Environment, The Perinatal Epigenome, and Risk for Autism and Related Disorders

描述（由申请人提供）：自闭症谱系障碍（ASD）和相关的发育表型是最具破坏性的儿童疾病之一，就终身挑战和家庭成本而言。我们建议测试自闭症和相关疾病具有表观遗传基础的假设。我们挑战自闭症的标准遗传范式是不完整的，并认为怀孕期间的环境因素在这种疾病中起着关键作用，这些因素是由表观遗传机制介导的。我们提出了一种整合遗传、表观遗传和环境信息的自闭症和相关疾病的病因学的新方法，通过一系列从怀孕开始到新生儿出生头几年的前瞻性数据的渐进流行病学分析。我们合作了两个互补的怀孕队列：1)早期自闭症风险纵向调查（EARLI）网络，它正在招募那些已经有自闭症孩子的孕妇，她们的新孩子患自闭症的风险很高；2)约翰霍普金斯大学国家儿童研究网站，它正在招募马里兰州两个县的有代表性的孕妇。总之，这些队列收集了800名母亲、父亲和儿童孕期和产后的大量数据，包括：母亲在怀孕期间至少两次的生物样本、出生时和12个月时的儿童、怀孕期间的父亲和300个胎盘的生物样本；记录和/或直接测量多次孕前和子宫内暴露；在出生时（胎龄、出生体重和头围）和12个月时（语言、社交、认知技能）测量与asd相关的儿童发展特征的评估。我们将对这些生物样本进行全基因组甲基化和等位基因特异性表达分析，以解决以下问题：1)表观基因组中是否存在易受怀孕前和怀孕期间环境损害的区域？2)表观基因组中是否存在与ASD相关的新生儿和婴儿定量发育表型相关的区域？3)遗传变异如何影响这些表观遗传学发现？该方法的主要特点包括a)新的全基因组表观遗传阵列和统计方法，b)两个互补的妊娠队列，c)妊娠和早期的纵向表观基因组分析，d)妊娠期间的暴露测量，e)出生和早期的定量发育特征，f) GWAS与表观基因组数据的整合。这项工作将作为“表观遗传流行病学”新领域的基础，并代表了一个非凡的机会，可以使用最先进的流行病学和表观基因组设计，在怀孕前和怀孕期间测试遗传学，表观遗传学和环境相互作用以调节破坏性和常见疾病风险的想法。它将首次对人类表观基因组中先天与后天的关系进行严谨的分析。公共卫生相关性：自闭症谱系障碍（ASD）和相关的发育表型是儿童疾病中最具破坏性的，就终生挑战和家庭成本而言，表观遗传变异的研究是传统遗传疾病研究的重要补充；与序列变异不同，表观遗传标记受环境影响。该项目将采取全面的全基因组方法来了解遗传、表观遗传学和子宫环境在出生和早期发育表型中的相互作用，这些表型通常是不良结局的重要预测因子，并且与ASD特异性相关。

DESCRIPTION (provided by applicant): Autism spectrum disorders (ASD) and related developmental phenotypes are among the most devastating of childhood disorders in terms of lifetime challenges and costs to families. We propose to test the hypothesis that autism and related disorders have an epigenetic basis. We challenge the standard genetic paradigm for autism as incomplete and argue that environmental factors during pregnancy play a critical role in the disorder and that these are mediated by epigenetic mechanisms. We propose a substantially new approach to the etiology of autism and related disorders that integrates genetic, epigenetic, and environmental information through a series of progressive epidemiologic analyses of prospective data beginning at the onset of pregnancy, through the first years of the newborn's life. We have partnered two complementary pregnancy cohorts: 1) the Early Autism Risk Longitudinal Investigation (EARLI) Network, which is recruiting pregnant women at high risk of having a new child with ASD because they already have an autistic child, 2) the Johns Hopkins University National Children's Study site, which is recruiting representative pregnancies in two Maryland counties. Together, these cohorts an extraordinary wealth of data across pregnancy and postnatally in 800 mothers, fathers, and children including: biosamples from mothers at least twice during pregnancy, from children at birth and 12 months, from fathers during the pregnancy, and from 300 placenta; multiple pre-conception and in utero exposures documented and/or directly measured; assessment of child development features associated with ASDs measured at birth (gestational age, birth weight and head circumference) and at 12 months (language, social, cognitive skills). We will perform genome-wide methylation and allele-specific expression analyses on these biosamples to address the following questions: 1) Are there regions of the epigenome that are susceptible to environmental insults occurring before and during pregnancy?; 2) Are there regions of the epigenome that correlate with quantitative newborn and infant developmental phenotypes related to ASD?; 3) How does genetic variation influence these epigenetic findings? The major features of our approach include a) novel genome-wide epigenetic array and statistical methods, b) two complementary pregnancy cohorts, c) longitudinal epigenome analysis through pregnancy and early life, d) exposure measurements through pregnancy, e) quantitative developmental traits at birth and in early life, and f) integration of GWAS with epigenome data. This work will serve as a foundation for a new field of "Epigenetic Epidemiology" and represents an extraordinary opportunity to test the idea that genetics, epigenetics and environment interact before and through pregnancy to modulate the risk of a devastating and common disease, using a state-of-the-art epidemiological and epigenomic design. It will provide the first rigorous analysis of the relationship between nature and nurture in the human epigenome. Public Health Relevance: Autism spectrum disorders (ASD) and related developmental phenotypes are among the most devastating of childhood disorders in terms of lifetime challenges and costs to families The study of epigenetic variation is an essential complement to conventional genetic disease studies; unlike sequence variation, epigenetic marks are affected by the environment. This project will take a comprehensive genome-wide approach to understand the interplay between genetics, epigenetics, and in utero environment in birth and early development phenotypes that are important predictors of adverse outcomes generally, and are related to ASD specifically.