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

项目总结 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障碍之一，对家庭来说是一生的挑战和成本。我们建议对自闭症和相关疾病具有表观遗传学基础的假设进行检验。我们对自闭症的标准遗传范式提出了质疑，认为它是不完整的，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。我们提出了一个实质性的 自闭症和相关疾病病因学的新方法，通过从怀孕开始到新生儿生命的第一年对预期数据进行一系列渐进的流行病学分析，整合遗传、表观遗传和环境信息。我们已经与两个互补的怀孕队列合作：1)早期自闭症风险纵向调查(EARLI)网络，该网络正在招募患有自闭症的高风险孕妇，因为她们已经患上了自闭症 一个自闭症儿童，2)约翰霍普金斯大学国家儿童研究网站，该网站正在马里兰州的两个县招募有代表性的孕妇。这些队列总共收集了800名母亲、父亲和孩子在怀孕和产后的大量数据，包括：怀孕期间母亲至少两次的生物样本，出生时和12个月的孩子的生物样本，怀孕期间父亲的生物样本，以及300个胎盘的生物样本；有记录和/或多次怀孕前和宫内暴露的数据。 直接测量；评估与自闭症有关的儿童发育特征，在出生时(胎龄、出生体重和头围)和12个月时测量(语言、社交、认知技能)。 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)表观基因组中是否有易受怀孕前和怀孕期间环境侮辱的区域？2)表观基因组中是否有与ASD相关的新生儿和婴儿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？我们的方法的主要特点包括a)新颖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)怀孕期间的暴露测量，e)出生和早期的数量发育性状，以及f)GWAs与表观基因组数据的整合。这项工作将作为“表观遗传学流行病学”新领域的基础，并代表着一个非同寻常的机会，利用最先进的流行病学和表观基因组设计，测试遗传学、表观遗传学和环境在怀孕前和怀孕期间相互作用，调节毁灭性和常见疾病的风险的想法。它将首次对人类表观基因组中先天和后天之间的关系进行严格的分析。

PROJECT SUMMARY 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.