Autism Risk and Maternal Cardiometabolic Health (ARCH) study

目前，美国每59名儿童中就有一名患有自闭症谱系障碍(ASD)，目前尚无治愈方法。无论是遗传还是 环境因素对ASD的风险有很大贡献，但这些因素在ASD病因中的综合作用 研究--迈向初级预防的关键步骤--很少见。心脏代谢状况(CMCS：肥胖、 妊娠期高血压或妊娠期糖尿病，妊娠期高血压疾病/先兆子痫或 妊娠期糖尿病(妊娠期糖尿病)在孕妇中很普遍，通常是同时发生的； 对妊娠和发育中的胎儿造成严重的并发症，并已显示出效果 神经发育，包括智力残疾(ID)和注意力缺陷多动障碍(ADHD)。这个 文献和我们的初步数据强烈表明，CMC与ASD风险有关，但关键的风险模式 潜在的关联(CMC组合、严重程度和时间；ID或ADHD共病导致的ASD结果 或按性别)没有得到充分调查，可能会加强风险检测。此外，还没有研究表明 调查母体巨噬细胞是否通过母子共同遗传影响自闭症风险 通过独立的机制。自闭症风险与母体心脏代谢健康(ARCH)的目标 这项研究旨在通过以下途径确定母体巨噬细胞及相关家族和遗传因素在ASD病因中的作用 三个具体目标(1)：严格评估母体CMCs和ASD协会，通过组合， 发病时间和严重程度；(2)通过ASD并存阐明母亲CMC-ASD的风险模式 (3)通过共同的遗传因素量化CMC对ASD风险的影响； 结合子代ASD遗传学和母体CMC效应；以及独立的CMC效应。我们使用一种 来自丹麦和瑞典的150万名活产婴儿(1998-2007)的强劲、强大的样本，并与3- 世代家谱，严格协调和可重复暴露(CMC诊断， 处方)，结果(ASD(2.5万例)，共患ID，截至2016年诊断为ADHD；ASD按儿童性别分类) 和协变量数据；来自丹麦全国IPSYCH研究的30,000例ASD病例的基因数据和 控制。我们的创新包括首次对CMCS进行严格、多方面的调查，作为一类 ASD的普遍的、潜在的可改变的风险；家族性和遗传性CMC对 ASD风险；对多种暴露和多变量结果进行独特的、大规模的综合分析 创建母体巨噬细胞作为ASD危险因素以及CMC-ASD遗传因素的整体图景 使用创新的遗传建模方法对系谱和基因组数据进行相互关系。我们的 综合的方法、严谨的方法和前所未有的研究力量掌握在我们的专家团队手中 为发现潜在的可更改风险因素、高风险亚组、关键风险途径和 未来的ASD预防策略。

Autism spectrum disorder (ASD) now affects 1 in 59 children in the US and there is no cure. Both genetic and environmental factors contribute substantially to ASD risk, but integration of these factors in ASD etiologic studies – critical steps towards primary prevention – are rare. Cardiometabolic conditions (CMCs: obesity, hypertension, or diabetes prior to pregnancy and hypertensive disorders in pregnancy/pre-eclampsia or gestational diabetes with onset in pregnancy) are prevalent in pregnant women and commonly co-occur; impose serious complications on the pregnancy and the developing fetus; and have shown to effect neurodevelopment, including intellectual disability (ID) and attention deficit hyperactivity disorder (ADHD). The literature and our preliminary data strongly suggest CMCs are associated with ASD risk but critical risk patterns underlying the association (CMC combination, severity, and timing; ASD outcome by ID or ADHD comorbidity or by sex) have been inadequately investigated and could enhance risk detection. Further, no study has investigated whether maternal CMCs affect ASD risk by shared genetics of the mother and her offspring or through independent mechanisms. The goal of the Autism Risk and maternal Cardiometabolic Health (ARCH) Study is to determine the role of maternal CMCs and related familial and genetic factors in ASD etiology via three specific aims (1): Rigorously evaluate maternal CMCs and ASD associations, by combination, timing of onset and severity; (2) Elucidate maternal CMC-ASD risk patterns by ASD comorbid subgroups and child sex; (3) Quantify CMC impact on ASD risk through shared genetic factors; combined offspring ASD genetics and maternal CMC effects; and independent CMC effects. We use a robust, well powered sample of 1.5 million live births (1998-2007) from Denmark and Sweden and linked 3- generation family pedigrees, rigorously harmonized and reproducible exposure (CMC diagnoses, prescriptions), outcome (ASD (25,000 cases), comorbid ID, ADHD diagnoses through 2016; ASD by child sex) and covariate data; and genotype data from the Danish nationwide iPSYCH study for 30,000 ASD cases and controls. Our innovations include the first, rigorous, multi-faceted investigation of CMCs as a class of prevalent, potentially modifiable risks for ASD; critical synthesis of familial and genetic CMC contributions to ASD risk; unique, large-scale comprehensive analysis of multiple exposures and multivariate outcomes to create a holistic picture of maternal CMCs as risk factors for ASD, as well as CMC-ASD genetic interrelationships using innovative genetic modeling approaches of both pedigree and genomic data. Our integrated approach, rigorous methods and unprecedented study power in the hands of our expert team will pave the way to discovery of potentially modifiable risk factors, high-risk subgroups, critical risk pathways, and future ASD prevention strategies.