Although Autism Spectrum Disorders (ASD) is recognized as being heavily influenced by genetic factors, the role of epigenetic and environmental factors is still being established. This study aimed to identify ASD vulnerability components based on familial history and intrauterine environmental stress exposure, explore possible vulnerability subgroups, access DNA methylation age acceleration (AA) as a proxy of stress exposure during life, and evaluate the association of ASD vulnerability components and AA to phenotypic severity measures. Principal Component Analysis (PCA) was used to search the vulnerability components from 67 mothers of autistic children. We found that PC1 had a higher correlation with psychosocial stress (maternal stress, maternal education, and social class), and PC2 had a higher correlation with biological factors (psychiatric family history and gestational complications). Comparing the methylome between above and below PC1 average subgroups we found 11,879 statistically significant differentially methylated probes (DMPs, p < 0.05). DMPs CpG sites were enriched in variably methylated regions (VMRs), most showing environmental and genetic influences. Hypermethylated probes presented higher rates in different regulatory regions associated with functional SNPs, indicating that the subgroups may have different affected regulatory regions and their liability to disease explained by common variations. Vulnerability components score moderated by epigenetic clock AA was associated with Vineland Total score (p = 0.0036, adjR² = 0.31), suggesting risk factors with stress burden can influence ASD phenotype.

中文翻译：

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出生时表观遗传时钟和脆弱性成分测量的环境影响影响临床 ASD 异质性

尽管自闭症谱系障碍 (ASD) 被认为受到遗传因素的严重影响，但表观遗传和环境因素的作用仍在确定中。本研究旨在根据家族史和宫内环境压力暴露识别 ASD 易感性成分，探索可能的易感性亚组，获取 DNA 甲基化年龄加速 (AA) 作为生命中压力暴露的代表，并评估 ASD 易感性成分与 AA 的关联表型严重程度测量。主成分分析（PCA）用于搜索来自 67 名自闭症儿童母亲的脆弱性成分。我们发现 PC1 与社会心理压力（母亲压力、母亲教育和社会阶层）的相关性更高，PC2与生物学因素（精神家族史和妊娠并发症）的相关性较高。比较高于和低于 PC1 平均亚组之间的甲基化组，我们发现了 11,879 个具有统计学意义的差异甲基化探针（DMP，p < 0.05)。DMPs CpG 位点富集于可变甲基化区域 (VMRs)，大多数表现出环境和遗传影响。高甲基化探针在与功能性 SNP 相关的不同调控区域中表现出更高的比率，表明亚组可能具有不同的受影响调控区域，并且它们对疾病的易感性由常见变异解释。由表观遗传时钟 AA 调节的脆弱性成分评分与 Vineland 总评分相关（p = 0.0036，adjR ² = 0.31），表明压力负担的风险因素可以影响 ASD 表型。