Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, PO Box 70259, Lamb Hall, Johnson City, TN 37614, USA.
J Psychiatr Res. 2011 Nov;45(11):1419-25. doi: 10.1016/j.jpsychires.2011.06.005. Epub 2011 Jun 24.
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 × 10(-7)) at 1q24-q25 within KIAA0040 gene while the second best novel hit was rs1869324 (p=4.71 × 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 × 10(-6)). We confirmed the association of PKNOX2 at 11q24.4 with alcohol dependence. The top hit of PKNOX2 (rs750338 with p=1.47 × 10(-6)) in the meta-analysis was replicated with the Australian Twin-Family Study of 778 families (p=1.39 × 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 × 10(-3), 2.1 × 10(-4), and 2.86 × 10(-3) for KIAA0040, NRD1 and THSD7B, respectively). In addition, ALK, CASC4, and SEMA5A were strongly associated with alcohol dependence (p<2 × 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.
家族、双胞胎和收养研究清楚地表明，遗传因素在调节对酒精依赖的易感性方面很重要。已经进行了几项针对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。对两个高加索人群中 1283 例酒精依赖病例和 1416 例对照的 GWA 研究进行了荟萃分析。通过荟萃分析，我们确定了 131 个与酒精依赖相关的 SNP，其 p 值<10(-4)。最佳新信号是位于 KIAA0040 基因内 1q24-q25 的 rs6701037(p=1.86×10(-7))，而第二个最佳新信号是位于 2q22.1 内 THSD7B 的 rs1869324(p=4.71×10(-7))。第三个新的基因座是 1p32.2 上的 NRD1（最佳 SNP 是 rs2842576，p=7.90×10(-6)）。我们证实了 PKNOX2 与 11q24.4 上的酒精依赖相关。荟萃分析中 PKNOX2 的最佳命中(rs750338，p=1.47×10(-6))在澳大利亚双胞胎家族研究中得到了复制（p=1.39×10(-2)）。此外，荟萃分析中最佳命中的几个侧翼 SNP 在家族样本中与酒精依赖呈边缘关联（最佳 SNP 是 KIAA0040 的 rs2269655、rs856613 和 rs10496768，p=4.58×10(-3)、2.1×10(-4)和 2.86×10(-3)）、NRD1 和 THSD7B）。此外，ALK、CASC4 和 SEMA5A 在荟萃分析中与酒精依赖强烈相关（p<2×10(-5)）。总之，我们确定了三个新的基因座（KIAA0040、THSD7B 和 NRD1），并证实了 PKNOX2 先前与酒精依赖的关联。这些发现为深入了解酒精依赖的发病机制提供了新的视角。
