A meta-analysis of two genome-wide association studies identifies 3 new loci for alcohol dependence
A meta-analysis of two genome-wide association studies identifies 3 new loci for alcohol dependence
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DOI：
10.1016/j.jpsychires.2011.06.005
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发表时间：
2011-11-01
影响因子：
4.8
通讯作者：
Zeng, Min
中科院分区：
文献类型：
--
作者：
Wang, Ke-Sheng;Liu, Xuefeng;Zeng, Min
家庭、双胞胎和收养研究清楚地表明，遗传因素对于调节酒精依赖的脆弱性很重要。已经进行了几项关于酒精依赖的全基因组关联（GWA）研究；然而，很少有基因座被复制。对两项 GWA 研究进行了荟萃分析，研究涉及白种人群体中的 1283 例酒精依赖病例和 1416 例对照病例。通过荟萃分析，我们确定了 131 个与酒精依赖相关的 SNP，p < 10(-4)。最好的新信号是 KIAA0040 基因内 1q24-q25 处的 rs6701037 (p = 1.86 x 10(-7))，而第二好的新信号是 THSD7B 内 2q22.1 处的 rs1869324 (p = 4.71 x 10(-7))。第三个新位点是 1p32.2 处的 NRD1（顶部 SNP 是 rs2842576，p = 7.90 x 10(-6)）。我们证实了 11q24.4 处的 PKNOX2 与酒精依赖的关联。荟萃分析中的 PKNOX2 (rs750338，p = 1.47 x 10(-6)) 的热门命中与 778 个家庭的澳大利亚双子家庭研究 (p = 1.39 x 10(-2)) 进行了重复。此外，荟萃分析中热门命中的几个侧翼 SNP 表明与家庭样本中的酒精依赖存在边界关联（热门 SNP 是rs2269655、rs856613 和 rs10496768，对于 KIAA0040、NRD1 和 THSD7B，p 分别为 4.58 x 10(-3)、2.1 x 10(-4) 和 2.86 x 10(-3)。此外，在荟萃分析中，ALK、CASC4 和 SEMA5A 与酒精依赖密切相关 (p < 2 x 10(-5))。总之，我们鉴定了三个新基因座（KIAA0040、THSD7B 和 NRD1），并证实了之前的 PKNOX2 与酒精依赖的关联。这些发现为了解酒精依赖的发病机制提供了新的见解。由爱思唯尔有限公司出版
Family, twin and adoption studies have clearly demonstrated that genetic factors are important in modulating the vulnerability to alcohol dependence. Several genome-wide association (GWA) studies of alcohol dependence have been conducted; however, few loci have been replicated. A meta-analysis was performed on two GWA studies of 1283 cases of alcohol dependence and 1416 controls in Caucasian populations. Through meta-analysis we identified 131 SNPs associated with alcohol dependence with p < 10(-4). The best novel signal was rs6701037 (p = 1.86 x 10(-7)) at 1q24-q25 within KIAA0040 gene while the second best novel hit was rs1869324 (p = 4.71 x 10(-7)) at 2q22.1 within THSD7B. The third novel locus was NRD1 at 1p32.2 (the top SNP was rs2842576 with p = 7.90 x 10(-6)). We confirmed the association of PKNOX2 at 11q24.4 with alcohol dependence. The top hit of PKNOX2 (rs750338 with p = 1.47 x 10(-6)) in the meta-analysis was replicated with the Australian Twin-Family Study of 778 families (p = 1.39 x 10(-2)) Furthermore, several flanking SNPs of the top hits in the meta-analysis demonstrated borderline associations with alcohol dependence in the family sample (top SNPs were rs2269655, rs856613, and rs10496768 with p = 4.58 x 10(-3), 2.1 x 10(-4), and 2.86 x 10(-3) for KIAA0040, NRD1 and THSD7B, respectively). In addition, ALK, CASC4, and SEMA5A were strongly associated with alcohol dependence (p < 2 x 10(-5)) in the meta-analysis. In conclusion, we identified three new loci (KIAA0040. THSD7B and NRD1) and confirmed the previous association of PKNOX2 with alcohol dependence. These findings offer the potential for new insights into the pathogenesis of alcohol dependence. Published by Elsevier Ltd.