Refining the scope of genetic influences on alcohol misuse through environmental stratification and gene-environment interaction

Background Gene-environment interaction (G×E) is likely an important influence shaping individual differences in alcohol misuse (AM), yet it has not been extensively studied in molecular genetic research. In this study, we utilize a series of genome-wide gene-environment interaction (GWEIS) and in silico annotation methods with the aim of improving gene identification and biological understanding of AM. Methods We carried out GWEIS for four AM phenotypes in the large UK Biobank sample ( N = 360,314), with trauma exposure and socioeconomic status (SES) as moderators of the genetic effects. Exploratory analyses compared stratified GWAS and GWEIS modelling approaches. We applied functional annotation, gene- and gene-set enrichment, and polygenic score analyses to interpret the GWEIS results. Results GWEIS models showed few genetic variants with significant interaction effects across all gene-environment pairs. Enrichment analyses identified moderation by SES of the genes NOXA1 , DLGAP1 , and UBE2L3, on drinking quantity and the gene IFIT1B on drinking frequency. Except for DLGAP1 , these genes have not previously been linked to AM. The most robust results (GWEIS interaction p = 4.59e-09) were seen for SES moderating the effects of variants linked to immune-related genes on a pattern of drinking with versus without meals. Conclusions Even in large samples, G×E effects are difficult to detect at the molecular level. Our results highlight several genes and a potential mechanism of immune system functioning behind the moderating effect of SES on the genetic influences on AM. While GWEIS seems to be a preferred approach over stratified GWAS, modelling molecular G×E effects remains a challenge that will require larger consortia and more in-depth phenotypic measurement. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was funded by a grant to J.E.S. (VI.VENI.201G-064) from The Netherlands Organization for Scientific Research (NWO) and has been conducted using the UK Biobank Resource (application no. 16406). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National computing and Networking Services SURFsara. Additional funding for the data collection was provided by by Virginia Commonwealth University, grants P20AA017828, R37AA011408, K02AA018755, P50AA022537, and K01AA024152 from the National Institute on Alcohol Abuse and Alcoholism, and UL1RR031990 from the National Center for Research Resources and National Institutes of Health Roadmap for Medical Research, and the Center for the Study of Tobacco Products at Virginia Commonwealth University. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study only used openly available human subjects data collected prior to the initiation of this study. Raw data are available via UK Biobank () and dbGaP (phs001754.v4.p2). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Genome-wide summary statistics will be made publicly available via upon publication. Raw data from this study are available to qualified researchers via UK Biobank () and dbGaP (phs001754.v4.p2).