Dataset Information

Genome-wide Association Study of Maximum Habitual Alcohol Intake in >140,000 U.S. European and African American Veterans Yields Novel Risk Loci.

ABSTRACT: BACKGROUND:Habitual alcohol use can be an indicator of alcohol dependence, which is associated with a wide range of serious health problems. METHODS:We completed a genome-wide association study in 126,936 European American and 17,029 African American subjects in the Veterans Affairs Million Veteran Program for a quantitative phenotype based on maximum habitual alcohol consumption. RESULTS:ADH1B, on chromosome 4, was the lead locus for both populations: for the European American sample, rs1229984 (p = 4.9 × 10-47); for African American, rs2066702 (p = 2.3 × 10-12). In the European American sample, we identified three additional genome-wide-significant maximum habitual alcohol consumption loci: on chromosome 17, rs77804065 (p = 1.5 × 10-12), at CRHR1 (corticotropin-releasing hormone receptor 1); the protein product of this gene is involved in stress and immune responses; and on chromosomes 8 and 10. European American and African American samples were then meta-analyzed; the associated region at CRHR1 increased in significance to 1.02 × 10-13, and we identified two additional genome-wide significant loci, FGF14 (p = 9.86 × 10-9) (chromosome 13) and a locus on chromosome 11. Besides ADH1B, none of the five loci have prior genome-wide significant support. Post-genome-wide association study analysis identified genetic correlation to other alcohol-related traits, smoking-related traits, and many others. Replications were observed in UK Biobank data. Genetic correlation between maximum habitual alcohol consumption and alcohol dependence was 0.87 (p = 4.78 × 10-9). Enrichment for cell types included dopaminergic and gamma-aminobutyric acidergic neurons in midbrain, and pancreatic delta cells. CONCLUSIONS:The present study supports five novel alcohol-use risk loci, with particularly strong statistical support for CRHR1. Additionally, we provide novel insight regarding the biology of harmful alcohol use.

SUBMITTER: Gelernter J

PROVIDER: S-EPMC6919570 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Genome-wide Association Study of Maximum Habitual Alcohol Intake in >140,000 U.S. European and African American Veterans Yields Novel Risk Loci.

Gelernter Joel J Sun Ning N Polimanti Renato R Pietrzak Robert H RH Levey Daniel F DF Lu Qiongshi Q Hu Yiming Y Li Boyang B Radhakrishnan Krishnan K Aslan Mihaela M Cheung Kei-Hoi KH Li Yuli Y Rajeevan Nallakkandi N Sayward Fred F Harrington Kelly K Chen Quan Q Cho Kelly K Honerlaw Jacqueline J Pyarajan Saiju S Lencz Todd T Quaden Rachel R Shi Yunling Y Hunter-Zinck Haley H Gaziano J Michael JM Kranzler Henry R HR Concato John J Zhao Hongyu H Stein Murray B MB

Biological psychiatry 20190408 5

<h4>Background</h4>Habitual alcohol use can be an indicator of alcohol dependence, which is associated with a wide range of serious health problems.<h4>Methods</h4>We completed a genome-wide association study in 126,936 European American and 17,029 African American subjects in the Veterans Affairs Million Veteran Program for a quantitative phenotype based on maximum habitual alcohol consumption.<h4>Results</h4>ADH1B, on chromosome 4, was the lead locus for both populations: for the European Amer ...[more]

PMID: 31151762

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Project description: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.

Dataset Information

Genome-wide Association Study of Maximum Habitual Alcohol Intake in >140,000 U.S. European and African American Veterans Yields Novel Risk Loci.

Publications

Genome-wide Association Study of Maximum Habitual Alcohol Intake in >140,000 U.S. European and African American Veterans Yields Novel Risk Loci.

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