title: Pooled association genome scanning for alcohol dependence using 104,268 SNPs: validation and use to identify alcoholism vulnerability loci in unrelated individuals from the collaborative study on the genetics of alcoholism.
abstract: Association genome scanning can identify markers for the allelic variants that contribute to vulnerability to complex disorders, including alcohol dependence. To improve the power and feasibility of this approach, we report validation of "100k" microarray-based allelic frequency assessments in pooled DNA samples. We then use this approach with unrelated alcohol-dependent versus control individuals sampled from pedigrees collected by the Collaborative Study on the Genetics of Alcoholism (COGA). Allele frequency differences between alcohol-dependent and control individuals are assessed in quadruplicate at 104,268 autosomal SNPs in pooled samples. One hundred eighty-eight SNPs provide (1) the largest allele frequency differences between dependent versus control individuals; (2) t values >or= 3 for these differences; and (3) clustering, so that 51 relatively small chromosomal regions contain at least three SNPs that satisfy criteria 1 and 2 above (Monte Carlo P = 0.00034). These positive SNP clusters nominate interesting genes whose products are implicated in cellular signaling, gene regulation, development, "cell adhesion," and Mendelian disorders. The results converge with linkage and association results for alcohol and other addictive phenotypes. The data support polygenic contributions to vulnerability to alcohol dependence. These SNPs provide new tools to aid the understanding, prevention, and treatment of alcohol abuse and dependence.
authors.affiliation: Molecular Neurobiology Branch, NIDA-IRP, NIH, Baltimore, Maryland 21224, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Johnson
authors.forename: Tomas
authors.initials: T
authors.lastname: Drgon
authors.forename: Qing-Rong
authors.initials: QR
authors.lastname: Liu
authors.forename: Donna
authors.initials: D
authors.lastname: Walther
authors.forename: Howard
authors.initials: H
authors.lastname: Edenberg
authors.forename: John
authors.initials: J
authors.lastname: Rice
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.forename: George R
authors.initials: GR
authors.lastname: Uhl
mesh_terms: D000437:Alcoholism / Q000235:genetics*; D002877:Chromosomes, Human / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics / Q000379:methods; D006801:Humans; D046228:Microarray Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D044465:White People / Q000235:genetics