Winham, Stacey J.

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 gene–environment interactions are now fairly common in human genetic research, and with the shift toward genome‐wide association studies, genome‐wide gene–environment interaction studies are beginning to emerge. Methods We summarize the basic ideas behind gene–environment interaction, and provide an overview of possible study designs and traditional analysis methods in the context of genome‐wide analysis. We then discuss novel approaches beyond the traditional strategy of analyzing the interaction between the environmental factor and each polymorphism individually. Results Two‐step filtering approaches that reduce the number of polymorphisms tested for interactions can substantially increase the power of genome‐wide gene–environment studies. New analytical methods including data‐mining approaches, and gene‐level and pathway‐level analyses, also have the capacity to improve our understanding of how complex genetic and environmental factors interact to influence psychologic and psychiatric traits. Such methods, however, have not yet been utilized much in behavioral and mental health research. Conclusions Although methods to investigate gene–environment interactions are available, there is a need for further development and extension of these methods to identify gene–environment interactions in the context of genome‐wide association studies. These novel approaches need to be applied in studies of psychology and psychiatry.

AbstractSynthetic κ-opioid receptor (KOR) agonists induce dysphoric and pro-depressive effects and variations in the KOR (OPRK1) and prodynorphin (PDYN) genes have been shown to be associated with alcohol dependence. We genotyped 23 single nucleotide polymorphisms (SNPs) in the PDYN and OPRK1 genes in 816 alcohol-dependent subjects and investigated their association with: (1) negative craving measured by a subscale of the Inventory of Drug Taking Situations; (2) a self-reported history of depression; (3) the intensity of depressive symptoms measured by the Beck Depression Inventory-II. In addition, 13 of the 23 PDYN and OPRK1 SNPs, which were previously genotyped in a set of 1248 controls, were used to evaluate association with alcohol dependence. SNP and haplotype tests of association were performed. Analysis of a haplotype spanning the PDYN gene (rs6045784, rs910080, rs2235751, rs2281285) revealed significant association with alcohol dependence (p = 0.00079) and with negative craving (p = 0.0499). A candidate haplotype containing the PDYN rs2281285-rs1997794 SNPs that was previously associated with alcohol dependence was also associated with negative craving (p = 0.024) and alcohol dependence (p = 0.0008) in this study. A trend for association between depression severity and PDYN variation was detected. No associations of OPRK1 gene variation with alcohol dependence or other studied phenotypes were found. These findings support the hypothesis that sequence variation in the PDYN gene contributes to both alcohol dependence and the induction of negative craving in alcohol-dependent subjects.

AbstractTo further explore reports of association of alcohol dependence and response to acamprosate treatment with the GATA4 rs13273672 single nucleotide polymorphism (SNP), we genotyped this and 10 other GATA4 SNPs in 816 alcohol‐dependent cases and 1248 controls. We tested for association of alcohol dependence with the 11 SNPs individually and performed a global test for association using a principle components analysis. Our analyses demonstrate significant association between GATA4 and alcohol dependence at the gene level (P = 0.009) but no association with rs13273672. Further studies are needed to identify potential causal GATA4 variation(s) and the functional mechanism(s) contributing to this association.