Is anxiety a pathway to Alcohol Use Disorders? A phenome-wide association study of the GABRA2 coding variant rs279858

Alcohol use disorders (AUDs) and related electrophysiological endophenotypes have been associated with the GABRA2 gene. However, the causal variants in GABRA2 and their mechanisms of influence on AUD and its correlates have not been established. Here we investigate the phenotypic spectrum of a GABRA2 coding variant (rs279858) through a phenome-wide association study (PheWAS) in two open-source datasets. We applied the PheWAS approach to identify a broad range of phenotypes associated with rs279858 in the MRC IEU OpenGWAS PheWAS and the Open Targets Genetics Portal. These databases extend the array of phenotypes beyond those available in electronic health records (EHR) to include numerous non-medical phenotypes and traits. We then followed up the results from those exploratory associations by examining the genetic correlations between our “top hits” and alcohol- and smoking-related phenotypes. In both data sources, rs279858 (C effect allele) was associated with anxiety-related phenotypes, including reduced risk-taking behavior and an increase in nervous feelings, as well as reduced number of lifetime sexual partners. Follow-up analyses revealed that these phenotypes were genetically correlated with each other and with alcohol- and smoking-related phenotypes. This work illustrates the utility of the PheWAS approach, particularly for phenotypes that extend beyond those that are typically captured in EHR data. In fact, the associations described here are all behavioral rather than clinical phenotypes. We postulate that these traits may be related to anxiety or behavioral inhibition that has been identified as a risk factor for AUD, and may represent pathophysiological intermediaries between GABRA2 and AUD. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Support for the work presented here was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401). The authors declare no conflicts of interest. ### 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 used ONLY openly available human data that were originally located at the Medical Research Council (MRC) Integrative Epidemiology Unit (IEU) at the University of Bristol OpenGWAS PheWAS tool (), and the Open Targets Genetics Portal (), as well as SNP-based heritability (h2) in the UKBB generated by the Neale Lab and genetic correlation (rg) between phenotypes in the UKBB via LDSC (). 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.