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

自闭症的围产期经历和表观遗传变化：发现可修改的干预途径

基本信息

批准号：
10660207
负责人：
Lane Strathearn
金额：
$ 66.07万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10660207
关键词：
2 year old Acceleration Address Affect Age Aging Algorithms Anxiety Behavior Behavioral Biological Birth Blood Cellular Phone Child Chronology Clinical assessments Communication DNA Methylation Data Day Care Development Developmental Delay Disorders Devices Diagnosis Diagnostic Dryness Early Intervention Early treatment Ecological momentary assessment Environment Epigenetic Process Etiology Family Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Goals Home Individual Infant Intervention Knowledge Language Life Link Measures Mediating Mental Depression Modern Medicine Modification Neurodevelopmental Disability Newborn Infant Outcome Oxytocin Oxytocin Receptor Parents Pathway interactions Patient Self-Report Pattern Perinatal Persons Phenotype Play Pregnancy Trimesters Pregnant Women Prevalence Process Questionnaires Race Receptor Gene Reporting Research Risk Risk Factors Role Sampling Social Development Social Interaction Societies Socioeconomic Status Spottings Standardization Stress Symptoms Testing Third Pregnancy Trimester Time Video Recording anxiety symptoms autism spectrum disorder cognitive development depressive symptoms digital disability epigenetic marker experience genetic predictors genomic locus innovation novel offspring polygenic risk score postnatal predictive marker prenatal stress prospective receptor recruit repetitive behavior sex skills smartphone application social social communication

项目摘要

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.

摘要：自闭症谱系障碍（ASD）是最常见的神经发育障碍之一。尽管其病因与以下因素密切相关，但对全世界越来越多的家庭产生了不利影响。遗传因素、围产期经历，包括产前压力和产后社会经历，也可能可能通过表观遗传机制导致自闭症谱系障碍的社交沟通缺陷。催产素受体基因（OXTR）是通过早期社会经验而产生的表观遗传，在哺乳动物的社会和认知发展，并且与自闭症谱系障碍的遗传和表观遗传风险相关。然而，围产期经历与 ASD 表观遗传变化之间的关系尚不清楚。假设是产前压力和早期社会经历可以预测特定基因的表观遗传变化，与自闭症谱系障碍 (ASD) 的社交沟通缺陷有关，以实现我们发现的总体目标。为了对有 ASD 风险的儿童进行可修改的干预途径，我们将招募 7,200 多名孕妇来使用创新的智能手机应用程序 BabySteps 收集妊娠第三个月的预期数据怀孕至产后 30 个月期间，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，这将触发全面的诊断评估患有一系列社交沟通缺陷的儿童。（包括诊断为 ASD 或非 ASD DD [n=200] 的人）将与典型发育情况进行比较种族、性别和社会经济地位匹配的儿童（TD；n=200）我们将检查 1) 差异。 DNA 甲基化 (DNAm) 的变化，以及 27 个特定 ASD 相关基因座和 3 个 OXTR 基因座随时间的变化，以及 2) 使用表观遗传时钟算法的生物年龄加速差异，作为年龄、围产期的函数我们将比较储存的新生儿干血中的 DNAm。我们将计算社会多基因风险评分。沟通、重复行为和自闭症谱系障碍，并评估相对多基因和表观遗传风险。围产期经历、DNAm 和社会沟通结果之间的关系将使用以下方法进行评估 4 项补充措施：1) 产前应激和亲代应激的生态瞬时评估 (EMA) 焦虑和抑郁，使用 BabySteps 收集 2) 应用程序记录父母和孩子之间的自由玩耍；分析二元同步性和互动行为；3）儿童社交的标准化评估 4) 使用 LENA 录音设备进行语言环境分析 (LENA) 我们希望找到与产前压力相关的表观遗传生物标志物。以及自闭症谱系障碍 (ASD) 中社交沟通结果的早期社交经验更好地了解如何进行。多基因风险和围产期经历——通过表观遗传机制——有助于自闭症谱系障碍表型通过确定可修改的干预途径，帮助克服该领域取得进展的关键障碍。