Multi 'Omics Integration and Neurobiological Signatures of Alcohol Use Disorder

项目摘要/摘要 这项拟议的研究的目标是发现酒精使用障碍的神经生物学因素。 (澳元)。我们将确定与AUD相关的DNA甲基化(DNaM)和RNA表达差异的基因 (RNAexp)在两个人脑组织中用于AUD(背外侧前额叶皮质[DLPFC]和核团 伏隔草[NAC])，定位这些差异背后的遗传变异，并进行大规模关联 用AUD检测调节性基因变异。我们提议的研究将需要全基因组测试， 有针对性地检测与饮酒和澳门氏症相关的越来越多的遗传基因座。 在美国，酒精是可预防的发病率和死亡率的第四大原因。AUD影响 超过1600万美国成年人和年轻人，具有高度的遗传性(50%-60%)。全基因组关联 研究(GWAS)分析已确定酒精脱氢酶或其附近的单核苷酸多态 以及乙醛脱氢酶基因和80+其他与饮酒和/或AUD风险相关的基因座。 然而，它们的神经生物学效应在很大程度上是未知的。因为复杂的疾病相关变种 被广泛观察到与邻近基因的dNaM和RNAexp相关(顺式甲基化 和表达数量性状基因座[分别为cis-meQTL和cis-eQTL])，我们假设 AUD的差异基因调控将增加对AUD风险潜在的神经生物学和 酒精暴露的后果以及DLPFC中潜在的cis-meQTL和cis-eQTL的定位 和NAC，将区分这些不同的、但信息丰富的神经生物学特征。我们提出以下建议 具体目标： 目的1：确定AUD患者与对照组NAC和DLPFC中dNaM和RNAexp的差异。 目的2：在NAC和DLPFC中定位与AUD相关的dNaM和RNAexp差异的QTL。 目的3：检测eQTL和meQTL与AUD风险的关系。 目的4：研究饮酒和AUD基因座的功能特征。 目标1、2和4将利用来自AUD病例和AUD病例的死后人脑组织的多个组学数据 对照死者(总计N=220人，这是迄今最大的已知AUD状态的死后脑收集)。 AIM 3将使用DSM-5(最新版本的 精神疾病诊断和统计手册)：总计N=76,296。AIM 4将循环返回到 在前面的AIMS中采取了一些方法，但它将重点放在80多个先前由GWAS确定的基因座上。我们的整合 人脑的表观基因组学、转录组学和基因组学及扩展到GWAAUD的Meta分析 将极大地提高有意义的发现的可能性，通过使用 高度的生物学相关性，特别是在大脑中，同时保持全基因组范围。

PROJECT SUMMARY/ABSTRACT The goal of the proposed research is to discover neurobiological factors underlying alcohol use disorder (AUD). We will identify genes with AUD-related differences in DNA methylation (DNAm) and RNA expression (RNAexp) in two human brain tissues for AUD (dorsolateral prefrontal cortex [DLPFC] and nucleus accumbens [NAc]), map genetic variants underlying these differences, and conduct large-scale association testing of the regulatory genetic variants with AUD. Our proposed study will entail genome-wide testing, along with targeted testing of the growing number of genetic loci associated with alcohol consumption and AUD. Alcohol is the fourth leading cause of preventable morbidity and mortality in the United States. AUD affects more than 16 million U.S. adults and youths and is highly heritable (50%–60%). Genome-wide association study (GWAS) analyses have identified single nucleotide polymorphisms in or near alcohol dehydrogenase and aldehyde dehydrogenase genes and 80+ other genetic loci for alcohol consumption and/or AUD risk. However, their neurobiological effects are largely unknown. Because complex disease-associated variants are widely observed to be enriched for association with DNAm and RNAexp of nearby genes (cis-methylation and expression quantitative trait loci [cis-meQTLs and cis-eQTLs], respectively), we hypothesize that differential gene regulation by AUD will add knowledge of the neurobiology underlying AUD risk and consequences of alcohol exposure and that mapping the underlying cis-meQTLs and cis-eQTLs in DLPFC and NAc, will distinguish these distinct, yet informative, neurobiological signatures. We propose the following specific aims: Aim 1: Identify DNAm and RNAexp differences in NAc and DLPFC of AUD cases vs. controls. Aim 2: Map QTLs that underlie AUD-related DNAm and RNAexp differences in NAc and DLPFC. Aim 3: Test association of eQTLs and meQTLs with AUD risk. Aim 4: Functionally characterize alcohol consumption and AUD GWAS loci. Aims 1, 2, and 4 will leverage multiple `omics data from postmortem human brain tissues from AUD case and control decedents (total N = 220, the largest-to-date postmortem brain collection with AUD status known). Aim 3 will use existing GWAS samples with AUD defined by DSM-5 (the most up-to-date version of the Diagnostic and Statistical Manual of Mental Disorders): total N = 76,296. Aim 4 will cycle back to the approaches taken in preceding aims, but it will focus on the 80+ prior GWAS-identified loci. Our integration of epigenomics, transcriptomics, and genomics in human brain and extension into GWAS meta-analysis of AUD will greatly improve the likelihood of meaningful discovery by targeting gene regions and specific variants with high biological relevance, specifically in the brain, while retaining a genome-wide scope.