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Genome-wide association study of alcohol dependence:significant findings in African- and European-Americans including novel risk loci

Molecular Psychiatry volume 19, pages 41–49 (2014)Cite this article

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Abstract

We report a GWAS of alcohol dependence (AD) in European-American (EA) and African-American (AA) populations, with replication in independent samples of EAs, AAs and Germans. Our sample for discovery and replication was 16 087 subjects, the largest sample for AD GWAS to date. Numerous genome-wide significant (GWS) associations were identified, many novel. Most associations were population specific, but in several cases were GWS in EAs and AAs for different SNPs at the same locus,showing biological convergence across populations. We confirmed well-known risk loci mapped to alcohol-metabolizing enzyme genes, notably ADH1B (EAs: Arg48His, P=1.17 × 10−31; AAs: Arg369Cys, P=6.33 × 10−17) and ADH1C in AAs (Thr151Thr, P=4.94 × 10−10), and identified novel risk loci mapping to the ADH gene cluster on chromosome 4 and extending centromerically beyond it to include GWS associations at LOC100507053 in AAs (P=2.63 × 10−11), PDLIM5 in EAs (P=2.01 × 10−8), and METAP in AAs (P=3.35 × 10−8). We also identified a novel GWS association (1.17 × 10−10) mapped to chromosome 2 at rs1437396, between MTIF2 and CCDC88A, across all of the EA and AA cohorts, with supportive gene expression evidence, and population-specific GWS for markers on chromosomes 5, 9 and 19. Several of the novel associations implicate direct involvement of, or interaction with, genes previously identified as schizophrenia risk loci. Confirmation of known AD risk loci supports the overall validity of the study; the novel loci are worthy of genetic and biological follow-up. The findings support a convergence of risk genes (but not necessarily risk alleles) between populations, and, to a lesser extent, between psychiatric traits.

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Acknowledgements

We appreciate the work in recruitment and assessment provided at Yale University School of Medicine and the APT Foundation by James Poling, PhD; at McLean Hospital by Roger Weiss, M.D., at the Medical University of South Carolina by Kathleen Brady, MD, Ph.D. and at the University of Pennsylvania by David Oslin, MD. Genotyping services for a part of our GWAS study were provided by the Center for Inherited Disease Research (CIDR) and Yale University (Center for Genome Analysis). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University (contract number N01-HG-65403). We are grateful to Ann Marie Lacobelle, Catherine Aldi and Christa Robinson for their excellent technical assistance, to the SSADDA interviewers, led by Yari Nuñez and Michelle Slivinsky, who devoted substantial time and effort to phenotype the study sample and to John Farrell and Alexan Mardigan for database management assistance. This study was supported by National Institutes of Health grants RC2 DA028909, R01 DA12690, R01 DA12849, R01 DA18432, R01 AA11330, R01 AA017535 and the VA Connecticut and Philadelphia VA MIRECCs. The publicly available data sets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000092.v1.p1 through dbGaP accession number phs000092.v1.p. Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative [GEI] (U01 HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of data sets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the Family Study of Cocaine Dependence (FSCD; R01 DA013423). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse and the NIH contract ‘High throughput genotyping for studying the genetic contributions to human disease’ (HHSN268200782096C).

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Authors and Affiliations

  1. Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine,

    J Gelernter & A H Smith

  2. VA CT Healthcare Center, West Haven, CT, USA

    J Gelernter & A H Smith

  3. Departments of Genetics and Neurobiology, Yale University School of Medicine, West Haven, CT, USA

    J Gelernter

  4. Department of Psychiatry, Philadelphia VA Medical Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    H R Kranzler

  5. Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA

    R Sherva, R Koesterer & L A Farrer

  6. Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA

    L Almasy

  7. Department of Psychiatry, Medical University of South Carolina, Charleston, SC, USA

    R Anton

  8. Departments of Psychiatry, Psychotherapy and Psychosomatics, Martin-Luther-University, Halle, Germany

    U W Preuss & D Rujescu

  9. Department of Psychiatry, Psychosomatics and Psychotherapy, University Medical Center, Regensburg, Germany

    M Ridinger & N Wodarz

  10. Department of Psychiatry and Psychotherapy, Ludwig-Maximilians University, Munich, Germany

    P Zill

  11. Department of Biostatistics, Yale School of Public Health, West Haven, CT, USA

    H Zhao

  12. Department of Genetics, Yale University School of Medicine, West Haven, CT, USA

    H Zhao

  13. Departments of Neurology, Ophthalmology, Genetics & Genomics, Epidemiology and Biostatistics, Boston University Schools of Medicine and Public Health, Boston, MA, USA

    L A Farrer

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Correspondence to J Gelernter.

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Competing interests

Although unrelated to the current study, Dr Kranzler has been a consultant or advisory board member for Alkermes, Lilly, Lundbeck, Pfizer and Roche. He is also a member of the American Society of Clinical Psychopharmacology's Alcohol Clinical Trials Initiative, which is supported by Lilly, Lundbeck, AbbVie and Pfizer.

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Gelernter, J., Kranzler, H., Sherva, R. et al. Genome-wide association study of alcohol dependence:significant findings in African- and European-Americans including novel risk loci. Mol Psychiatry 19, 41–49 (2014). https://doi.org/10.1038/mp.2013.145

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