Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam.
Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam.
Biol Psychiatry. 2019 Oct 15;86(8):599-607. doi: 10.1016/j.biopsych.2019.02.016. Epub 2019 Mar 1.
Previous studies have reported associations between attention-deficit/hyperactivity disorder symptoms and DNA methylation in children. We report the first epigenome-wide association study meta-analysis of adult attention-deficit/hyperactivity disorder symptoms, based on peripheral blood DNA methylation (Infinium HumanMethylation450K array) in three population-based adult cohorts.
An epigenome-wide association study was performed in the Netherlands Twin Register (N = 2258, mean age 37 years), Dunedin Multidisciplinary Health and Development Study (N = 800, age 38 years), and Environmental Risk Longitudinal Twin Study (N = 1631, age 18 years), and results were combined through meta-analysis (total sample size N = 4689). Region-based analyses accounting for the correlation between nearby methylation sites were also performed.
One epigenome-wide significant differentially methylated position was detected in the Dunedin study, but meta-analysis did not detect differentially methylated positions that were robustly associated across cohorts. In region-based analyses, six significant differentially methylation regions (DMRs) were identified in the Netherlands Twin Register, 19 in the Dunedin study, and none in the Environmental Risk Longitudinal Twin Study. Of these DMRs, 92% were associated with methylation quantitative trait loci, and 68% showed moderate to large blood-brain correlations for DNA methylation levels. DMRs included six nonoverlapping DMRs (three in the Netherlands Twin Register, three in the Dunedin study) in the major histocompatibility complex, which were associated with expression of genes in the major histocompatibility complex, including C4A and C4B, previously implicated in schizophrenia.
Our findings point at new candidate loci involved in immune and neuronal functions that await further replication. Our work also illustrates the need for further research to examine to what extent epigenetic associations with psychiatric traits depend on characteristics such as age, comorbidities, exposures, and genetic background.
先前的研究报告了儿童注意力缺陷/多动障碍症状与 DNA 甲基化之间的关联。我们报告了第一个基于成人外周血 DNA 甲基化（Infinium HumanMethylation450K 阵列）的注意力缺陷/多动障碍症状的全基因组关联研究荟萃分析，该研究基于三个基于人群的成人队列。
在荷兰双胞胎登记处（N=2258，平均年龄 37 岁）、达尼丁多学科健康与发展研究（N=800，年龄 38 岁）和环境风险纵向双胞胎研究（N=1631，年龄 18 岁）中进行了全基因组关联研究，通过荟萃分析（总样本量 N=4689）合并结果。还进行了基于区域的分析，以考虑附近甲基化位点之间的相关性。
在达尼丁研究中检测到一个全基因组显著差异甲基化位置，但荟萃分析没有检测到在队列之间稳健相关的差异甲基化位置。在基于区域的分析中，在荷兰双胞胎登记处鉴定出 6 个显著差异甲基化区域（DMR），在达尼丁研究中鉴定出 19 个，在环境风险纵向双胞胎研究中没有鉴定出。在这些 DMR 中，92%与甲基化数量性状基因座相关，68%显示 DNA 甲基化水平与大脑之间存在中等至较大的相关性。DMR 包括主要组织相容性复合体中的六个非重叠 DMR（荷兰双胞胎登记处 3 个，达尼丁研究 3 个），与主要组织相容性复合体中基因的表达相关，包括先前与精神分裂症相关的 C4A 和 C4B。
我们的研究结果指向了涉及免疫和神经元功能的新候选基因座，这些基因座需要进一步复制。我们的工作还说明了需要进一步研究，以研究精神疾病特征与表观遗传关联在多大程度上取决于年龄、合并症、暴露和遗传背景等特征。
