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. 2011;6(11):e26726.
doi: 10.1371/journal.pone.0026726. Epub 2011 Nov 7.

A Novel, Functional and Replicable Risk Gene Region for Alcohol Dependence Identified by Genome-Wide Association Study

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Free PMC article

A Novel, Functional and Replicable Risk Gene Region for Alcohol Dependence Identified by Genome-Wide Association Study

Lingjun Zuo et al. PLoS One. .
Free PMC article

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.

Conflict of interest statement

Competing Interests: The authors have read the journal's policy and have the following conflicts: JHK has been a paid consultant for Aisling Capital, LLC, AstraZeneca Pharmaceuticals, Brintnall & Nicolini, Inc., Easton Associates, Gilead Sciences, Inc., GlaxoSmithKline, Janssen Pharmaceuticals, Lundbeck Research USA, Medivation, Inc., Merz Pharmaceuticals, MK Medical Communications, F. Hoffmann-La Roche Ltd., SK Holdings Co., Ltd., Sunovion Pharmaceuticals, Inc., Takeda Industries and Teva Pharmaceutical Industries, Ltd. JHK serves as a member of Scientific Advisory Boards for Abbott Laboratories, Bristol-Myers Squibb, Eisai, Inc., Eli Lilly and Co., Forest Laboratories, Inc., Lohocla Research Corporation, Mnemosyne Pharmaceuticals, Inc., Naurex, Inc., Pfizer Pharmaceuticals and Shire Pharmaceuticals. JHK is the Editor for Biological Psychiatry, a member of Board of Directors of Coalition for Translational Research in Alcohol and Substance Use Disorders, and the President Elect for American College of Neuropsychopharmacology. JHK also gets support from Tetragenex Pharmaceuticals. Other authors have no conflicts of interest.

Figures

Figure 1
Figure 1. 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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