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Genome-wide association study of alcohol dependence implicates a region on chromosome 11.
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
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Alcoholism, clinical and experimental research
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2010-03-01
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34
Publication Issue
5
Publication Begin
840
Publication End
52
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nihms-172647.pdf
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Abstract
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.
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 < or = 2.1 x 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.
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.
We have identified several promising associations that warrant further examination in independent samples.
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 < or = 2.1 x 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.
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.
We have identified several promising associations that warrant further examination in independent samples.
Citation
Edenberg HJ, Koller DL, Xuei X, Wetherill L, McClintick JN, Almasy L, Bierut LJ, Bucholz KK, Goate A, Aliev F, Dick D, Hesselbrock V, Hinrichs A, Kramer J, Kuperman S, Nurnberger JI Jr, Rice JP, Schuckit MA, Taylor R, Todd Webb B, Tischfield JA, Porjesz B, Foroud T. Genome-wide association study of alcohol dependence implicates a region on chromosome 11. Alcohol Clin Exp Res. 2010 May;34(5):840-52. doi: 10.1111/j.1530-0277.2010.01156.x. Epub 2010 Mar 1. PMID: 20201924; PMCID: PMC2884073.