Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
J Hum Genet. 2012 Oct;57(10):670-5. doi: 10.1038/jhg.2012.98. Epub 2012 Aug 23.
The μ-opioid receptor mediates rewarding effects of alcohol and illicit drugs. We hypothesized that altered DNA methylation in the μ-opioid receptor gene (OPRM1) might influence the vulnerability to alcohol dependence (AD). Genomic DNA was extracted from the peripheral blood of 125 European Americans with AD and 69 screened European American controls. Methylation levels of 16 CpGs in the OPRM1 promoter region were examined by bisulfite sequencing analysis. A multivariate analysis of covariance was conducted to analyze AD-associated methylation changes in the OPRM1 promoter region, using days of intoxication in the past 30 days, sex, age, ancestry proportion and childhood adversity (CA) as covariates. Three CpGs (80, 71, and 10 bp upstream of the OPRM1 translation start site) were more highly methylated in AD cases than in controls (CpG-80: P=0.033; CpG-71: P=0.004; CpG-10: P=0.008). Although these sites were not significant after correction for multiple comparisons, the overall methylation level of the 16 CpGs was significantly higher in AD cases (13.6%) than in controls (10.6%) (P=0.049). Sex and CA did not significantly influence OPRM1 promoter methylation levels. Our findings suggest that OPRM1 promoter hypermethylation may increase the risk for AD and other substance dependence disorders.
μ 阿片受体介导酒精和非法药物的奖赏效应。我们假设μ 阿片受体基因（OPRM1）中的 DNA 甲基化改变可能会影响酒精依赖（AD）的易感性。从 125 名患有 AD 的欧洲裔美国人的外周血和 69 名经过筛选的欧洲裔美国对照者中提取基因组 DNA。通过亚硫酸氢盐测序分析检测 OPRM1 启动子区域的 16 个 CpG 的甲基化水平。采用协方差的多变量分析，以分析 OPRM1 启动子区域与 AD 相关的甲基化变化，使用过去 30 天内醉酒天数、性别、年龄、祖先比例和儿童逆境（CA）作为协变量。与对照组相比，AD 病例中三个 CpG（OPRM1 翻译起始位点上游的 80、71 和 10bp）的甲基化程度更高（CpG-80：P=0.033；CpG-71：P=0.004；CpG-10：P=0.008）。尽管经过多次比较校正后这些位点没有统计学意义，但 AD 病例的 16 个 CpG 的总体甲基化水平（13.6%）明显高于对照组（10.6%）（P=0.049）。性别和 CA 对 OPRM1 启动子甲基化水平没有显著影响。我们的研究结果表明，OPRM1 启动子过度甲基化可能会增加 AD 和其他物质依赖障碍的风险。
