Multi 'Omics Integration and Neurobiological Signatures of Alcohol Use Disorder

酒精使用障碍的多组学整合和神经生物学特征

• 批准号: 10023922
• 负责人: Laura J. Bierut
• 金额: $ 61.47万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-24 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10023922
• 关键词: Affect; Age; Alcohol consumption; Alcohol dehydrogenase; Alcohol or Other Drugs use; Alcohols; Autopsy; Back; Biological; Brain; Cause of Death; Collection; Complex; Copy Number Polymorphism; DNA Methylation; DSM-V; Data; Development; Diagnostic and Statistical Manual of Mental Disorders; Disease; Etiology; Exons; Freedom; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genomics; Goals; Haplotypes; Health; Heritability; Human; Individual; Institutes; Joints; Knowledge; Maps; Meta-Analysis; Methylation; Morbidity - disease rate; Multiomic Data; Neurobiology; Nicotine Dependence; Nucleus Accumbens; Other Genetics; Outcome; Pathway interactions; Phenotype; Positioning Attribute; Prefrontal Cortex; Quantitative Trait Loci; RNA Splicing; Regulation; Regulator Genes; Research; Risk; Risk Factors; Sampling; Sampling Studies; Single Nucleotide Polymorphism; Smoking; Testing; Tissues; Transcript; United States; Untranslated RNA; Variant; alcohol consequences; alcohol effect; alcohol exposure; alcohol use disorder; aldehyde dehydrogenases; biobank; brain tissue; case control; clinically relevant; design; disorder risk; epigenomics; gene discovery; genetic variant; genome wide association study; genome-wide; genomic locus; improved; insertion/deletion mutation; mortality; multiple omics; novel; psychogenetics; sex; success; transcriptome sequencing; transcriptomics; young adult

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.

项目摘要/摘要 拟议的研究的目的是发现酒精使用障碍的神经生物学因素 （aud）。我们将确定在DNA甲基化（DNAM）和RNA表达方面具有与AUD相关差异的基因 （RNAExp）在两个人脑组织中用于AUD的（负前额叶皮层[DLPFC]和核 Accumbens [NAC]），绘制这些差异的基础遗传变异，并进行大规模关联 使用AUD测试调节性遗传变异。我们提出的研究将需要全基因组测试 通过针对与饮酒和AUD相关的遗传位置数量越来越多的目标测试。 酒精是美国可预防的发病率和死亡率的第四个主要原因。 aud会影响 超过1600万的美国成年人和年轻人，高度可遗传（50％–60％）。全基因组关联 研究（GWAS）分析已经确定了酒精脱氢酶或附近的单一核肽多态性 和醛脱氢酶基因和80多种饮酒和/或AUD风险的其他遗传位置。 但是，它们的神经生物学作用在很大程度上尚不清楚。因为复杂的疾病相关变体 被广泛观察到与附近基因的DNAM和RNAExp相关的富含（顺式甲基化） 和表达定量性状局部[cis-meqtls和cis-eqtls]，我们假设 通过AUD调节差异基因将增加对AUD风险的神经生物学的了解和 酒精暴露的后果以及在DLPFC中绘制基本的顺式MEQTL和CIS-EQTL NAC将区分这些独特但内容丰富的神经生物学特征。我们提出以下内容 具体目的： AIM 1：确定AUD病例与控件的NAC和DLPFC中的DNAM和RNAExp差异。 AIM 2：MAP QTL是NAC和DLPFC中与AUD相关DNAM和RNAExp差异的基础的QTL。 AIM 3：EQTL和MEQTL与AUD风险的测试关联。 AIM 4：在功能上表征饮酒和AUD GWAS基因座。 AIM 1、2和4将利用来自AUD病例的事后人脑组织的多个OMIC数据， 控制决定（总n = 220，是已知AUD状态的最大到日期的尸体脑收集）。 AIM 3将使用DSM-5定义的AUD的现有GWAS样品（最新版本 精神障碍的诊断和统计手册）：n = 76,296。 AIM 4将循环回到 提前采取的方法，但它将集中于80多个以前的GWAS认可的地方。我们的整合 人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 通过针对基因区域和特定变体，将大大提高有意义发现的可能性 高生物学相关性，特别是在大脑中，同时保留了全基因组范围。