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Biol Psychiatry. 2019 Apr 8. pii: S0006-3223(19)31156-4. doi: 10.1016/j.biopsych.2019.03.984. [Epub ahead of print]

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

Author information

1
Psychiatry Service, VA Connecticut Healthcare System, West Haven, Connecticut; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. Electronic address: joel.gelernter@yale.edu.
2
Veterans Affairs (VA) Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, Connecticut; Department of Biostatistics, Yale University School of Medicine, New Haven, Connecticut.
3
Psychiatry Service, VA Connecticut Healthcare System, West Haven, Connecticut; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
4
Department of Biostatistics, Yale University School of Medicine, New Haven, Connecticut.
5
Veterans Affairs (VA) Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, Connecticut.
6
Veterans Affairs (VA) Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, Connecticut; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.
7
Veterans Affairs (VA) Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, Connecticut; Department of Emergency Medicine, Yale University School of Medicine, New Haven, Connecticut.
8
Veterans Affairs (VA) Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, Connecticut; Yale Center for Medical Informatics, Yale University School of Medicine, New Haven, Connecticut.
9
Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, Massachusetts; Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts.
10
Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, Massachusetts; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
11
Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, Massachusetts.
12
Department of Psychiatry, Hofstra Northwell School of Medicine, Hempstead, New York; Department of Molecular Medicine, Hofstra Northwell School of Medicine, Hempstead, New York; Department of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of Northwell Health, Glen Oaks, New York; Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, New York.
13
Veterans Integrated Services Networks (VISN) 4 Mental Illness Research, Education and Clinical Center, Crescenz VA Medical Center, Philadelphia, Pennsylvania; Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
14
Psychiatry Service, VA San Diego Healthcare System, San Diego, California; Department of Psychiatry, University of California San Diego, La Jolla, California. Electronic address: mstein@ucsd.edu.

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

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