title: A quantitative-trait genome-wide association study of alcoholism risk in the community: findings and implications.
abstract: BACKGROUND
  Given moderately strong genetic contributions to variation in alcoholism and heaviness of drinking (50% to 60% heritability) with high correlation of genetic influences, we have conducted a quantitative trait genome-wide association study (GWAS) for phenotypes related to alcohol use and dependence.
  
  
  METHODS
  Diagnostic interview and blood/buccal samples were obtained from sibships ascertained through the Australian Twin Registry. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed with 8754 individuals (2062 alcohol-dependent cases) selected for informativeness for alcohol use disorder and associated quantitative traits. Family-based association tests were performed for alcohol dependence, dependence factor score, and heaviness of drinking factor score, with confirmatory case-population control comparisons using an unassessed population control series of 3393 Australians with genome-wide SNP data.
  
  
  RESULTS
  No findings reached genome-wide significance (p = 8.4 × 10(-8) for this study), with lowest p value for primary phenotypes of 1.2 × 10(-7). Convergent findings for quantitative consumption and diagnostic and quantitative dependence measures suggest possible roles for a transmembrane protein gene (TMEM108) and for ANKS1A. The major finding, however, was small effect sizes estimated for individual SNPs, suggesting that hundreds of genetic variants make modest contributions (1/4% of variance or less) to alcohol dependence risk.
  
  
  CONCLUSIONS
  We conclude that 1) meta-analyses of consumption data may contribute usefully to gene discovery; 2) translation of human alcoholism GWAS results to drug discovery or clinically useful prediction of risk will be challenging; and 3) through accumulation across studies, GWAS data may become valuable for improved genetic risk differentiation in research in biological psychiatry (e.g., prospective high-risk or resilience studies).
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA. aheath@wustl.edu
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Heath
authors.forename: John B
authors.initials: JB
authors.lastname: Whitfield
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.forename: Michele L
authors.initials: ML
authors.lastname: Pergadia
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Lind
authors.forename: Brian P
authors.initials: BP
authors.lastname: McEvoy
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Schrage
authors.forename: Julia D
authors.initials: JD
authors.lastname: Grant
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Chou
authors.forename: Rachel
authors.initials: R
authors.lastname: Zhu
authors.forename: Anjali K
authors.initials: AK
authors.lastname: Henders
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Medland
authors.forename: Scott D
authors.initials: SD
authors.lastname: Gordon
authors.forename: Elliot C
authors.initials: EC
authors.lastname: Nelson
authors.forename: Arpana
authors.initials: A
authors.lastname: Agrawal
authors.forename: Dale R
authors.initials: DR
authors.lastname: Nyholt
authors.forename: Kathleen K
authors.initials: KK
authors.lastname: Bucholz
authors.forename: Pamela A F
authors.initials: PA
authors.lastname: Madden
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics*; D000437:Alcoholism / Q000175:diagnosis / Q000235:genetics*; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data*; D005838:Genotype; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D012111:Residence Characteristics