Genetic Heterogeneity Across Dimensions of Alcohol Use Behaviors

Background Increasingly large samples in genome-wide association studies (GWAS) for alcohol use behaviors (AUBs) have led to an influx of implicated genes, yet the clinical and functional understanding of these associations remains low. This is, in part, because most GWASs do not account for complex and varied manifestations of AUBs. This study applied a multidimensional framework to investigate the latent genetic structure underlying heterogeneous dimensions of AUBs. Methods Multi-modal assessments (self-report, interview, electronic health records) were obtained from approximately 400,000 UK Biobank participants. GWAS was conducted for 18 distinct AUBs, including consumption, drinking patterns, alcohol problems, and clinical sequelae. Latent genetic factors were identified and carried forward to GWAS using genomic structural equation modeling, followed by functional annotation, genetic correlation, and enrichment analyses to interpret the genetic associations. Results Four latent factors were identified: Problems, Consumption, BeerPref (declining alcohol consumption with a preference for drinking beer), and AtypicalPref (drinking fortified wine and spirits). The latent factors were moderately correlated ( rg= .12-.57) and had distinct patterns of associations, with BeerPref in particular implicating many novel genomic regions. Patterns of regional and cell type specific gene expression in the brain also differed between the latent factors. Conclusion Deep phenotyping and multi-modal assessment is an important next step to improve understanding of the genetic etiology of AUBs, in addition to increasing sample size. Further effort is required to uncover the genetic heterogeneity underlying AUBs using methods that account for their complex, multidimensional nature. ### Competing Interest Statement J.W.S. is a member of the Leon Levy Foundation Neuroscience Advisory Board, the Scientific Advisory Board of Sensorium Therapeutics (with equity), has received grant support from Biogen Inc, and is principal investigator of a collaborative study of the genetics of depression and bipolar disorder sponsored by 23andMe for which 23andMe provides analysis time as in-kind support but no payments. The authors report no other financial relationships with commercial interests. ### Funding Statement This research was funded by a grant to J.E.S. (VENI 201G-064) from The Netherlands Organization for Scientific Research (NWO). Support for the biobank data used in this research was provided by National Health Services England, Health Data Research UK, UK Research and Innovation, the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute on Drug Abuse (NIDA), and the staff of the BioVU and MGB Biobanks. The funding agencies had no role in the study design, data analysis, manuscript preparation, or decision to submit for publication. ### 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 obtained from previously collected biobanks whose raw data is available to qualified researchers upon request at the links below. All study data was de-identified prior to use in research. UK Biobank: COGA: MGBB: BioVU: 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][1]. 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 Data was obtained from previously collected biobanks whose raw data is available to qualified researchers upon request. UK Biobank: COGA: MGBB: BioVU: Genome-wide summary statistics will be made publicly available via upon publication. [1]: http://ClinicalTrials.gov