Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
Hum Mol Genet. 2018 Sep 1;27(17):2955-2964. doi: 10.1093/hmg/ddy193.
Autism spectrum disorders (ASDs) include a group of syndromes characterized by impaired language, social and communication skills, in addition to restrictive behaviors or stereotypes. However, with a prevalence of 1.5% in developed countries and high comorbidity rates, no clear underlying mechanism that unifies the heterogeneous phenotypes of ASD exists. 5-hydroxymethylcytosine (5hmC) is highly enriched in the brain and recognized as an essential epigenetic mark in developmental and brain disorders. To explore the role of 5hmC in ASD, we used the genomic DNA isolated from the postmortem cerebellum of both ASD patients and age-matched controls to profile genome-wide distribution of 5hmC. We identified 797 age-dependent differentially hydroxymethylated regions (DhMRs) in the young group (age ≤ 18), while no significant DhMR was identified in the groups over 18 years of age. Pathway and disease association analyses demonstrated that the intragenic DhMRs were in the genes involved in cell-cell communication and neurological disorders. Also, we saw significant 5hmC changes in the larger group of psychiatric genes. Interestingly, we found that the predicted cis functions of non-coding intergenic DhMRs strikingly associate with ASD and intellectual disorders. A significant fraction of intergenic DhMRs overlapped with topologically associating domains. These results together suggest that 5hmC alteration is associated with ASD, particularly in the early development stage, and could contribute to the pathogenesis of ASD.
自闭症谱系障碍（ASD）包括一组以语言、社交和沟通技能受损为特征的综合征，此外还有限制性行为或刻板行为。然而，在发达国家 ASD 的患病率为 1.5%，且共病率较高，目前尚无明确的潜在机制能够将 ASD 异质表型统一起来。5-羟甲基胞嘧啶（5hmC）在大脑中高度富集，被认为是发育和大脑疾病中的一种重要表观遗传标记。为了探索 5hmC 在 ASD 中的作用，我们使用从 ASD 患者和年龄匹配的对照组死后小脑分离的基因组 DNA 来分析全基因组范围内 5hmC 的分布。我们在年轻组（年龄≤18 岁）中鉴定出 797 个与年龄相关的差异羟甲基化区域（DhMR），而在 18 岁以上的组中没有发现显著的 DhMR。通路和疾病关联分析表明，基因内 DhMR 位于涉及细胞-细胞通讯和神经紊乱的基因中。此外，我们还观察到更大的一组精神疾病基因中存在显著的 5hmC 变化。有趣的是，我们发现非编码基因间 DhMR 的预测顺式功能与 ASD 和智力障碍显著相关。相当一部分基因间 DhMR 与拓扑关联域重叠。这些结果共同表明，5hmC 的改变与 ASD 有关，特别是在早期发育阶段，可能有助于 ASD 的发病机制。
