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

摘要：研究项目 在美国，智力和发育障碍(IDD)影响多达六分之一的儿童， 提出的病因从遗传到多因素都有。对于绝大多数儿童来说，没有明确的基因或 虽然有证据表明遗传(内在)风险可能与 早期学习和社会环境(外部风险)预测后期神经发育结果 生命的各个阶段。例如，神经肽催产素及其受体(OXTR)在表观遗传学上受 早期的社会经验，在哺乳动物的社会和认知发展中起着至关重要的作用，并与 具有患自闭症谱系障碍(ASD)的遗传和表观遗传风险。HAWK-IDDRC的目标 研究项目是研究IDD的表观遗传、多基因和环境风险因素，重点是ASD 作为一个原型。我们将使用一款创新的新智能手机应用程序BabySteps来注册和收集数据 300名母亲及其2至3岁的孩子，为期6个月。160 ASD儿童将与80名有非ASD发育迟缓(DD)的儿童一起登记，其中80名典型 发育(TD)对照儿童，与种族/民族、性别和家庭社会经济地位相匹配。我们会 检测27个特定的ASD相关基因座以及3个OXTR基因座的DNA甲基化(DNaM)的变化 年龄和社会经验在自闭症儿童和非自闭症儿童中的作用比较 诊断时采集的样本中有新生儿干血斑点。ASD的多基因风险分数将为 使用Illumina心理阵列计算，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 经验评估将使用两个相辅相成的措施：1)语言经验分析(Lena) 根据儿童在家中和托儿所4天期间佩戴的Lena设备的音频记录； 以及2)使用以下方法收集的父母社交和情感可用性的生态瞬时评估(EMAS) Baby Steps应用程序。儿童将通过临床翻译核心和自闭症中心招募后 根据ADOS测试和/或严格的临床评估，ASD要么得到确认，要么被排除。的子集 20名ASD儿童和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，以及大脑连通性的差异。有了行政核心，我们将分享 与IDDRC网络中的其他中心一起使用BabySteps应用程序，并前瞻性比较围产期的影响 尚未诊断为自闭症的儿童对dNaM的压力和社交/学习经历。这是假设的 多基因因素和早期社会经历(通过表观遗传修饰)都与ASD或IDD有关 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.