) model. Directional selection is then applied to the population of genotypes, based on their predicted phenotypes, to simulate the dynamic aspects of genetic improvement by a plant-breeding program. The outcomes of the simulated breeding are evaluated across cycles of selection in terms of the changes in allele frequencies for the N genes and the genotypic and phenotypic values of the populations of genotypes.

The MAOA promoter polymorphism, disruptive behavior disorders, and early onset substance use disorder: gene-environment interaction.

PubMed

Vanyukov, Michael M; Maher, Brion S; Devlin, Bernie; Kirillova, Galina P; Kirisci, Levent; Yu, Ling-Mei; Ferrell, Robert E

2007-12-01

Conduct, oppositional defiant, and attention deficit hyperactivity disorders, reflecting early antisociality and behavior dysregulation, are predictive of substance use disorders. Liabilities to these disorders share genetic and environmental variance. Parenting characteristics have been shown to influence development of antisociality, moderated by variation at the MAOA gene, which has also been associated with the risk for substance use disorders. To extend these findings, we tested the relationships between the MAOA promoter polymorphism (variable number tandem repeat), indices of child's perception of paternal and maternal parenting, and disruptive behavior disorders and substance use disorders. A sample of 148 European-American males was assessed prospectively at ages from 10-12 to 18-19 years and genotyped for the monoamine oxidase A variable number tandem repeat. The Diagnostic and statistical manual of mental disorder-III-R diagnoses were obtained using standard methodology. Parenting was assessed using a scale summarizing the child's evaluation of the parenting style (parent's behavior toward him, parental emotional distance and involvement). Correlation, logistic regression, and Cox proportional hazard regression analysis was used to determine the relationships between the variables. The strength of association between parenting index and conduct and attention deficit hyperactivity disorders depended on the MAOA genotype. Unlike earlier findings, the parenting-risk relationships were observed in the 'high-' rather than 'low-activity' genotypes. The strength and direction of relationships depended on the parental sex. The MAOA polymorphism's association with the risk for substance use disorders was detected when parenting was controlled for. The results are consistent with the contribution of the MAOA gene, parenting style and their interactions to variation in the risk for early onset behavior disorders and liability to substance use disorders.

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 exposures, their timeframes, quantification and covariables, with respect to study size and with respect to the rigor of multivariate analyses, are more pertinent than ever before. PMID:17502287

AURKA Phe31Ile polymorphism interacted with use of alcohol, betel quid, and cigarettes at multiplicative risk of oral cancer occurrence.

PubMed

Lee, Chi-Pin; Chiang, Shang-Lun; Lee, Chien-Hung; Tsai, Yi-Shan; Wang, Zhi-Hong; Hua, Chun-Hung; Chen, Yuan-Chien; Tsai, Eing-Mei; Ko, Ying-Chin

2015-11-01

The expression levels of two DNA repair genes (CHAF1A and CHAF1B) and a chromosome segregation gene (AURKA) were susceptible to arecoline exposure, a major alkaloid of areca nut. We hypothesize that genetic variants of these genes might also be implicated in the risk of oral cancer and could be modified by substance use of betel quid or alcohol and cigarettes. A case-control study, which included 507 patients with oral cancer and 717 matched controls, was performed in order to evaluate the cancer susceptibility by the tagging single-nucleotide polymorphisms (tagSNPs) in AURKA, CHAF1A, and CHAF1B using a genotyping assay and gene-environment interaction analysis. The Phe31Ile polymorphism (rs2273535, T91A) of AURKA was significantly associated with an increased risk of oral cancer (odds ratio (OR) = 2.1, 95% confidence interval (CI) 1.2-3.5). The gene dosage of the 91A allele also showed a significant trend in risk of oral cancer (P = 0.008). Furthermore, we found the AURKA 91AA homozygote was modifiable by substance use of alcohol, betel quid, and cigarettes (ABC), leading to increased risk of oral cancer in an additive or a multiplicative model (combined effect indexes = 1.2-4.0 and 1.5-2.2, respectively). However, no association was observed between the genetic variants of CHAF1A or CHAF1B and oral cancer risk in the study. These findings reveal the functional Phe31Ile polymorphism tagSNP of AURKA may be a strong susceptibility gene in ABC-related oral cancer occurrence. The results of this betel-related oral cancer study provide the evidence of environment-gene interaction for early prediction and molecular diagnosis.

Interaction between the SLC19A1 gene and maternal first trimester fever on offspring neural tube defects.

PubMed

Pei, Lijun; Zhu, Huiping; Ye, Rongwei; Wu, Jilei; Liu, Jianmeng; Ren, Aiguo; Li, Zhiwen; Zheng, Xiaoying

2015-01-01

Many studies have indicated that the reduced folate carrier gene (SLC19A1) is associated with an increased risk of neural tube defects (NTDs). However, the interaction between the SLC19A1 gene variant and maternal fever exposure and NTD risk remains unknown. The aim of this study was to investigate whether the risk for NTDs was influenced by the interactions between the SLC19A1 (rs1051266) variant and maternal first trimester fever. We investigated the potential interaction between maternal first trimester fever and maternal or offspring SLC19A1 polymorphism through a population-based case-control study. One hundred and four nuclear families with NTDs and 100 control families with nonmal newborns were included in the study. SLC19A1 polymorphism was determined using polymerase chain reaction-restricted fragment length polymorphism. Mothers who had the GG/GA genotype and first trimester fever had an elevated risk of NTDs (adjusted odds ratio, 11.73; 95% confidence interval, 3.02-45.58) as compared to absence of maternal first trimester fever and AA genotype after adjusting for maternal education, paternal education, and age, and had a significant interactive coefficient (γ = 3.17) between maternal GG/GA genotype and first trimester fever. However, there was no interaction between offspring's GG/GA genotype and maternal first trimester fever (the interactive coefficient γ = 0.97) after adjusting for confounding factors. Our findings suggested that the risk of NTDs was potentially influenced by a gene-environment interaction between maternal SLC19A1 rs1051266 GG/GA genotype and first trimester fever. Maternal GG/GA genotype may strengthen the effect of maternal fever exposure on NTD risk in this Chinese population. © 2014 Wiley Periodicals, Inc.

Interaction between FKBP5 variability and recent life events in the anxiety spectrum: Evidence for the differential susceptibility model.

PubMed

Pérez-Pérez, Beatriz; Cristóbal-Narváez, Paula; Sheinbaum, Tamara; Kwapil, Thomas R; Ballespí, Sergi; Peña, Elionora; de Castro-Catala, Marta; Riba, Maria Dolors; Rosa, Araceli; Barrantes-Vidal, Neus

2018-01-01

Gene-environment interaction (GxE) research has highlighted the importance of investigating the FK506 binding protein 51 (FKBP5) gene as a sensitivity gene. However, previous GxE studies with FKBP5 have not measured the full environmental spectrum or applied statistical tests to discern whether the GxE interaction fits better with the differential-susceptibility or diathesis-stress hypotheses. This study examined whether single nucleotide polymorphisms (SNPs) on FKBP5 gene moderate the association of positive and negative recent life events (LEs) with depressive symptoms, state-anxiety, neuroticism, and social anxiety traits. A total of 86 nonclinical young adults were administered psychological measures and were genotyped for five FKBP5 SNPs (rs3800373, rs9296158, rs1360780, rs9470080 and rs4713916). Regression analyses indicated significant GxE interactions for social anxiety and neuroticism. The interactions predicting neuroticism fit different models for different SNPs, although the overall effect indicated by the haplotype was consistent with the differential-susceptibility hypothesis: the risk-haplotype group presented higher neuroticism in the presence of more negative LEs and lower neuroticism in the presence of more positive LEs. The GxE interactions for social anxiety were consistent with the diathesis-stress model. The lack of significance in the for-better side for social anxiety might be related to the fact that it mapped onto low extraversion, which is associated with a lower permeability to positive experiences. Findings underscore the importance of testing the differential-susceptibility model in relation to FKBP5 to adequately characterize its role in healthy and pathological developmental processes.

Matrix metalloproteinases and educational attainment in refractive error: evidence of gene-environment interactions in the AREDS study

PubMed Central

Wojciechowski, Robert; Yee, Stephanie S.; Simpson, Claire L.; Bailey-Wilson, Joan E.; Stambolian, Dwight

2012-01-01

Purpose A previous study of Old Order Amish families has shown association of ocular refraction with markers proximal to matrix metalloproteinase (MMP) genes MMP1 and MMP10 and intragenic to MMP2. We conducted a candidate gene replication study of association between refraction and single nucleotide polymorphisms (SNPs) within these genomic regions. Design Candidate gene genetic association study. Participants 2,000 participants drawn from the Age Related Eye Disease Study (AREDS) were chosen for genotyping. After quality control filtering, 1912 individuals were available for analysis. Methods Microarray genotyping was performed using the HumanOmni 2.5 bead array. SNPs originally typed in the previous Amish association study were extracted for analysis. In addition, haplotype tagging SNPs were genotyped using TaqMan assays. Quantitative trait association analyses of mean spherical equivalent refraction (MSE) were performed on 30 markers using linear regression models and an additive genetic risk model, while adjusting for age, sex, education, and population substructure. Post-hoc analyses were performed after stratifying on a dichotomous education variable. Pointwise (P-emp) and multiple-test study-wise (P-multi) significance levels were calculated empirically through permutation. Main outcome measures MSE was used as a quantitative measure of ocular refraction. Results The mean age and ocular refraction were 68 years (SD=4.7) and +0.55 D (SD=2.14), respectively. Pointwise statistical significance was obtained for rs1939008 (P-emp=0.0326). No SNP attained statistical significance after correcting for multiple testing. In stratified analyses, multiple SNPs reached pointwise significance in the lower-education group: 2 of these were statistically significant after multiple testing correction. The two highest-ranking SNPs in Amish families (rs1939008 and rs9928731) showed pointwise P-emp<0.01 in the lower-education stratum of AREDS participants. Conclusions We show suggestive evidence of replication of an association signal for ocular refraction to a marker between MMP1 and MMP10. We also provide evidence of a gene-environment interaction between previously-reported markers and education on refractive error. Variants in MMP1- MMP10 and MMP2 regions appear to affect population variation in ocular refraction in environmental conditions less favorable for myopia development. PMID:23098370

DIFFERENTIAL LUNG GENE EXPRESSION IN IMMUNOLOGICALLY-CHALLENGED RATS EXPOSED TO CONCENTRATED AIRBORNE PARTICULATES

EPA Science Inventory

Children residing in urbanized areas suffer disproportionately higher asthma-related morbidity and mortality. One explanation is that inner city children are exposured to higher levels of environmental asthma triggers such as airborne particulate matter. To elucidate gene-environ...

Immune system gene dysregulation in autism and schizophrenia.

PubMed

Michel, Maximilian; Schmidt, Martin J; Mirnics, Karoly

2012-10-01

Gene*environment interactions play critical roles in the emergence of autism and schizophrenia pathophysiology. In both disorders, recent genetic association studies have provided evidence for disease-linked variation in immune system genes and postmortem gene expression studies have shown extensive chronic immune abnormalities in brains of diseased subjects. Furthermore, peripheral biomarker studies revealed that both innate and adaptive immune systems are dysregulated. In both disorders symptoms of the disease correlate with the immune system dysfunction; yet, in autism this process appears to be chronic and sustained, while in schizophrenia it is exacerbated during acute episodes. Furthermore, since immune abnormalities endure into adulthood and anti-inflammatory agents appear to be beneficial, it is likely that these immune changes actively contribute to disease symptoms. Modeling these changes in animals provided further evidence that prenatal maternal immune activation alters neurodevelopment and leads to behavioral changes that are relevant for autism and schizophrenia. The converging evidence strongly argues that neurodevelopmental immune insults and genetic background critically interact and result in increased risk for either autism or schizophrenia. Further research in these areas may improve prenatal health screening in genetically at-risk families and may also lead to new preventive and/or therapeutic strategies. Copyright © 2012 Wiley Periodicals, Inc.

Effects of divorce on Dutch boys' and girls' externalizing behavior in Gene × Environment perspective: diathesis stress or differential susceptibility in the Dutch Tracking Adolescents' Individual Lives Survey study?

PubMed

Nederhof, Esther; Belsky, Jay; Ormel, Johan; Oldehinkel, Albertine J

2012-08-01

The effects of divorce on children's behavioral development have proven to be quite varied across studies, and most developmental and family scholars today appreciate the great heterogeneity in divorce effects. Thus, this inquiry sought to determine whether select dopaminergic genes previously associated with externalizing behavior and/or found to moderate diverse environmental effects (dopamine receptors D2 and D4, catechol-O-methyltransferase) might moderate divorce effects on adolescent self-reported externalizing problems; and, if so, whether evidence of gene-environment (G × E) interaction would prove consistent with diathesis-stress or differential-susceptibility models of environmental action. Data from the first and third wave of the Dutch Tracking Adolescents' Individual Lives Survey (n = 1,134) revealed some evidence of G × E interaction reflecting diathesis-stress but not differential susceptibility. It is intriguing that some evidence pointed to "vantage sensitivity," which are benefits accruing to those with a specific genotype when their parents remained together, the exact opposite of diathesis-stress. The limits of this work are considered, especially with regard to the conditions for testing differential susceptibility, and future directions are outlined.

Witnessing Substance Use and Same-Day Antisocial Behavior among At-Risk Adolescents: Gene-Environment Interaction in a 30-Day Ecological Momentary Assessment Study

PubMed Central

Russell, Michael A.; Wang, Lin; Odgers, Candice L.

2017-01-01

Many young adolescents are embedded in neighborhoods, schools, and homes where alcohol and drugs are frequently used. However, little is known about (a) how witnessing others’ substance use affects adolescents in their daily lives and (b) which adolescents will be most affected. The current study used ecological momentary assessment with 151 young adolescents (ages 11–15) to examine the daily association between witnessing substance use and antisocial behavior across 38 consecutive days. Results from multilevel logistic regression models indicated that adolescents were more likely to engage in antisocial behavior on days when they witnessed others using substances—an association that held both when substance use was witnessed inside the home as well as outside the home (e.g., at school or in their neighborhoods). A significant gene-by-environment interaction suggested that the same-day association between witnessing substance use and antisocial behavior was significantly stronger among adolescents with, versus without, with the DRD4-7R allele. The implications of our findings for theory and research related to adolescent antisocial behavior are discussed. PMID:26648004

Interactions between genetic variation and cellular environment in skeletal muscle gene expression.

PubMed

Taylor, D Leland; Knowles, David A; Scott, Laura J; Ramirez, Andrea H; Casale, Francesco Paolo; Wolford, Brooke N; Guan, Li; Varshney, Arushi; Albanus, Ricardo D'Oliveira; Parker, Stephen C J; Narisu, Narisu; Chines, Peter S; Erdos, Michael R; Welch, Ryan P; Kinnunen, Leena; Saramies, Jouko; Sundvall, Jouko; Lakka, Timo A; Laakso, Markku; Tuomilehto, Jaakko; Koistinen, Heikki A; Stegle, Oliver; Boehnke, Michael; Birney, Ewan; Collins, Francis S

2018-01-01

From whole organisms to individual cells, responses to environmental conditions are influenced by genetic makeup, where the effect of genetic variation on a trait depends on the environmental context. RNA-sequencing quantifies gene expression as a molecular trait, and is capable of capturing both genetic and environmental effects. In this study, we explore opportunities of using allele-specific expression (ASE) to discover cis-acting genotype-environment interactions (GxE)-genetic effects on gene expression that depend on an environmental condition. Treating 17 common, clinical traits as approximations of the cellular environment of 267 skeletal muscle biopsies, we identify 10 candidate environmental response expression quantitative trait loci (reQTLs) across 6 traits (12 unique gene-environment trait pairs; 10% FDR per trait) including sex, systolic blood pressure, and low-density lipoprotein cholesterol. Although using ASE is in principle a promising approach to detect GxE effects, replication of such signals can be challenging as validation requires harmonization of environmental traits across cohorts and a sufficient sampling of heterozygotes for a transcribed SNP. Comprehensive discovery and replication will require large human transcriptome datasets, or the integration of multiple transcribed SNPs, coupled with standardized clinical phenotyping.

An integrated genetic linkage map and comparative genome analysis for the estuarine Atlantic killifish, Fundulus heteroclitus

USDA-ARS?s Scientific Manuscript database

Background: Fundulus heteroclitus (Atlantic killifish), a non-migratory estuarine fish, exhibits high allelic and phenotypic diversity, partitioned among subpopulations that reside in disparate environmental conditions. An ideal candidate model organism for studying gene-environment reactions, th...

Adolescent age moderates genetic and environmental influences on parent-adolescent positivity and negativity: Implications for genotype-environment correlation.

PubMed

Marceau, Kristine; Knopik, Valerie S; Neiderhiser, Jenae M; Lichtenstein, Paul; Spotts, Erica L; Ganiban, Jody M; Reiss, David

2016-02-01

We examined how genotype-environment correlation processes differ as a function of adolescent age. We tested whether adolescent age moderates genetic and environmental influences on positivity and negativity in mother-adolescent and father-adolescent relationships using parallel samples of twin parents from the Twin and Offspring Study in Sweden and twin/sibling adolescents from the Nonshared Environment in Adolescent Development Study. We inferred differences in the role of passive and nonpassive genotype-environment correlation based on biometric moderation findings. The findings indicated that nonpassive gene-environment correlation played a stronger role for positivity in mother- and father-adolescent relationships in families with older adolescents than in families with younger adolescents, and that passive gene-environment correlation played a stronger role for positivity in the mother-adolescent relationship in families with younger adolescents than in families with older adolescents. Implications of these findings for the timing and targeting of interventions on family relationships are discussed.

Affiliation with substance-using peers: Examining gene-environment correlations among parent monitoring, polygenic risk, and children's impulsivity.

PubMed

Elam, Kit K; Chassin, Laurie; Lemery-Chalfant, Kathryn; Pandika, Danielle; Wang, Frances L; Bountress, Kaitlin; Dick, Danielle; Agrawal, Arpana

2017-07-01

Parental monitoring can buffer the effect of deviant peers on adolescents' substance use by reducing affiliation with substance-using peers. However, children's genetic predispositions may evoke poorer monitoring, contributing to negative child outcomes. We examined evocative genotype-environment correlations underlying children's genetic predisposition for behavioral undercontrol and parental monitoring in early adolescence via children's impulsivity in middle childhood, and the influence of parental monitoring on affiliation with substance-using peers a year and a half later (n = 359). Genetic predisposition for behavioral undercontrol was captured using a polygenic risk score, and a portion of passive rGE was controlled by including parents' polygenic risk scores. Children's polygenic risk predicted poorer parental monitoring via greater children's impulsivity, indicating evocative rGE, controlling for a portion of passive rGE. Poorer parental monitoring predicted greater children's affiliation with substance-using peers a year and a half later. Results are discussed with respect to gene-environment correlations within developmental cascades. © 2017 Wiley Periodicals, Inc.

Genetic Influences on Conduct Disorder

PubMed Central

Salvatore, Jessica E.; Dick, Danielle M.

2016-01-01

Conduct disorder (CD) is a moderately heritable psychiatric disorder of childhood and adolescence characterized by aggression toward people and animals, destruction of property, deceitfulness or theft, and serious violation of rules. Genome-wide scans using linkage and association methods have identified a number of suggestive genomic regions that are pending replication. A small number of candidate genes (e.g., GABRA2, MAOA, SLC6A4, AVPR1A) are associated with CD related phenotypes across independent studies; however, failures to replicate also exist. Studies of gene-environment interplay show that CD genetic predispositions also contribute to selection into higher-risk environments, and that environmental factors can alter the importance of CD genetic factors and differentially methylate CD candidate genes. The field’s understanding of CD etiology will benefit from larger, adequately powered studies in gene identification efforts; the incorporation of polygenic approaches in gene-environment interplay studies; attention to the mechanisms of risk from genes to brain to behavior; and the use of genetically informative data to test quasi-causal hypotheses about purported risk factors. PMID:27350097