{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T23:26:22Z","timestamp":1793316382347,"version":"4.5.0"},"reference-count":46,"publisher":"American Medical Association (AMA)","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n Alcohol 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).<\/jats:p>\n <\/jats:sec>\n \n Objectives<\/jats:title>\n To identify genetic loci associated with MaxAlc and to elucidate the genetic architecture across alcohol traits.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n \n This 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\u2009=\u2009218\u202f623) and African (n\u2009=\u200929\u202f132) ancestry, then meta-analyzed (N\u2009=\u2009247\u202f755). Linkage-disequilibrium score regression was used to estimate single nucleotide variant (SNV)\u2013heritability and genetic correlations (\n r<\/jats:italic>\n g<\/jats:sub>\n ) 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.\n <\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n Genetic associations.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n MaxAlc was defined from the following survey item: \u201cin a typical month, what is\/was the largest number of drinks of alcohol you may have had in one day?\u201d with ordinal responses from 0 to 15 or more drinks.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n GWASs were conducted on sample sizes of as many as 247\u202f455 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\n ADH1B<\/jats:italic>\n gene, namely rs1229984 (\n P<\/jats:italic>\n \u2009=\u20093.12\u2009\u00d7\u200910\n \u2212101<\/jats:sup>\n ) and rs2066702 (\n P<\/jats:italic>\n \u2009=\u20096.30\u2009\u00d7\u200910\n \u221217<\/jats:sup>\n ), 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 (\n r<\/jats:italic>\n g<\/jats:sub>\n \u2009=\u20090.79;\n P<\/jats:italic>\n \u2009=\u20093.95\u2009\u00d7\u200910\n \u2212149<\/jats:sup>\n ) and AUD (\n r<\/jats:italic>\n g<\/jats:sub>\n \u2009=\u20090.76;\n P<\/jats:italic>\n \u2009=\u20091.26\u2009\u00d7\u200910\n \u2212127<\/jats:sup>\n ) and had negative\n r<\/jats:italic>\n g<\/jats:sub>\n with the UK Biobank \u201calcohol usually taken with meals\u201d (\n r<\/jats:italic>\n g<\/jats:sub>\n \u2009=\u2009\u22120.53;\n P<\/jats:italic>\n \u2009=\u20091.40\u2009\u00d7\u200910\n \u221250<\/jats:sup>\n ). For psychiatric traits, MaxAlc had the strongest genetic correlation with suicide attempt (\n r<\/jats:italic>\n g<\/jats:sub>\n \u2009=\u20090.40;\n P<\/jats:italic>\n \u2009=\u20093.02\u2009\u00d7\u200910\n \u221221<\/jats:sup>\n ). 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 (\u03b2\u2009=\u20090.012;\n P<\/jats:italic>\n \u2009=\u20092.66\u2009\u00d7\u200910\n \u221210<\/jats:sup>\n ). MaxAlc MTAG resulted in 31 genome-wide significant loci.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n The 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.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2022.38880","type":"journal-article","created":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T11:09:53Z","timestamp":1666868993000},"page":"e2238880","source":"Crossref","is-referenced-by-count":45,"title":["Genome-Wide Investigation of Maximum Habitual Alcohol Intake in US Veterans in Relation to Alcohol Consumption Traits and Alcohol Use Disorder"],"prefix":"10.1001","volume":"5","author":[{"given":"Joseph D.","family":"Deak","sequence":"first","affiliation":[{"name":"Yale School of Medicine, New Haven, Connecticut"},{"name":"VA Connecticut Healthcare Center, West Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel F.","family":"Levey","sequence":"additional","affiliation":[{"name":"Yale School of Medicine, New Haven, Connecticut"},{"name":"VA Connecticut Healthcare Center, West Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank R.","family":"Wendt","sequence":"additional","affiliation":[{"name":"Yale School of Medicine, New Haven, Connecticut"},{"name":"VA Connecticut Healthcare Center, West Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Yale School of Medicine, New Haven, Connecticut"},{"name":"VA Connecticut Healthcare Center, West Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Galimberti","sequence":"additional","affiliation":[{"name":"Yale School of Medicine, New Haven, Connecticut"},{"name":"VA Connecticut Healthcare Center, West Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry R.","family":"Kranzler","sequence":"additional","affiliation":[{"name":"University of Pennsylvania Perelman School of Medicine, Philadelphia"},{"name":"Crescenz VA Medical Center, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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