title: Examining the role of common genetic variants on alcohol, tobacco, cannabis and illicit drug dependence: genetics of vulnerability to drug dependence.
abstract: OBJECTIVE
  Twin and family studies suggest that genetic influences are shared across substances of abuse. However, despite evidence of heritability, genome-wide association and candidate gene studies have indicated numerous markers of limited effects, suggesting that much of the heritability remains missing. We estimated (1) the aggregate effect of common single nucleotide polymorphisms (SNPs) on multiple indicators of comorbid drug problems that are typically employed across community and population-based samples, and (2) the genetic covariance across these measures.
  
  
  METHODS
  A total of 2596 unrelated subjects from the Study of Addiction: Genetics and Environment provided information on alcohol, tobacco, cocaine, cannabis and other illicit substance dependence. Phenotypic measures included: (1) a factor score based on DSM-IV drug dependence diagnoses (DD), (2) a factor score based on problem use (PU; i.e. 1+ DSM-IV symptoms) and (3) dependence vulnerability (DV; a ratio of DSM-IV symptoms to the number of substances used).
  
  
  RESULTS
  Univariate and bivariate genome-wide complex trait analyses of this selected sample indicated that common SNPs explained 25-36% of the variance across measures, with DD and DV having the largest effects [h(2) SNP (standard error) = 0.36 (0.13) and 0.33 (0.13), respectively; PU = 0.25 (0.13)]. Genetic effects were shared across the three phenotypic measures of comorbid drug problems [rDD-PU = 0.92 (0.08), rDD-DV = 0.97 (0.08) and rPU-DV = 0.96 (0.07)].
  
  
  CONCLUSIONS
  At least 20% of the variance in the generalized vulnerability to substance dependence is attributable to common single nucleotide polymorphisms. The additive effect of common single nucleotide polymorphisms is shared across important indicators of comorbid drug problems.
authors.affiliation: Division of Behavioral Genetics, Department of Psychiatry, Rhode Island Hospital, Providence, RI, USA; Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Rohan H C
authors.initials: RH
authors.lastname: Palmer
authors.forename: Leslie
authors.initials: L
authors.lastname: Brick
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Nugent
authors.forename: L Cinnamon
authors.initials: LC
authors.lastname: Bidwell
authors.forename: John E
authors.initials: JE
authors.lastname: McGeary
authors.forename: Valerie S
authors.initials: VS
authors.lastname: Knopik
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Keller
mesh_terms: D000437:Alcoholism / Q000453:epidemiology / Q000235:genetics*; D019970:Cocaine-Related Disorders / Q000453:epidemiology / Q000235:genetics*; D015897:Comorbidity; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D002189:Marijuana Abuse / Q000453:epidemiology / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D025341:Principal Component Analysis; D019966:Substance-Related Disorders / Q000453:epidemiology / Q000235:genetics; D014029:Tobacco Use Disorder / Q000453:epidemiology / Q000235:genetics*; D014481:United States / Q000453:epidemiology
keywords: Addiction; dependence vulnerability; drug dependence; genetics; genome-wide association studies (GWAS); genome-wide complex trait analysis