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

• Published in: Biological psychiatry (1969) Vol. 86; no. 5; pp. 365 - 376
• Main Authors: Gelernter, Joel, Sun, Ning, Polimanti, Renato, Pietrzak, Robert H., Levey, Daniel F., Lu, Qiongshi, Hu, Yiming, Li, Boyang, Radhakrishnan, Krishnan, Aslan, Mihaela, Cheung, Kei-Hoi, Li, Yuli, Rajeevan, Nallakkandi, Sayward, Fred, Harrington, Kelly, Chen, Quan, Cho, Kelly, Honerlaw, Jacqueline, Pyarajan, Saiju, Lencz, Todd, Quaden, Rachel, Shi, Yunling, Hunter-Zinck, Haley, Gaziano, J. Michael, Kranzler, Henry R., Concato, John, Zhao, Hongyu, Stein, Murray B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2019
• Subjects: ADH1B; Adolescent; Adult; Aged; Aged, 80 and over; Alcohol Drinking - ethnology; Alcohol Drinking - genetics; Alcoholism - ethnology; Alcoholism - genetics; Black or African American - statistics & numerical data; CRF Receptor, Type 1; CRHR1; Female; Genome-Wide Association Study; Habitual alcohol use; Humans; Linear Models; Male; Middle Aged; Million Veteran Program; Psychiatric/Mental Health; Receptors, Corticotropin-Releasing Hormone - genetics; United States; Veterans; White People - statistics & numerical data; Young Adult; United States; Genome-wide association study; Habitual alcohol use; ADH1B; Million Veteran Program; CRHR1
• ISSN: 0006-3223; 1873-2402; 1873-2402
• DOI: 10.1016/j.biopsych.2019.03.984

Habitual alcohol use can be an indicator of alcohol dependence, which is associated with a wide range of serious health problems. 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. 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. 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.