Department of Psychological Sciences, Birkbeck College, University of London, UK.
Department of Psychological Sciences, Birkbeck College, University of London, UK.
Infant Behav Dev. 2020 Aug;60:101409. doi: 10.1016/j.infbeh.2019.101409. Epub 2020 Jul 2.
Preliminary evidence suggests that changes in DNA methylation, a widely studied epigenetic mechanism, contribute to the etiology of Autism Spectrum Disorder (ASD). However, data is primarily derived from post-mortem brain samples or peripheral tissue from adults. Deep-phenotyped longitudinal infant cohorts are essential to understand how epigenetic modifications relate to early developmental trajectories and emergence of ASD symptoms. We present a proof-of-principle study designed to evaluate the potential of prospective epigenetic studies of infant siblings of children with ASD. Illumina genome-wide 450 K DNA methylation data from buccal swabs was generated for 63 male infants at multiple time-points from 8 months to 2 years of age (total N = 107 samples). 11 of those infants received a diagnosis of ASD at 3 years. We conducted a series of analyses to characterize DNA methylation signatures associated with categorical outcome and neurocognitive measures from parent-report questionnaire, eye-tracking and electro-encephalography. Effects observed across the entire genome (epigenome-wide association analyses) suggest that collecting DNA methylation samples within infant-sibling designs allows for the detection of meaningful signals with smaller sample sizes than previously estimated. Mapping networks of co-methylated probes associated with neural correlates of social attention implicated enrichment of pathways involved in brain development. Longitudinal modelling found covariation between phenotypic traits and DNA methylation levels in the proximity of genes previously associated with cognitive development, although larger samples and more complete datasets are needed to obtain generalizable results. In conclusion, assessment of DNA methylation profiles at multiple time-points in infant-sibling designs is a promising avenue to comprehend developmental origins and mechanisms of ASD.
初步证据表明，广泛研究的表观遗传机制 DNA 甲基化的变化可能导致自闭症谱系障碍 (ASD) 的发病机制。然而，数据主要来自成人死后的脑组织样本或外周组织。深入表型的纵向婴儿队列对于理解表观遗传修饰如何与早期发育轨迹和 ASD 症状的出现相关至关重要。我们提出了一项原理验证研究，旨在评估对 ASD 儿童的婴儿兄弟姐妹进行前瞻性表观遗传学研究的潜力。从 8 个月到 2 岁的多个时间点，从 63 名男性婴儿的口腔拭子中生成了 Illumina 全基因组 450K DNA 甲基化数据（总共 N=107 个样本）。其中 11 名婴儿在 3 岁时被诊断为 ASD。我们进行了一系列分析，以描述与分类结果和来自父母报告问卷、眼动追踪和脑电图的神经认知测量相关的 DNA 甲基化特征。整个基因组（全基因组关联分析）的效应表明，在婴儿兄弟姐妹设计中收集 DNA 甲基化样本可以在比以前估计的更小的样本量下检测到有意义的信号。与社会注意力的神经相关物相关的共甲基化探针网络的映射表明，与认知发展相关的基因附近的途径富集。纵向建模发现表型特征和 DNA 甲基化水平之间的协变在以前与认知发展相关的基因附近，尽管需要更大的样本和更完整的数据集来获得可推广的结果。总之，在婴儿兄弟姐妹设计中多次评估 DNA 甲基化谱是理解 ASD 的发展起源和机制的有前途的途径。
