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

Department of Veterans Affairs Cooperative Studies Program (No. 575B); Million Veteran Program

doi:10.1016/j.biopsych.2019.03.984

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

Department of Veterans Affairs Cooperative Studies Program (No. 575B), Million Veteran Program

Research output: Contribution to journal › Article › peer-review

46 Scopus citations

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.

Original language	English
Pages (from-to)	365-376
Number of pages	12
Journal	Biological Psychiatry
Volume	86
Issue number	5
DOIs	https://doi.org/10.1016/j.biopsych.2019.03.984
State	Published - 1 Sep 2019
Externally published	Yes

Keywords

ADH1B
CRHR1
Genome-wide association study
Habitual alcohol use
Million Veteran Program

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10.1016/j.biopsych.2019.03.984

Cite this

@article{e55ded709fce4a54951aff8d51423928,

title = "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.",

keywords = "ADH1B, CRHR1, Genome-wide association study, Habitual alcohol use, Million Veteran Program",

author = "{Department of Veterans Affairs Cooperative Studies Program (No. 575B)} and {Million Veteran Program} and Joel Gelernter and Ning Sun and Renato Polimanti and Pietrzak, {Robert H.} and Levey, {Daniel F.} and Qiongshi Lu and Yiming Hu and Boyang Li and Krishnan Radhakrishnan and Mihaela Aslan and Cheung, {Kei Hoi} and Yuli Li and Nallakkandi Rajeevan and Fred Sayward and K. Harrington and Quan Chen and K. Cho and Jacqueline Honerlaw and S. Pyarajan and Todd Lencz and Rachel Quaden and Yunling Shi and H. Hunter-Zinck and Gaziano, {J. Michael} and Kranzler, {Henry R.} and John Concato and Hongyu Zhao and Stein, {Murray B.}",

note = "Funding Information: This research is based on data from the MVP, Office of Research and Development, Veterans Health Administration, and was supported by MVP and the Veterans Affairs Cooperative Studies Program study No. 575B . The Psychiatric Genomics Consortium Substance Use Disorders working group (PGC-SUD) is supported by funds from the National Institute on Drug Abuse and the National Institute of Mental Health through Grant No. MH109532 and, previously, had analyst support from the National Institute on Alcohol Abuse and Alcoholism through Grant No. U01AA008401 (Collaborative Study on the Genetics of Alcoholism). Funding Information: This research is based on data from the MVP, Office of Research and Development, Veterans Health Administration, and was supported by MVP and the Veterans Affairs Cooperative Studies Program study No. 575B. The Psychiatric Genomics Consortium Substance Use Disorders working group (PGC-SUD) is supported by funds from the National Institute on Drug Abuse and the National Institute of Mental Health through Grant No. MH109532 and, previously, had analyst support from the National Institute on Alcohol Abuse and Alcoholism through Grant No. U01AA008401 (Collaborative Study on the Genetics of Alcoholism). We appreciate the availability of summary statistic data from the PGC-SUD. The PGC-SUD gratefully acknowledges its contributing studies and the participants in those studies without whom this effort would not be possible. Summary statistics for all genome-wide association study analyses are freely available. The dbGaP accession assigned to the MVP is phs001672.v1.p (https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001672.v1.p1). Additionally, investigators who wish to gain access to the individual-level data may contact JG or MBS; access to these data will be available in one of our laboratories on a collaborative basis. MVP is presently working toward developing ways to make individual-level coded data more broadly accessible as allowed by the consent and consistent with the MVP data access policies and procedures. JG and HRK are named as coinventors on Patent Cooperation Treaty Patent Application No. 15/878,640: ?Genotype-guided dosing of opioid agonists,? filed January 24, 2018. MBS has in the past 3 years been a consultant for Actelion, Aptinyx, Bionomics, Dart Neuroscience, Healthcare Management Technologies, Janssen, Jazz Pharmaceuticals, Neurocrine Biosciences, Oxeia Biopharmaceuticals, and Pfizer; owns founders shares and stock options in Resilience Therapeutics; and has stock options in Oxeia Biopharmaceuticals. HRK has been an advisory board member, consultant, or continuing medical education speaker for Alkermes, Indivior, and Lundbeck; and is a member of the American Society of Clinical Psychopharmacology's Alcohol Clinical Trials Initiative, which was supported in the last 3 years by AbbVie, Alkermes, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, Pfizer, Arbor, and Amygdala Neurosciences. The other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: {\textcopyright} 2019",

year = "2019",

month = sep,

day = "1",

doi = "10.1016/j.biopsych.2019.03.984",

language = "English",

volume = "86",

pages = "365--376",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier USA",

number = "5",

}

Genome-wide Association Study of Maximum Habitual Alcohol Intake in >140,000 U.S. European and African American Veterans Yields Novel Risk Loci. / Department of Veterans Affairs Cooperative Studies Program (No. 575B); Million Veteran Program.
In: Biological Psychiatry, Vol. 86, No. 5, 01.09.2019, p. 365-376.

Research output: Contribution to journal › Article › peer-review

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 - Funding Information: This research is based on data from the MVP, Office of Research and Development, Veterans Health Administration, and was supported by MVP and the Veterans Affairs Cooperative Studies Program study No. 575B . The Psychiatric Genomics Consortium Substance Use Disorders working group (PGC-SUD) is supported by funds from the National Institute on Drug Abuse and the National Institute of Mental Health through Grant No. MH109532 and, previously, had analyst support from the National Institute on Alcohol Abuse and Alcoholism through Grant No. U01AA008401 (Collaborative Study on the Genetics of Alcoholism). Funding Information: This research is based on data from the MVP, Office of Research and Development, Veterans Health Administration, and was supported by MVP and the Veterans Affairs Cooperative Studies Program study No. 575B. The Psychiatric Genomics Consortium Substance Use Disorders working group (PGC-SUD) is supported by funds from the National Institute on Drug Abuse and the National Institute of Mental Health through Grant No. MH109532 and, previously, had analyst support from the National Institute on Alcohol Abuse and Alcoholism through Grant No. U01AA008401 (Collaborative Study on the Genetics of Alcoholism). We appreciate the availability of summary statistic data from the PGC-SUD. The PGC-SUD gratefully acknowledges its contributing studies and the participants in those studies without whom this effort would not be possible. Summary statistics for all genome-wide association study analyses are freely available. The dbGaP accession assigned to the MVP is phs001672.v1.p (https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001672.v1.p1). Additionally, investigators who wish to gain access to the individual-level data may contact JG or MBS; access to these data will be available in one of our laboratories on a collaborative basis. MVP is presently working toward developing ways to make individual-level coded data more broadly accessible as allowed by the consent and consistent with the MVP data access policies and procedures. JG and HRK are named as coinventors on Patent Cooperation Treaty Patent Application No. 15/878,640: ?Genotype-guided dosing of opioid agonists,? filed January 24, 2018. MBS has in the past 3 years been a consultant for Actelion, Aptinyx, Bionomics, Dart Neuroscience, Healthcare Management Technologies, Janssen, Jazz Pharmaceuticals, Neurocrine Biosciences, Oxeia Biopharmaceuticals, and Pfizer; owns founders shares and stock options in Resilience Therapeutics; and has stock options in Oxeia Biopharmaceuticals. HRK has been an advisory board member, consultant, or continuing medical education speaker for Alkermes, Indivior, and Lundbeck; and is a member of the American Society of Clinical Psychopharmacology's Alcohol Clinical Trials Initiative, which was supported in the last 3 years by AbbVie, Alkermes, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, Pfizer, Arbor, and Amygdala Neurosciences. The other authors report no biomedical financial interests or potential conflicts of interest. 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

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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 -

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

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