Department of Molecular and Cell Biology, University of Cape Town, Cape Town, South Africa.
Cytoreason LTD, Tel Aviv, Israel.
Autism Res. 2020 Jul;13(7):1079-1093. doi: 10.1002/aur.2310. Epub 2020 Jun 3.
Autism spectrum disorder (ASD) is characterized by phenotypic heterogeneity and a complex genetic architecture which includes distinctive epigenetic patterns. We report differential DNA methylation patterns associated with ASD in South African children. An exploratory whole-epigenome methylation screen using the Illumina 450 K MethylationArray identified differentially methylated CpG sites between ASD and controls that mapped to 898 genes (P ≤ 0.05) which were enriched for nine canonical pathways converging on mitochondrial metabolism and protein ubiquitination. Targeted Next Generation Bisulfite Sequencing of 27 genes confirmed differential methylation between ASD and control in our cohort. DNA pyrosequencing of two of these genes, the mitochondrial enzyme Propionyl-CoA Carboxylase subunit Beta (PCCB) and Protocadherin Alpha 12 (PCDHA12), revealed a wide range of methylation levels (9-49% and 0-54%, respectively) in both ASD and controls. Three CpG loci were differentially methylated in PCCB (P ≤ 0.05), while PCDHA12, previously linked to ASD, had two significantly different CpG sites (P ≤ 0.001) between ASD and control. Differentially methylated CpGs were hypomethylated in ASD. Metabolomic analysis of urinary organic acids revealed that three metabolites, 3-hydroxy-3-methylglutaric acid (P = 0.008), 3-methyglutaconic acid (P = 0.018), and ethylmalonic acid (P = 0.043) were significantly elevated in individuals with ASD. These metabolites are directly linked to mitochondrial respiratory chain disorders, with a putative link to PCCB, consistent with impaired mitochondrial function. Our data support an association between DNA methylation and mitochondrial dysfunction in the etiology of ASD. Autism Res 2020, 13: 1079-1093. © 2020 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: Epigenetic changes are chemical modifications of DNA which can change gene function. DNA methylation, a type of epigenetic modification, is linked to autism. We examined DNA methylation in South African children with autism and identified mitochondrial genes associated with autism. Mitochondria are power-suppliers in cells and mitochondrial genes are essential to metabolism and energy production, which are important for brain cells during development. Our findings suggest that some individuals with ASD also have mitochondrial dysfunction.
自闭症谱系障碍（ASD）的表型具有异质性，其遗传结构复杂，包括独特的表观遗传模式。我们报告了南非儿童自闭症相关的 DNA 甲基化模式差异。使用 Illumina 450K 甲基化芯片进行的全基因组甲基化扫描，确定了 ASD 与对照组之间差异甲基化的 CpG 位点，这些位点映射到 898 个基因（P≤0.05），这些基因富集了 9 个经典途径，汇聚到线粒体代谢和蛋白质泛素化。对我们队列中 27 个基因的靶向下一代焦磷酸测序证实了 ASD 与对照组之间的差异甲基化。对其中两个基因（线粒体酶丙二酰辅酶 A 羧化酶亚基β（PCCB）和原钙黏蛋白 α 12（PCDHA12））的 DNA 焦磷酸测序显示，ASD 和对照组中都存在广泛的甲基化水平（分别为 9-49%和 0-54%）。PCCB 中有三个 CpG 位点存在差异甲基化（P≤0.05），而 PCDHA12 是与 ASD 相关的基因，在 ASD 与对照组之间有两个显著不同的 CpG 位点（P≤0.001）。ASD 中差异甲基化的 CpG 呈低甲基化。尿有机酸代谢组学分析显示，3 种代谢物 3-羟基-3-甲基戊二酸（P=0.008）、3-甲基戊烯二酸（P=0.018）和乙基丙二酸（P=0.043）在 ASD 个体中显著升高。这些代谢物直接与线粒体呼吸链紊乱有关，与 PCCB 有潜在联系，与线粒体功能受损一致。我们的数据支持自闭症病因中 DNA 甲基化与线粒体功能障碍之间的关联。自闭症研究 2020, 13: 1079-1093。©2020 自闭症研究协会国际协会出版自闭症研究由 Wiley Periodicals, Inc. 出版。
