A novel, functional and replicable risk gene region for alcohol dependence identified by genome-wide association study

• Published in: PloS one Vol. 6; no. 11; p. e26726
• Main Authors: Zuo, Lingjun, Zhang, Clarence K, Wang, Fei, Li, Chiang-Shan R, Zhao, Hongyu, Lu, Lingeng, Zhang, Xiang-Yang, Lu, Lin, Zhang, Heping, Zhang, Fengyu, Krystal, John H, Luo, Xingguang
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07-11-2011; Public Library of Science (PLoS)
• Subjects: Acids; Adult; Alcohol use; Alcoholism; Alcoholism - genetics; Alcohols; Biology; Black or African American - genetics; Brain; Cell Cycle Proteins - genetics; Datasets; Drug dependence; Epidemiology; Ethanol; Female; Gene expression; Genes; Genetic Predisposition to Disease - genetics; Genetic research; Genetics; Genome-wide association studies; Genome-Wide Association Study - methods; Genomes; Genomics; Humans; Linkage disequilibrium; Linkage Disequilibrium - genetics; Male; Medicine; Membrane Proteins - genetics; Middle Aged; Protein Tyrosine Phosphatases - genetics; Proteins; Psychiatry; Public health; Quantitative trait loci; Replication; Risk analysis; Single-nucleotide polymorphism; Social and Behavioral Sciences; Studies; Transcription factors; Transcription Factors - genetics; Trends; Veterans; United States > US; Connecticut
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0026726

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.