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

摘要。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不利影响。尽管其病因与 遗传因素、围产期经历，包括产前压力和产后社会经历，也可能 导致ASD中社会沟通的缺陷，可能通过表观遗传机制。比如说 催产素受体基因（oxytocin receptor gene，OXTR）在早期社会经历中发生表观遗传学改变，在 哺乳动物的社会和认知发展，并与遗传和表观遗传的ASD的风险。 然而，围产期的经验和ASD的表观遗传变化之间的关系尚不清楚。我们的中央 有一种假说认为，产前压力和早期社会经历预示着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。为了实现我们的总体目标， 为了对有ASD风险的儿童进行干预，我们将招募7,200多名孕妇， 使用创新的智能手机应用程序BabySteps，从妊娠晚期收集前瞻性数据， 怀孕至分娩后30个月。在18至27个月之间，BabySteps将用于筛查 后代出现ASD或发育迟缓（DD）症状，这将引发全面的诊断评估 在残疾人和发展中心。有一系列社会沟通缺陷的儿童 （包括诊断为ASD或非ASD DD的患者[n=200]）将与典型的发展中国家进行比较。 儿童（TD; n=200）谁是匹配的种族，性别和社会经济地位。我们将研究1）差异 在27个特定的ASD相关基因座和3个OXTR基因座中，DNA甲基化（DNAm）和随时间的变化， 2)使用表观遗传时钟算法的生物年龄加速差异，作为年龄、围产期 经验和社会沟通成果。我们将比较储存的新生儿干血中的DNA 点到诊断时收集的样本。我们将计算多基因风险评分的社会 交流，重复行为和ASD，并评估相对多基因和表观遗传风险。的 围产期经验，DNAm和社会沟通结果之间的关系将使用 4个补充措施：1）产前压力和父母的生态瞬时评估（EMAs） 焦虑和抑郁，使用BabySteps收集; 2）应用程序记录的父母和孩子之间的自由玩耍 分析了二元同步和互动行为; 3）儿童社会行为的标准化评估 沟通技巧;以及4）语言强化分析（LENA），使用LENA录音设备 孩子在家里和日托所穿的衣服。我们希望能找出与产前压力有关的表观遗传生物标志物 和早期社会经验与ASD的社会沟通结果。更好地了解如何 多基因风险和围产期经验-通过表观遗传机制-有助于ASD表型将 通过确定可改变的干预途径，帮助克服实地进展的关键障碍。

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.