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Genome‐Wide Association Study of Alcohol Dependence Implicates a Region on Chromosome 11
Author(s) -
Edenberg Howard J.,
Koller Daniel L.,
Xuei Xiaoling,
Wetherill Leah,
McClintick Jeanette N.,
Almasy Laura,
Bierut Laura J.,
Bucholz Kathleen K.,
Goate Alison,
Aliev Fazil,
Dick Danielle,
Hesselbrock Victor,
Hinrichs Anthony,
Kramer John,
Kuperman Sam,
Nurnberger John I.,
Rice John P.,
Schuckit Marc A.,
Taylor Robert,
Todd Webb B.,
Tischfield Jay A.,
Porjesz Bernice,
Foroud Tatiana
Publication year - 2010
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2010.01156.x
Subject(s) - genome wide association study , single nucleotide polymorphism , alcohol dependence , genetics , snp , genetic association , biology , candidate gene , gene , alcohol , genotype , biochemistry
Background: Alcohol dependence is a complex disease, and although linkage and candidate gene studies have identified several genes associated with the risk for alcoholism, these explain only a portion of the risk. Methods: We carried out a genome‐wide association study (GWAS) on a case–control sample drawn from the families in the Collaborative Study on the Genetics of Alcoholism. The cases all met diagnostic criteria for alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition ; controls all consumed alcohol but were not dependent on alcohol or illicit drugs. To prioritize among the strongest candidates, we genotyped most of the top 199 single nucleotide polymorphisms (SNPs) ( p ≤ 2.1 × 10 −4 ) in a sample of alcohol‐dependent families and performed pedigree‐based association analysis. We also examined whether the genes harboring the top SNPs were expressed in human brain or were differentially expressed in the presence of ethanol in lymphoblastoid cells. Results: Although no single SNP met genome‐wide criteria for significance, there were several clusters of SNPs that provided mutual support. Combining evidence from the case–control study, the follow‐up in families, and gene expression provided strongest support for the association of a cluster of genes on chromosome 11 ( SLC22A18, PHLDA2, NAP1L4, SNORA54, CARS , and OSBPL5 ) with alcohol dependence. Several SNPs nominated as candidates in earlier GWAS studies replicated in ours, including CPE , DNASE2B , SLC10A2 , ARL6IP5 , ID4 , GATA4 , SYNE1 , and ADCY3 . Conclusions: We have identified several promising associations that warrant further examination in independent samples.