Zuo Lingjun, Wang Kesheng, Zhang Xiangyang, Pan Xinghua, Wang Guilin, Krystal John H, Zhang Heping, Luo Xingguang
Departments of aPsychiatry and bGenetics, Yale University School of Medicine cDepartment of Genetics, Yale Center for Genome Analysis, Yale University School of Medicine dDepartment of Biostatistics, Yale University School of Public Health, New Haven, Connecticut eDepartment of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, Johnson City, Tennessee fMenninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas, USA.
Psychiatr Genet. 2013 Dec;23(6):233-8. doi: 10.1097/YPG.0b013e328364b8c7.
Alcohol dependence is more common among men than among women. Potential explanations for this include the role of genes in sex chromosomes (X and Y). In the present study, we scanned the entire Y chromosome and its homologs on the X chromosome in men to identify male-specific risk genes for alcohol dependence.
Two thousand nine hundred and twenty-seven individuals in two independent cohorts were analyzed. The European-American male cohort (883 cases with alcohol dependence and 445 controls) served as the discovery cohort and the European-American female cohort (526 cases and 1073 controls) served as a contrast group. All individuals were genotyped on the Illumina Human 1M beadchip. Two thousand two hundred and twenty-four single nucleotide polymorphisms (SNPs) on the Y chromosome or in the homologs on the X chromosome were analyzed. The allele frequencies were compared between cases and controls within each cohort using logistic regression analysis.
We found that, after experiment-wide correction, two SNPs on the X chromosome were associated significantly with alcohol dependence in European-American men (P = 1.0 × 10 for rs5916144 and P = 5.5 × 10 for rs5961794 at 3' UTR of NLGN4X), but not in the women. A total of 26 SNPs at 3'UTR of or within NLGN4X were nominally associated with alcohol dependence in men (5.5 × 10 ≤ P ≤ 0.05), all of which were not statistically significant in women.
We conclude that NLGN4X was a significant male-specific risk gene for alcohol dependence in European-Americans. NLGN4X might harbor a causal variant(s) for alcohol dependence. A defect of synaptogenesis in neuronal circuitry caused by NLGN4X mutations is believed to play a role in alcohol dependence.
酒精依赖在男性中比在女性中更为常见。对此的潜在解释包括性染色体（X和Y）中基因的作用。在本研究中，我们扫描了男性的整个Y染色体及其在X染色体上的同源物，以确定酒精依赖的男性特异性风险基因。
对两个独立队列中的2927名个体进行了分析。欧美男性队列（883例酒精依赖患者和445名对照）作为发现队列，欧美女性队列（526例患者和1073名对照）作为对照组。所有个体均在Illumina Human 1M芯片上进行基因分型。分析了Y染色体或X染色体同源物上的2224个单核苷酸多态性（SNP）。使用逻辑回归分析比较每个队列中病例组和对照组之间的等位基因频率。
我们发现，在进行全实验校正后，X染色体上的两个SNP与欧美男性的酒精依赖显著相关（NLGN4X基因3'UTR区域的rs5916144，P = 1.0×10；rs5961794，P = 5.5×10），但在女性中无此关联。共有26个位于NLGN4X基因3'UTR区域内或其附近的SNP在男性中与酒精依赖呈名义上的关联（5.5×10≤P≤0.05），所有这些在女性中均无统计学意义。
我们得出结论，NLGN4X是欧美人群中酒精依赖的一个重要的男性特异性风险基因。NLGN4X可能包含导致酒精依赖的因果变异。据信，由NLGN4X突变引起的神经元回路中突触形成缺陷在酒精依赖中起作用。
