Perinatal Experience and Epigenetic Change in Autism: Discovering Modifiable Pathways for Intervention

抽象的。自闭症谱系障碍(ASD)是最常见的神经发育障碍之一， 对全世界越来越多的家庭产生了不利影响。尽管它的病因学与 遗传因素、围产期经历，包括产前应激和产后社会经历，也可能 可能通过表观遗传机制，导致自闭症患者的社会沟通障碍。例如， 催产素受体基因(OXTR)受早期社会经验的表观遗传改变，在 哺乳动物的社会和认知发育，并与ASD的遗传和表观遗传风险有关。 然而，围产期经历与ASD的表观遗传学改变之间的关系尚不清楚。我们的中央 假设是，产前压力和早期社会经验预测了特定基因的表观遗传变化， 这与自闭症患者的社会沟通缺陷有关。为了实现我们发现的总体目标 干预ASD高危儿童的可修改途径，我们将招募7200多名孕妇 使用创新的智能手机应用程序BabySteps收集怀孕第三个月的预期数据 怀孕至产后30个月。年龄在18到27个月之间的婴儿将被用来筛查 子代的自闭症或发育迟缓(DD)的症状，这将引发全面的诊断评估 在残疾人与发展中心。有一系列社交沟通障碍的儿童 (包括被诊断为ASD或非ASD的患者[n=200])将与典型的发展中的进行比较 种族、性别和社会经济地位相匹配的儿童(TD；n=200)。我们将考察1)差异 在DNA甲基化(DNaM)中，并随着时间的推移而变化，在27个特定的ASD相关基因座和3个OXTR基因座，以及 2)使用表观遗传时钟算法的生物年龄加速的差异，作为年龄、围产期的函数 体验和社交成果。我们将比较储存的新生儿干血中的dNaM 斑点是在诊断前后采集的样本。我们将计算社会风险的多基因风险分数 沟通、重复行为和自闭症，并评估相对多基因和表观遗传风险。这个 围产期经历、dNaM和社会沟通结果之间的关系将使用以下工具进行评估 4)补充措施：1)产前压力和父母的生态瞬时评估(EMAS) 焦虑和抑郁，通过婴儿式收集；2)应用程序记录父母和孩子之间的自由游戏 分析二元同步性和交互行为；3)标准化的儿童社交评估 交流技能；以及4)语言环境分析(Lena)，使用Lena录音设备 孩子在家里和托儿所穿的衣服。我们希望识别与产前应激有关的表观遗传生物标记物 以及自闭症患者的早期社会经验和社会沟通结果。更好地了解如何 多基因风险和围产期经历--通过表观遗传机制--导致ASD表型 通过确定可修改的干预途径，帮助克服在实地取得进展的关键障碍。

ABSTRACT. Autism spectrum disorder (ASD) is one of the most common neurodevelopmental disabilities, adversely affecting an increasing number of families worldwide. Although its etiology is strongly linked to genetic factors, perinatal experience, including prenatal stress and post-natal social experience, may also contribute to deficits in social communication in ASD, potentially via epigenetic mechanisms. For example, the oxytocin receptor gene (OXTR) is epigenetically altered by early social experience, plays a crucial role in mammalian social and cognitive development, and is associated with both genetic and epigenetic risk for ASD. However, the relationship between perinatal experience and epigenetic change in ASD is unclear. Our central hypothesis is that prenatal stress and early social experience predicts epigenetic changes in specific genes, which are associated with social communication deficits in ASD. To achieve our overall goal of discovering modifiable pathways for intervention in children at risk for ASD, we will recruit over 7,200 pregnant women to use an innovative smartphone application, BabySteps, to collect prospective data from the 3rd trimester of pregnancy until 30 months post-delivery. Between ages 18 to 27 months, BabySteps will be used to screen for symptoms of ASD or developmental delay (DD) in the offspring, which will trigger a full diagnostic assessment at the Center for Disabilities and Development. Children with a range of social communication deficits (including those diagnosed with ASD or non-ASD DD [n=200]) will be compared with typically developing children (TD; n=200) who are matched on race, sex, and socioeconomic status. We will examine 1) differences in DNA methylation (DNAm), and change over time, in 27 specific ASD-associated loci and 3 OXTR loci, and 2) differences in biologic age acceleration using epigenetic clock algorithms, as a function of age, perinatal experience, and social communication outcomes. We will compare DNAm from stored newborn dried blood spots to samples collected around the time of diagnosis. We will calculate polygenic risk scores for social communication, repetitive behavior, and ASD, and assess the relative polygenic and epigenetic risk. The relationship between perinatal experience, DNAm, and social communication outcomes will be evaluated using 4 complementary measures: 1) ecological momentary assessments (EMAs) of prenatal stress and parental anxiety and depression, collected using BabySteps; 2) app-recorded free play between parent and child analyzed for dyadic synchrony and interactive behavior; 3) standardized assessments of child social communication skills; and 4) a Language ENvironment Analysis (LENA), using a LENA audio-recording device worn by the child at home and in daycare. We expect to identify epigenetic biomarkers that link prenatal stress and early social experience with social communication outcomes in ASD. A better understanding of how polygenic risk and perinatal experience—via epigenetic mechanisms—contribute to the ASD phenotype will help overcome a critical barrier to progress in the field, by identifying modifiable pathways for intervention.