A novel, functional and replicable risk gene region for alcohol dependence identified by genome-wide association study.
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. Ass...
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oai:doaj.org-article:53235d783acd46028766444deddc2dc82021-11-18T07:34:47ZA novel, functional and replicable risk gene region for alcohol dependence identified by genome-wide association study.1932-620310.1371/journal.pone.0026726https://doaj.org/article/53235d783acd46028766444deddc2dc82011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22096494/?tool=EBIhttps://doaj.org/toc/1932-6203Several 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.Lingjun ZuoClarence K ZhangFei WangChiang-Shan R LiHongyu ZhaoLingeng LuXiang-Yang ZhangLin LuHeping ZhangFengyu ZhangJohn H KrystalXingguang LuoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 11, p e26726 (2011) |
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DOAJ |
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EN |
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Medicine R Science Q |
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Medicine R Science Q Lingjun Zuo Clarence K Zhang Fei Wang Chiang-Shan R Li Hongyu Zhao Lingeng Lu Xiang-Yang Zhang Lin Lu Heping Zhang Fengyu Zhang John H Krystal Xingguang Luo A novel, functional and replicable risk gene region for alcohol dependence identified by genome-wide association study. |
| description |
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. |
| format |
article |
| author |
Lingjun Zuo Clarence K Zhang Fei Wang Chiang-Shan R Li Hongyu Zhao Lingeng Lu Xiang-Yang Zhang Lin Lu Heping Zhang Fengyu Zhang John H Krystal Xingguang Luo |
| author_facet |
Lingjun Zuo Clarence K Zhang Fei Wang Chiang-Shan R Li Hongyu Zhao Lingeng Lu Xiang-Yang Zhang Lin Lu Heping Zhang Fengyu Zhang John H Krystal Xingguang Luo |
| author_sort |
Lingjun Zuo |
| title |
A novel, functional and replicable risk gene region for alcohol dependence identified by genome-wide association study. |
| title_short |
A novel, functional and replicable risk gene region for alcohol dependence identified by genome-wide association study. |
| title_full |
A novel, functional and replicable risk gene region for alcohol dependence identified by genome-wide association study. |
| title_fullStr |
A novel, functional and replicable risk gene region for alcohol dependence identified by genome-wide association study. |
| title_full_unstemmed |
A novel, functional and replicable risk gene region for alcohol dependence identified by genome-wide association study. |
| title_sort |
novel, functional and replicable risk gene region for alcohol dependence identified by genome-wide association study. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2011 |
| url |
https://doaj.org/article/53235d783acd46028766444deddc2dc8 |
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