Multi 'Omics Integration and Neurobiological Signatures of Alcohol Use Disorder

项目总结/摘要 这项研究的目的是发现酒精使用障碍的神经生物学因素 （AUD）.我们将鉴定与AUD相关的DNA甲基化（DNAm）和RNA表达差异的基因 （RNAexp）在两个人脑组织中的AUD（背外侧前额叶皮层[DLPFC]和核 [NAc]），绘制这些差异背后的遗传变异，并进行大规模的关联 用AUD检测调节性遗传变异。我们提出的研究将需要全基因组测试，沿着 有针对性地测试越来越多的与酒精消费和AUD相关的基因位点。 酒精是美国可预防的发病率和死亡率的第四大原因。澳元影响 超过1600万美国成年人和青少年，具有高度遗传性（50%-60%）。全基因组关联 GWAS分析已经鉴定了乙醇脱氢酶中或附近的单核苷酸多态性 和乙醛脱氢酶基因和80多个其他遗传位点的酒精消费和/或AUD风险。 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异 被广泛观察到与邻近基因的DNAm和RNAexp（顺式甲基化）相关 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AUD风险的神经生物学基础知识， 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。我们提议下列 具体目标： 目的1：确定AUD病例与对照组的NAc和DLPFC中的DNAm和RNAexp差异。 目标2：绘制NAc和DLPFC中AUD相关DNA m和RNA ex差异的QTL。 目的3：检验eQTL和meQTL与AUD风险的关联。 目的4：功能性表征酒精消耗和AUD GWAS基因座。 目标1、2和4将利用AUD病例死后人脑组织的多个组学数据， 对照死亡动物（总N = 220，迄今为止已知AUD状态的最大死后脑采集）。 Aim 3将使用DSM-5定义的AUD的现有GWAS样本（DSM-5的最新版本）。 精神疾病诊断和统计手册）：总计N = 76，296。目标4将循环回到 在先前的目标中采取的方法，但它将集中在80+先前GWAS鉴定的基因座上。我们的整合 人类大脑中的表观基因组学、转录组学和基因组学，并扩展到AUD的GWAS荟萃分析 将大大提高有意义的发现的可能性，通过靶向基因区域和特定变异， 高生物相关性，特别是在大脑中，同时保留全基因组范围。

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.