Project: Epigenetics, Polygenic Risk and the Social Environment in Autism

项目：自闭症的表观遗传学、多基因风险和社会环境

基本信息

批准号：
10451569
负责人：
Lane Strathearn
金额：
$ 24.76万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-16 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10451569
关键词：
3 year old Affect Age Anxiety Autism Diagnosis Behavior Birth Blood Brain Cellular Phone Child Clinical Clinical assessments Collection DNA DNA Methylation Data Development Developmental Delay Disorders Developmental Disabilities Devices Diagnosis Disease Early Intervention Ecological momentary assessment Emotional Enrollment Environment Environmental Risk Factor Epigenetic Process Ethnic Origin Etiology Family Genetic Genetic Predisposition to Disease Genetic study Genomics Goals Hawks Home Individual Intellectual and Developmental Disabilities Research Centers Intellectual functioning disability Intervention Iowa Language Life Longevity Longitudinal Studies Measures Mediating Mental Depression Methylation Modeling Modification Mothers Neuropeptides Newborn Infant Oranges Outcome Oxytocin Oxytocin Receptor Perinatal Play Pregnancy Prevalence Prevention strategy Race Receptor Gene Research Research Project Grants Resources Rest Risk Risk Marker Role Sampling Scanning Site Social Development Social Environment Societies Socioeconomic Status Spottings Stress Testing Time United States Universities adolescent with autism spectrum disorder autism spectrum disorder autistic behaviour autistic children base cognitive development cohort cost estimate disability disability risk educational atmosphere experience innovation neural circuit polygenic risk score prospective prototype rare condition receptor recruit repetitive behavior sex smartphone Application social social communication social learning trait

项目摘要

ABSTRACT: RESEARCH PROJECT Intellectual and developmental disabilities (IDD) affect up to one in six children in the United States, with proposed etiologies ranging from genetic to multi-factorial. For a vast majority of children, no clear genetic or environmental etiology is identified, although evidence suggests that genetic (intrinsic) risk may interact with the early learning and social environment (extrinsic risk) to predict neurodevelopmental outcomes in later stages of life. For example, the neuropeptide oxytocin and its receptor (OXTR) are epigenetically altered by early social experience, play crucial roles in mammalian social and cognitive development, and are associated with both genetic and epigenetic risk for autism spectrum disorder (ASD). The objective of this Hawk-IDDRC Research Project is to examine epigenetic, polygenic and environmental risk factors for IDD, focusing on ASD as a prototype. We will use an innovative new smartphone application, BabySteps, to enroll and collect data on 300 mothers and their children between 2 and 3 years of age, over a 6-month period. One hundred and sixty ASD children will be enrolled, along with 80 children with non-ASD developmental delay (DD), and 80 typically developing (TD) control children, matched by race/ethnicity, sex and family socioeconomic status. We will examine changes in DNA methylation (DNAm) in 27 specific ASD-associated loci, as well as 3 OXTR loci, as a function of age and social experience, in children with and without autism, comparing DNAm from stored newborn dried blood spots to samples collected at the time of diagnosis. Polygenic risk scores for ASD will be calculated using Illumina PsychArray, and the relative polygenic and epigenetic risk assessed using resources from the Developmental Genomics/Epigenetics Core. The relationship between DNAm and social experience will be assessed using 2 complementary measures: 1) the Language Experience Analysis (LENA) based on audio recordings from a LENA device worn by the child over a 4-day period at home and in daycare; and 2) ecological momentary assessments (EMAs) of parental social and emotional availability collected using the BabySteps app. Children will be recruited through the Clinical Translational Core and Autism Center after ASD is either confirmed or excluded, based on ADOS testing and/or rigorous clinical assessment. A subset of 20 ASD and 20 TD children will participate in pilot resting state functional connectivity scanning through the Neurocircuitry and Behavior Core, to examine associations between DNAm of ASD-associated loci, including OXTR, and differences in brain connectivity. With the Administrative Core, we will share the BabySteps app with other Centers in the IDDRC Network and prospectively compare the effects of perinatal stress and social/learning experience on DNAm in children yet to be diagnosed with ASD. It is hypothesized that both polygenic factors and early social experience (via epigenetic modifications) contribute to ASD or IDD risk. Understanding how the environment interacts with genetic vulnerability will provide an unprecedented opportunity to re-assess early intervention and prevention strategies.

摘要：研究项目在美国，多达六分之一的儿童患有智力和发育障碍 (IDD)，其中提出的病因范围从遗传到多因素。对于绝大多数儿童来说，没有明确的遗传或尽管有证据表明遗传（内在）风险可能与环境因素相互作用，但已确定环境病因。早期学习和社会环境（外在风险）来预测以后的神经发育结果人生的各个阶段。例如，神经肽催产素及其受体 (OXTR) 通过表观遗传改变早期的社会经验在哺乳动物的社会和认知发展中发挥着至关重要的作用，并且与具有自闭症谱系障碍 (ASD) 的遗传和表观遗传风险。 Hawk-IDDDRC 的目标研究项目旨在研究 IDD 的表观遗传、多基因和环境风险因素，重点关注自闭症谱系障碍 (ASD) 作为原型。我们将使用创新的智能手机应用程序 BabySteps 来注册和收集数据 300 名母亲及其 2 至 3 岁的孩子，历时 6 个月。一百六十 ASD 儿童以及 80 名患有非 ASD 发育迟缓 (DD) 的儿童将被纳入其中，通常为 80 名发育中（TD）控制儿童，与种族/民族、性别和家庭社会经济地位相匹配。我们将检查 27 个特定 ASD 相关基因座以及 3 个 OXTR 基因座中 DNA 甲基化 (DNAm) 的变化，作为年龄和社会经验的函数，在患有和没有自闭症的儿童中，比较来自存储的 DNAm 诊断时采集的样本中含有新生儿干血点。 ASD 的多基因风险评分将为使用 Illumina PsychArray 进行计算，并使用资源评估相对多基因和表观遗传风险来自发育基因组学/表观遗传学核心。 DNAm与社会的关系将使用 2 项补充措施来评估经验：1) 语言经验分析 (LENA) 基于孩子在家里和日托中心佩戴的 LENA 设备 4 天的录音； 2）使用收集的父母社交和情感可用性的生态瞬时评估（EMA） BabySteps 应用程序。儿童将在之后通过临床转化核心和自闭症中心招募根据 ADOS 测试和/或严格的临床评估，可以确认或排除 ASD。的一个子集 20 名 ASD 和 20 名 TD 儿童将通过神经回路和行为核心，检查 ASD 相关基因座 DNAm 之间的关联，包括 OXTR 以及大脑连接的差异。通过行政核心，我们将分享 BabySteps 应用程序与 IDDRC 网络中的其他中心进行前瞻性比较围产期的影响尚未被诊断患有自闭症谱系障碍 (ASD) 的儿童的压力和社交/学习经历对 DNAm 的影响。据推测多基因因素和早期社会经历（通过表观遗传修饰）都会导致 ASD 或 IDD 风险。了解环境如何与遗传脆弱性相互作用将提供前所未有的重新评估早期干预和预防策略的机会。