title: Genome-wide association study of alcohol dependence:significant findings in African- and European-Americans including novel risk loci.
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.
authors.affiliation: 1] 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.
authors.forename: J
authors.initials: J
authors.lastname: Gelernter
authors.affiliation: Department of Psychiatry, Philadelphia VA Medical Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: H R
authors.initials: HR
authors.lastname: Kranzler
authors.affiliation: Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Sherva
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Almasy
authors.affiliation: Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Koesterer
authors.affiliation: Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine; and VA CT Healthcare Center, West Haven, CT, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Smith
authors.affiliation: Department of Psychiatry, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: R
authors.initials: R
authors.lastname: Anton
authors.affiliation: Departments of Psychiatry, Psychotherapy and Psychosomatics, Martin-Luther-University, Halle, Germany.
authors.forename: U W
authors.initials: UW
authors.lastname: Preuss
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, University Medical Center, Regensburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Ridinger
authors.affiliation: Departments of Psychiatry, Psychotherapy and Psychosomatics, Martin-Luther-University, Halle, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Rujescu
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, University Medical Center, Regensburg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Wodarz
authors.affiliation: Department of Psychiatry and Psychotherapy, Ludwig-Maximilians University, Munich, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Zill
authors.affiliation: 1] 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.
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.affiliation: 1] 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.
authors.forename: L A
authors.initials: LA
authors.lastname: Farrer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D001741:Black or African American / Q000235:genetics; D000426:Alcohol Dehydrogenase / Q000235:genetics; D000437:Alcoholism / Q000453:epidemiology* / Q000235:genetics*; D000626:Aminopeptidases / Q000235:genetics; D002874:Chromosome Mapping; D015331:Cohort Studies; D039642:Eukaryotic Initiation Factors / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011569:Psychiatric Status Rating Scales; D014481:United States / Q000453:epidemiology; D033921:Vesicular Transport Proteins / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502451:CCDC88A protein, human; D039642:Eukaryotic Initiation Factors; D060588:LIM Domain Proteins; C486735:MTIF2 protein, human; D008840:Microfilament Proteins; D024101:Mitochondrial Proteins; C512485:PDLIM5 protein, human; D033921:Vesicular Transport Proteins; C489332:ADH1B protein, human; C420272:ADH1C protein, human; D000426:Alcohol Dehydrogenase; D000626:Aminopeptidases; C506619:METAP1 protein, human