Diagnostic and prognostic methylation biomarkers for alcohol and related health risks

项目总结 尽管进行了广泛的禁酒努力，但8.5%的美国成年人滥用或依赖酒精。过份 饮酒者的发病率和负面健康后果的风险更高，如癌症和 神经认知能力下降。虽然基因序列变异是酒精成瘾的原因，但越来越多的证据表明 这表明DNA甲基化可能提供了补充信息。首先，甲基化标记可能会改善 酒精成瘾风险的预测，因为它们可以捕捉到根本不同的疾病过程和 直接影响基因表达。其次，甲基化研究可能会增加我们对酒精的理解 上瘾。例如，戒断和耐受等现象表明，反复饮酒 创造一种“生物记忆”，影响未来对酒精的反应。因为酒精 诱发表观遗传学 变化可以随着时间的推移而持续并产生持久的影响，DNA甲基化可能会揭示这一点 机械装置。 第三，除了组织特异性外，甲基化也经常存在实质上的一致性 跨组织，包括大脑和血液。大脑中的甲基化位点可能具有相应的 血液中的标记可以在易于从血液中收集基因组DNA的情况下进行经济高效的测量，使这些 潜在非常强大的生物标志物用于临床改善酒精成瘾的轨迹 发展、诊断和治疗。 PAR-16-234要求对现有数据进行创新分析，以研究酒精成瘾。识别甲基化 预测酒精使用和相关健康风险的生物标记物，我们将带来前所未有的 结合现有的下一代测序数据进行全基因组关联研究 用PhenX测量酒精的三个样品中的(Mwas)。此外，鉴于酒精甲基化研究 历来仅限于有限数量的CPG，我们建议筛选所有~2800万共同 人类基因组中的CPGS。样本量为~3,300，这将是最大的酒精甲基化研究 Date，是史无前例的，提供了进行高甲基化生物标记物研究的机会 低成本的统计能力，因为甲基化数据已经产生。 该项目的成功完成将产生生物标志物，以改善该病的诊断和预后 酒精成瘾和相关的健康风险。

PROJECT SUMMARY Despite extensive anti-drinking efforts, 8.5% of US adults abuse or are dependent on alcohol. Excessive drinkers are at higher risk for morbidity and negative health consequences such as such as cancer and neurocognitive decline. While genetic sequence variation contributes to alcohol addiction, mounting evidence suggests that DNA methylation may provide complementary information. First, methylation marks may improve the prediction of alcohol addiction risk as they can capture fundamentally different disease processes and directly affect gene expression. Second, methylation studies may increase our understanding of alcohol addiction. For example, phenomena such as withdrawal and tolerance suggest that repeated alcohol use creates a “biological memory” affecting future responses to alcohol. Because alcohol induced epigenetic changes can persist over time and have lasting effects, DNA methylation could shed light on such mechanisms. Third, in addition to tissue specificity, substantial concordance in methylation also often exists across tissues, including brain and blood. The possibility that methylation sites in brain can have corresponding marks in blood that can be measured cost-effectively in easy to collect genomic DNA from blood, makes these sites potentially very powerful biomarkers for use in the clinic to improve the trajectory of alcohol addiction development, diagnosis, and treatment. PAR-16-234 calls for innovative analyses of existing data to study alcohol addiction. To identify methylation biomarkers predicting alcohol use and related health risks, we will bring together an unprecedented combination of existing next-generation sequencing data to perform methylome-wide association studies (MWAS) in three samples with PhenX measures of alcohol. Furthermore, whereas alcohol methylation studies have historically been restricted to a limited number of CpGs, we propose to screen all ~28 million common CpGs in the human genome. The sample size, ~3,300, which will be the largest alcohol methylation study to date, is unprecedented, offering the opportunity to perform methylation biomarker investigations with high statistical power at low cost because the methylation data has already been generated. Successful completion of this project will generate biomarkers to improve the diagnosis and prognosis of alcohol addiction and related health risks.