Genome-wide investigation of maximum habitual alcohol intake (MaxAlc) in 247,755 European and African Ancestry U.S. Veterans informs the relationship between habitual alcohol consumption and alcohol use disorder

Importance Alcohol genome-wide association studies (GWAS) have generally focused on alcohol consumption and alcohol use disorder (AUD); few have examined habitual drinking behaviors like maximum habitual alcohol intake (MaxAlc). Objective Identify MaxAlc loci and elucidate the genetic architecture across alcohol traits. Design The MaxAlc GWAS was performed in Million Veteran Program (MVP) participants enrolled from January 10, 2011 to September 30, 2020. Ancestry-specific GWAS were conducted in European (EUR) (n=218,623) and African (AFR) (n=29,132) ancestry subjects, then meta-analyzed (N=247,755). Linkage-disequilibrium score regression (LDSC) was used to estimate SNP-heritability and genetic correlations (rg) with other alcohol and psychiatric traits. Genomic structural equation modeling (gSEM) was used to evaluate genetic relationships between MaxAlc and other alcohol traits. Mendelian randomization (MR) was used to examine causal relationships. MTAG (multi-trait analysis of GWAS) was used to analyze MaxAlc and problematic alcohol use (PAU) jointly. Setting The study was performed in a sample of U.S military Veterans. Participants Participants were 92.68% male and had mean age=65.92 ( SD =11.70). 36.92% reported MaxAlc ≥ the binge-drinking threshold. Main Outcomes(s) and Measure(s) MaxAlc was defined from survey item: “in a typical month, what is/was the largest number of drinks of alcohol you may have had in one day?” with ordinal responses from 0 ≥ 15 drinks. Results The MaxAlc GWAS resulted in 15 genome-wide significant (GWS) loci. Top associations in EUR and AFR were with known functional variants ADH1B *rs1229984 ( p =3.12×10−104) and rs2066702 ( p =6.30×10−17), respectively. Multiple novel associations were found. The SNP-heritability was 6.65% (s.e.=0.41%) in EUR and 3.42% (s.e.=1.46%) in AFR. MaxAlc was positively correlated with PAU (rg=0.79; p =3.95×10−149) and AUD (rg=0.76; p =1.26×10−127), and had negative rg with “alcohol usually taken with meals” (rg=-0.53; p =1.40×10−50). For psychiatric traits, MaxAlc had the strongest rg with suicide attempt (rg=0.40; p =3.02×10−21). gSEM supported a two-factor model with MaxAlc loading on a factor with PAU and AUD, and other alcohol consumption measures loading a separate factor. MR supported a small causal effect of MaxAlc on the liver enzyme gamma-glutamyltransferase (β=0.012; p =2.66×10−10). MaxAlc MTAG resulted in 31 GWS loci. Conclusions and Relevance MaxAlc closely aligns genetically with the etiology of problematic alcohol use traits. Question What is the genetic etiology of maximum habitual alcohol intake (MaxAlc) and how does it compare to other alcohol consumption measures. Findings This MaxAlc study in 247,455 European and African ancestry individuals identified 15 genome-wide significant loci, including multiple novel associations. MaxAlc was strongly genetically correlated (rg) with measures of alcohol-related problems, demonstrated significantly different rg with psychiatric traits compared to other alcohol consumption traits, and loaded on a factor with alcohol problem traits while alcohol consumption state measures loaded on a separate factor. Meaning MaxAlc is genetically different from trait consumption measures in relation to problematic alcohol use. ### Competing Interest Statement HRK is a member of scientific advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals, and Enthion Pharmaceuticals, a consultant to Sophrosyne Pharmaceuticals, a recipient of research funding and medication supplies from Alkermes for an investigator-initiated study, and a member of the American Society of Clinical Psychopharmacologys Alcohol Clinical Trials Initiative, which during the past three years was supported by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, and Otsuka. HRK and JG hold U.S. patent US10900082B2 Genotype-guided dosing of opioid agonists. RP and JG are paid for their editorial work on the journal Complex Psychiatry. All other authors report no biomedical financial interests or potential conflicts of interest. ### Funding Statement This research is based on data from the MVP, Office of Research and Development, Veterans Health Administration, and was supported by MVP and the Veterans Affairs Cooperative Studies Program study No. 575B. This work was supported by NIH grants R01DA054869 (JG), R01 AA026364 (JG), P50 AA012870 (JG), T32 AA028259 (JDD), R33 DA047527 (RP), R21 DC018098 (RP), and F32 MH122058 (FRW); the Brain & Behavior Research Foundation (HZ; DFL); and by funding from the Department of Veterans Affairs Office of Research and Development grants I01CX001849, I01BX003342, I01BX004820, IK2BX005058, and I01 CX001734, the VA Cooperative Studies Program study, no. 575B, and the VISN4 Mental Illness Research, Education and Clinical Center, and the West Haven VA Mental Illness Research, Education and Clinical Center. This publication does not represent the views of the Department of Veterans Affairs or the United States Government. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes 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