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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要拟议研究的目标是发现酒精使用障碍背后的神经生物学因素 (AUD)。我们将鉴定在 DNA 甲基化 (DNAm) 和 RNA 表达方面具有 AUD 相关差异的基因。 (RNAexp) 在两个人脑组织中进行 AUD（背外侧前额皮质 [DLPFC] 和核）伏隔核 [NAc]），绘制这些差异背后的遗传变异，并进行大规模关联我们提议的研究将需要进行全基因组测试以及 AUD 测试。对越来越多与饮酒和 AUD 相关的基因位点进行有针对性的测试。酒精是美国可预防的发病率和死亡率的第四大原因。超过 1600 万美国成年人和青少年，具有高度遗传性（50%–60%）。研究（GWAS）分析已鉴定出乙醇脱氢酶内或附近的单核苷酸多态性和乙醛脱氢酶基因以及 80 多个其他与饮酒和/或 AUD 风险有关的基因位点。然而，由于与疾病相关的复杂变异，它们的神经生物学效应在很大程度上是未知的。被广泛观察到与附近基因的 DNAm 和 RNAexp 相关（顺式甲基化和表达数量性状位点[分别是cis-meQTLs和cis-eQTLs]），我们捕捉到了 AUD 的差异基因调控将增加对 AUD 风险背后的神经生物学的了解酒精暴露的后果以及绘制 DLPFC 中潜在的 cis-meQTL 和 cis-eQTL 和 NAc，将区分这些独特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：目标 1：确定 AUD 病例与对照的 NAc 和 DLPFC 中 DNAm 和 RNAexp 的差异。目标 2：绘制 NAc 和 DLPFC 中 AUD 相关 DNAm 和 RNAexp 差异背后的 QTL。目标 3：测试 eQTL 和 meQTL 与 AUD 风险的关联。目标 4：从功能上描述酒精消费和 AUD GWAS 位点。目标 1、2 和 4 将利用来自 AUD 病例和死后人类脑组织的多个组学数据对照死者（总数 N = 220，迄今为止最大的死后大脑收集，具有已知的 AUD 状态）。目标 3 将使用现有的 GWAS 样本以及 DSM-5（最新版本的 DSM-5）定义的 AUD。精神障碍诊断与统计手册）：总数 N = 76,296 将循环回到目标 4。之前目标中采取的方法，但它将重点关注 80 多个先前 GWAS 识别的基因座。人脑表观基因组学、转录组学和基因组学及其扩展到 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度的生物学相关性，特别是在大脑中，同时保留全基因组范围。