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.

中文翻译：

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对两项全基因组关联研究的荟萃分析确定了3个新的酒精依赖基因座。

家庭，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脆弱性方面很重要。已经进行了几项关于酒精依赖的全基因组关联研究。但是，很少有基因座被复制。对两项针对白人人群中1283例酒精依赖和1416例对照的GWA研究进行了荟萃分析。通过荟萃分析，我们确定了与酒精依赖相关的131个SNP，p <10（-4）。最佳小说信号是KIAA0040基因中1q24-q25处的rs6701037（p = 1.86×10（-7）），而次佳小说小说是THSD7B中2q22.1处的rs1869324（p = 4.71×10（-7））。第三个新基因座是1p32.2处的NRD1（最高SNP为rs2842576，p = 7.90×10（-6））。我们证实了11q24.4的PKNOX2与酒精依赖有关。在荟萃分析中，PKNOX2（rs750338，p = 1.47×10（-6）的最高命中）与778个家庭的澳大利亚双胞胎研究（p = 1.39×10（-2））重复。在荟萃分析中，热门命中的SNP在家庭样本中显示出与酒精依赖的临界关联（顶部SNP为rs2269655，rs856613和rs10496768，p = 4.58×10（-3），2.1×10（-4）和对于KIAA0040，NRD1和THSD7B，分别为2.86×10（-3）。此外，在荟萃分析中，ALK，CASC4和SEMA5A与酒精依赖密切相关（p <2×10（-5））。总之，我们确定了三个新基因座（KIAA0040，THSD7B和NRD1），并确认了PKNOX2与酒精依赖的先前关联。这些发现为酒精依赖的发病机理提供了新的认识。