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

摘要：研究项目 智力和发育障碍（IDD）影响美国多达六分之一的儿童， 提出的病因从遗传到多因素。对于绝大多数儿童来说，没有明确的遗传或 虽然有证据表明遗传（内在）风险可能与环境因素相互作用， 早期学习和社会环境（外在风险）预测神经发育结果， 人生的各个阶段。例如，神经肽催产素及其受体（OXTR）被表观遗传改变， 早期社会经验，在哺乳动物的社会和认知发展中起着至关重要的作用， 自闭症谱系障碍（ASD）的遗传和表观遗传风险。本Hawk-IDDRC的目标是 研究计划旨在探讨碘缺乏症的表观遗传、多基因及环境危险因素，并以自闭症为重点 作为原型。我们将使用一个创新的新的智能手机应用程序，婴儿步骤，登记和收集数据， 300名母亲及其2至3岁的子女，为期6个月。一百六十 将招募ASD儿童，沿着招募80名非ASD发育迟缓（DD）儿童，80名典型ASD儿童。 发育中（TD）对照儿童，按种族/民族，性别和家庭社会经济地位匹配。我们将 检查27个特定ASD相关基因座以及3个OXTR基因座的DNA甲基化（DNAm）变化，作为一种 年龄和社会经验的功能，在儿童与非自闭症，比较DNA m存储 新生儿干血斑与诊断时采集的样本。ASD的多基因风险评分将是 使用Illumina PsychArray计算，并使用资源评估相对多基因和表观遗传风险 从发育基因组学/表观遗传学核心。DNA与社会的关系 将使用两种补充措施评估经验：1）语言经验分析（LENA） 基于儿童在家中和日托所佩戴的LENA设备的4天内的音频记录; 和2）生态瞬时评估（EMA）的父母的社会和情感的可用性收集使用 儿童将通过临床翻译核心和自闭症中心招募后， ASD是确认或排除，基于ADOS测试和/或严格的临床评估。的子集 20名ASD和20名TD儿童将通过 神经回路和行为核心，以检查ASD相关基因座的DNAm之间的关联， 包括OXTR和大脑连接的差异。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， 压力和社会/学习经验对尚未诊断为ASD的儿童的DNA m的影响。据推测 多基因因素和早期社会经验（通过表观遗传修饰）都有助于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 有机会重新评估早期干预和预防战略。

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.