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

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

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.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • African Americans / genetics
  • Alcohol Dehydrogenase / genetics
  • Alcoholism / epidemiology*
  • Alcoholism / genetics*
  • Aminopeptidases / genetics
  • Chromosome Mapping
  • Cohort Studies
  • Eukaryotic Initiation Factors / genetics
  • Female
  • Follow-Up Studies
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study*
  • Genotype
  • Humans
  • LIM Domain Proteins / genetics
  • Male
  • Microfilament Proteins / genetics*
  • Mitochondrial Proteins / genetics
  • Polymorphism, Single Nucleotide / genetics
  • Psychiatric Status Rating Scales
  • United States / epidemiology
  • Vesicular Transport Proteins / genetics*
  • Whites / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • CCDC88A protein, human
  • Eukaryotic Initiation Factors
  • LIM Domain Proteins
  • MTIF2 protein, human
  • Microfilament Proteins
  • Mitochondrial Proteins
  • PDLIM5 protein, human
  • Vesicular Transport Proteins
  • ADH1B protein, human
  • ADH1C protein, human
  • Alcohol Dehydrogenase
  • Aminopeptidases
  • METAP1 protein, human