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

Autor: Gelernter J; 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., Sun N; 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., Polimanti R; Psychiatry Service, VA Connecticut Healthcare System, West Haven, Connecticut; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut., Pietrzak RH; Psychiatry Service, VA Connecticut Healthcare System, West Haven, Connecticut; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut., Levey DF; Psychiatry Service, VA Connecticut Healthcare System, West Haven, Connecticut; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut., Lu Q; Department of Biostatistics, Yale University School of Medicine, New Haven, Connecticut., Hu Y; Department of Biostatistics, Yale University School of Medicine, New Haven, Connecticut., Li B; Department of Biostatistics, Yale University School of Medicine, New Haven, Connecticut., Radhakrishnan K; Veterans Affairs (VA) Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, Connecticut., Aslan M; 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., Cheung KH; 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., Li Y; 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., Rajeevan N; 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., Sayward F; 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., Harrington K; Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, Massachusetts; Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts., Chen Q; 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., Cho K; 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., Honerlaw J; Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, Massachusetts., Pyarajan S; 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., Lencz T; 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., Quaden R; Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, Massachusetts., Shi Y; Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, Massachusetts., Hunter-Zinck H; Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, Massachusetts., Gaziano JM; 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., Kranzler HR; 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., Concato J; 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., Zhao H; 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., Stein MB; 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.
Jazyk: angličtina
Zdroj: Biological psychiatry [Biol Psychiatry] 2019 Sep 01; Vol. 86 (5), pp. 365-376. Date of Electronic Publication: 2019 Apr 08.
DOI: 10.1016/j.biopsych.2019.03.984
Abstrakt: 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.
(Copyright © 2019. Published by Elsevier Inc.)
Databáze: MEDLINE
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