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

Biol Psychiatry. 2019 Sep 1;86(5):365-376. doi: 10.1016/j.biopsych.2019.03.984. Epub 2019 Apr 8.

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.

Keywords: ADH1B; CRHR1; Genome-wide association study; Habitual alcohol use; Million Veteran Program.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Alcohol Drinking / ethnology
  • Alcohol Drinking / genetics*
  • Alcoholism / ethnology
  • Alcoholism / genetics
  • Black or African American / statistics & numerical data*
  • 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

Substances

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