TY - JOUR
T1 - Genome-wide Association Study of Maximum Habitual Alcohol Intake in >140,000 U.S. European and African American Veterans Yields Novel Risk Loci
AU - Department of Veterans Affairs Cooperative Studies Program (No. 575B)
AU - Million Veteran Program
AU - Gelernter, Joel
AU - Sun, Ning
AU - Polimanti, Renato
AU - Pietrzak, Robert H.
AU - Levey, Daniel F.
AU - Lu, Qiongshi
AU - Hu, Yiming
AU - Li, Boyang
AU - Radhakrishnan, Krishnan
AU - Aslan, Mihaela
AU - Cheung, Kei Hoi
AU - Li, Yuli
AU - Rajeevan, Nallakkandi
AU - Sayward, Fred
AU - Harrington, K.
AU - Chen, Quan
AU - Cho, K.
AU - Honerlaw, Jacqueline
AU - Pyarajan, S.
AU - Lencz, Todd
AU - Quaden, Rachel
AU - Shi, Yunling
AU - Hunter-Zinck, H.
AU - Gaziano, J. Michael
AU - Kranzler, Henry R.
AU - Concato, John
AU - Zhao, Hongyu
AU - Stein, Murray B.
N1 - Publisher Copyright:
© 2019
PY - 2019/9/1
Y1 - 2019/9/1
N2 - 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.
AB - 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.
KW - ADH1B
KW - CRHR1
KW - Genome-wide association study
KW - Habitual alcohol use
KW - Million Veteran Program
UR - http://www.scopus.com/inward/record.url?scp=85071353245&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2019.03.984
DO - 10.1016/j.biopsych.2019.03.984
M3 - Article
C2 - 31151762
AN - SCOPUS:85071353245
SN - 0006-3223
VL - 86
SP - 365
EP - 376
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 5
ER -