Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Neuropsychopharmacology. 2022 Mar;47(4):832-839. doi: 10.1038/s41386-021-01228-7. Epub 2021 Nov 13.
Alcohol use disorder (AUD) is closely linked to the brain regions forming the neurocircuitry of addiction. Postmortem human brain tissue enables the direct study of the molecular pathomechanisms of AUD. This study aims to identify these mechanisms by examining differential DNA-methylation between cases with severe AUD (n = 53) and controls (n = 58) using a brain-region-specific approach, in which sample sizes ranged between 46 and 94. Samples of the anterior cingulate cortex (ACC), Brodmann Area 9 (BA9), caudate nucleus (CN), ventral striatum (VS), and putamen (PUT) were investigated. DNA-methylation levels were determined using the Illumina HumanMethylationEPIC Beadchip. Epigenome-wide association analyses were carried out to identify differentially methylated CpG-sites and regions between cases and controls in each brain region. Weighted correlation network analysis (WGCNA), gene-set, and GWAS-enrichment analyses were performed. Two differentially methylated CpG-sites were associated with AUD in the CN, and 18 in VS (q < 0.05). No epigenome-wide significant CpG-sites were found in BA9, ACC, or PUT. Differentially methylated regions associated with AUD case-/control status (q < 0.05) were found in the CN (n = 6), VS (n = 18), and ACC (n = 1). In the VS, the WGCNA-module showing the strongest association with AUD was enriched for immune-related pathways. This study is the first to analyze methylation differences between AUD cases and controls in multiple brain regions and consists of the largest sample to date. Several novel CpG-sites and regions implicated in AUD were identified, providing a first basis to explore epigenetic correlates of AUD.
酒精使用障碍（AUD）与形成成瘾神经回路的大脑区域密切相关。尸检人脑组织可直接研究 AUD 的分子发病机制。本研究旨在通过使用大脑区域特异性方法，在样本量介于 46 到 94 之间的情况下，检查严重 AUD 病例（n=53）和对照组（n=58）之间的差异 DNA 甲基化，来识别这些机制。研究了前扣带皮层（ACC）、Brodmann 区域 9（BA9）、尾状核（CN）、腹侧纹状体（VS）和壳核（PUT）的样本。使用 Illumina HumanMethylationEPIC Beadchip 测定 DNA 甲基化水平。在每个脑区，进行了全基因组关联分析，以识别病例和对照组之间差异甲基化的 CpG 位点和区域。进行了加权相关网络分析（WGCNA）、基因集和 GWAS 富集分析。在 CN 中，有两个差异甲基化 CpG 位点与 AUD 相关，在 VS 中有 18 个（q<0.05）。在 BA9、ACC 或 PUT 中未发现全基因组显著的 CpG 位点。与 AUD 病例/对照状态相关的差异甲基化区域（q<0.05）在 CN（n=6）、VS（n=18）和 ACC（n=1）中发现。在 VS 中，与 AUD 相关性最强的 WGCNA 模块富含免疫相关途径。本研究是首次分析多个脑区 AUD 病例和对照组之间的甲基化差异，也是迄今为止最大的样本量研究。确定了一些与 AUD 相关的新 CpG 位点和区域，为探索 AUD 的表观遗传相关性提供了第一个基础。
