title: A novel, functional and replicable risk gene region for alcohol dependence identified by genome-wide association study.
abstract: Several genome-wide association studies (GWASs) reported tens of risk genes for alcohol dependence, but most of them have not been replicated or confirmed by functional studies. The present study used a GWAS to search for novel, functional and replicable risk gene regions for alcohol dependence. Associations of all top-ranked SNPs identified in a discovery sample of 681 African-American (AA) cases with alcohol dependence and 508 AA controls were retested in a primary replication sample of 1,409 European-American (EA) cases and 1,518 EA controls. The replicable associations were then subjected to secondary replication in a sample of 6,438 Australian family subjects. A functional expression quantitative trait locus (eQTL) analysis of these replicable risk SNPs was followed-up in order to explore their cis-acting regulatory effects on gene expression. We found that within a 90 Mb region around PHF3-PTP4A1 locus in AAs, a linkage disequilibrium (LD) block in PHF3-PTP4A1 formed the only peak associated with alcohol dependence at p<10(-4). Within this block, 30 SNPs associated with alcohol dependence in AAs (1.6×10(-5)≤p≤0.050) were replicated in EAs (1.3×10(-3)≤p≤0.038), and 18 of them were also replicated in Australians (1.8×10(-3)≤p≤0.048). Most of these risk SNPs had strong cis-acting regulatory effects on PHF3-PTP4A1 mRNA expression across three HapMap samples. The distributions of -log(p) values for association and functional signals throughout this LD block were highly consistent across AAs, EAs, Australians and three HapMap samples. We conclude that the PHF3-PTP4A1 region appears to harbor a causal locus for alcohol dependence, and proteins encoded by PHF3 and/or PTP4A1 might play a functional role in the disorder.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America. Lingjun.Zuo@yale.edu
authors.forename: Lingjun
authors.initials: L
authors.lastname: Zuo
authors.forename: Clarence K
authors.initials: CK
authors.lastname: Zhang
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.forename: Chiang-Shan R
authors.initials: CS
authors.lastname: Li
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.forename: Lingeng
authors.initials: L
authors.lastname: Lu
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
authors.forename: Heping
authors.initials: H
authors.lastname: Zhang
authors.forename: Fengyu
authors.initials: F
authors.lastname: Zhang
authors.forename: John H
authors.initials: JH
authors.lastname: Krystal
authors.forename: Xingguang
authors.initials: X
authors.lastname: Luo
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D000437:Alcoholism / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D008565:Membrane Proteins; C451413:PHF3 protein, human; D014157:Transcription Factors; C490198:PTP4A1 protein, human; D017027:Protein Tyrosine Phosphatases
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