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Mol Psychiatry. 2014 Jan;19(1):41-9. doi: 10.1038/mp.2013.145. Epub 2013 Oct 29.

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

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  • 11] Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine; and VA CT Healthcare Center, West Haven, CT, USA [2] Departments of Genetics and Neurobiology, Yale University School of Medicine, West Haven, CT, USA.
  • 2Department of Psychiatry, Philadelphia VA Medical Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  • 3Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
  • 4Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA.
  • 5Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine; and VA CT Healthcare Center, West Haven, CT, USA.
  • 6Department of Psychiatry, Medical University of South Carolina, Charleston, SC, USA.
  • 7Departments of Psychiatry, Psychotherapy and Psychosomatics, Martin-Luther-University, Halle, Germany.
  • 8Department of Psychiatry, Psychosomatics and Psychotherapy, University Medical Center, Regensburg, Germany.
  • 9Department of Psychiatry and Psychotherapy, Ludwig-Maximilians University, Munich, Germany.
  • 101] Department of Biostatistics, Yale School of Public Health, West Haven, CT, USA [2] Department of Genetics, Yale University School of Medicine, West Haven, CT, USA.
  • 111] Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA [2] Departments of Neurology, Ophthalmology, Genetics & Genomics, Epidemiology and Biostatistics, Boston University Schools of Medicine and Public Health, Boston, MA, USA.

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.

PMID:
24166409
[PubMed - indexed for MEDLINE]
PMCID:
PMC4165335
Free PMC Article

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