A novel, functional and replicable risk gene region for alcohol dependence identified by genome-wide association study.
- 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
- Year
- 2011
- Journal
- PloS one
- PMID
- 22096494
- DOI
- 10.1371/journal.pone.0026726
- PMCID
- PMC3210123
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.
Regional association and eQTL plots around PHF3-PTP4A1 region.[Left Y-axis corresponds to −log(p) value; right Y-axis corresponds to recombination rates; quantitative color gradient corresponds to r2; red squares represent peak SNPs. (a) regional association plot in AAs for a 10 Mb region surrounding the peak association SNP (rs9294269) in PHF3-PTP4A1; (b, c) regional association plots in AAs or EAs for a 1 Mb region surrounding the peak association SNP (rs9294269) in PHF3-PTP4A1; (d–h) regional eQTL plots in HapMap populations for a 1 MB region surrounding rs9294269; (i) LD map for all available markers for a region surrounding rs9294269 in EAs (Illumina Human1M beadchip), in which red bars represent the peak SNPs in each population].
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