| Title | 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 |
| Affiliation | Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. Vet Affairs Connecticut Healthcare Syst, West Haven, CT USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. China Med Univ, Affiliated Hosp 1, Dept Psychiat, Shenyang, Peoples R China. Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. Peking Univ, Natl Inst Drug Dependence, Beijing 100871, Peoples R China. NIMH, Gene Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. |
| Keywords | POLYMORPHISMS POPULATION EXPRESSION FINGER |
| Issue Date | 2011 |
| Publisher | plos one |
| Citation | PLOS ONE.2011,6,(11). |
| 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 (1.6x10(-5) <= p <= 0.050) were replicated in EAs (1.3x10(-3)<= p <= 0.038), and 18 of them were also replicated in Australians (1.8x10(-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. |
| URI | http://hdl.handle.net/20.500.11897/394121 |
| ISSN | 1932-6203 |
| DOI | 10.1371/journal.pone.0026726 |
| Indexed | SCI(E) |
| Appears in Collections: | 医学部待认领 |
