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.

• Authors: Joel Gelernter, Ning Sun, Renato Polimanti, Robert H Pietrzak, Daniel F Levey, Qiongshi Lu, Yiming Hu, Boyang Li, Krishnan Radhakrishnan, Mihaela Aslan, Kei-Hoi Cheung, Yuli Li, Nallakkandi Rajeevan, Fred Sayward, Kelly Harrington, Quan Chen, Kelly Cho, Jacqueline Honerlaw, Saiju Pyarajan, Todd Lencz, Rachel Quaden, Yunling Shi, Haley Hunter-Zinck, J Michael Gaziano, Henry R Kranzler, John Concato, Hongyu Zhao, Murray B Stein, Department of Veterans Affairs Cooperative Studies Program (No. 575B), Million Veteran Program
• Journal: Biological psychiatry (Biol Psychiatry) Vol. 86 Issue 5 Pg. 365-376 (09 01 2019) ISSN: 1873-2402 [Electronic] United States
• PMID: 31151762 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2019. Published by Elsevier Inc.

Chemical References

• Receptors, Corticotropin-Releasing Hormone
• CRF receptor type 1

Topics

• Adolescent
• Adult
• Black or African American (statistics & numerical data)
• Aged
• Aged, 80 and over
• Alcohol Drinking (ethnology, genetics)
• Alcoholism (ethnology, genetics)
• Female
• Genome-Wide Association Study
• Humans
• Linear Models
• Male
• Middle Aged
• Receptors, Corticotropin-Releasing Hormone (genetics)
• United States
• Veterans
• White People (statistics & numerical data)
• Young Adult