Genome-Wide Investigation of Maximum Habitual Alcohol Intake in US Veterans in Relation to Alcohol Consumption Traits and Alcohol Use Disorder
Authors: Deak Joseph D. , Levey Daniel F. , Wendt Frank R. , Zhou Hang , Galimberti Marco , Kranzler Henry R. , Gaziano J. Michael , Stein Murray B. , Polimanti Renato , Gelernter Joel ,   Million Veteran Program, Muralidhar Sumitra , Moser Jennifer , Deen Jennifer E. , Gaziano J. Michael , Beckham Jean , Chang Kyong-Mi , Tsao Philip S , Luoh Shiuh-Wen , Casas Juan P. , Churby Lori , Whitbourne Stacey B. , Brewer Jessica V. , Brophy Mary T. , Selva Luis E. , Shayan Shahpoor , Cho Kelly , Pyarajan Saiju , DuVall Scott L. , Connor Todd A. , Argyres Dean P. , Aslan Mihaela , Stephens Brady , Concato John , Gelernter Joel , Gleason Terri , Huang Grant D. , Koenen Karestan C. , Marx Christine , Radhakrishnan Krishnan  , Schork Nicholas , Stein Murray , Zhao Hongyu , Kaufman Joan , Nunez Yaira , Pietrzak Robert H. , Beck Danielle  , Cissell Shada , Crutchfield Patricia , Lance William , Cheung Kei-Hoi , Li Yuli , Sun Ning , Chen Quan , Rajeevan Nallakkandi  , Sayward Frederick , Gagnon David R. , Harrington Kelly , Quaden Rachel , O'Leary Timothy , Ramoni Rachel B 
Published: October 2022

ImportanceAlcohol genome-wide association studies (GWASs) have generally focused on alcohol consumption and alcohol use disorder (AUD); few have examined habitual drinking behaviors like maximum habitual alcohol intake (MaxAlc).ObjectivesTo identify genetic loci associated with MaxAlc and to elucidate the genetic architecture across alcohol traits.Design, Setting, and ParticipantsThis MaxAlc genetic association study was performed among Million Veteran Program participants enrolled from January 10, 2011, to September 30, 2020. Ancestry-specific GWASs were conducted in participants with European (n = 218 623) and African (n = 29 132) ancestry, then meta-analyzed (N = 247 755). Linkage-disequilibrium score regression was used to estimate single nucleotide variant (SNV)–heritability and genetic correlations (rg) with other alcohol and psychiatric traits. Genomic structural equation modeling (gSEM) was used to evaluate genetic associations between MaxAlc and other alcohol traits. Mendelian randomization was used to examine potential causal relationships between MaxAlc and liver enzyme levels. MTAG (multitrait analysis of GWAS) was used to analyze MaxAlc and problematic alcohol use (PAU) jointly.ExposuresGenetic associations.Main Outcomes and MeasuresMaxAlc was defined from the following 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 to 15 or more drinks.ResultsGWASs were conducted on sample sizes of as many as 247 455 US veterans. Participants were 92.68% male and had mean (SD) age of 65.92 (11.70) years. The MaxAlc GWAS resulted in 15 genome-wide significant loci. Top associations in European-ancestry and African-ancestry participants were with known functional variants in the ADH1B gene, namely rs1229984 (P = 3.12 × 10−101) and rs2066702 (P = 6.30 × 10−17), respectively. Novel associations were also found. SNV-heritability was 6.65% (SE, 0.41) in European-ancestry participants and 3.42% (SE, 1.46) in African-ancestry participants. 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 the UK Biobank “alcohol usually taken with meals” (rg = −0.53; P = 1.40 × 10−50). For psychiatric traits, MaxAlc had the strongest genetic correlation with suicide attempt (rg = 0.40; P = 3.02 × 10−21). gSEM supported a 2-factor model with MaxAlc loading on a factor with PAU and AUD and other alcohol consumption measures loading on a separate factor. Mendelian randomization supported an association between MaxAlc and the liver enzyme gamma-glutamyltransferase (β = 0.012; P = 2.66 × 10−10). MaxAlc MTAG resulted in 31 genome-wide significant loci.Conclusions and RelevanceThe findings suggest that MaxAlc closely aligns genetically with PAU traits. This study improves understanding of the mechanisms associated with normative alcohol consumption vs problematic habitual use and AUD as well as how MaxAlc relates to psychiatric and medical conditions genetically and biologically.