Autism Risk and Maternal Cardiometabolic Health (ARCH) study

自闭症谱系障碍（ASD）现在影响美国59名儿童中的1名，并且没有治愈方法。遗传和 环境因素在很大程度上导致ASD风险，但这些因素在ASD病因学中的整合 研究-初级预防的关键步骤-很少。心脏代谢疾病（CMC：肥胖， 妊娠前高血压或糖尿病和妊娠期高血压疾病/先兆子痫，或 妊娠期糖尿病（在妊娠期发病）在孕妇中普遍存在，并且通常同时发生; 对怀孕和发育中的胎儿造成严重并发症;并已显示影响 神经发育，包括智力残疾（ID）和注意力缺陷多动障碍（ADHD）。的 文献和我们的初步数据强烈表明CMC与ASD风险相关，但关键风险模式 相关性的基础（CMC组合、严重程度和时间; ID或ADHD合并症的ASD结局 或按性别分列）没有得到充分调查，可能会加强风险检测。此外，没有任何研究 研究母体CMC是否通过母亲及其后代的共同遗传学影响ASD风险， 通过独立的机制。自闭症风险和孕产妇心脏代谢健康的目标 本研究旨在确定母体CMC和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CMC和ASD协会，通过组合， 发病时间和严重程度;（2）通过ASD共病阐明母体CMC-ASD风险模式 （3）通过共有的遗传因素量化CMC对ASD风险的影响; 结合后代ASD遗传学和母体CMC效应;和独立CMC效应。我们使用一个 来自丹麦和瑞典的150万例活产婴儿（1998-2007年）的稳健、功效良好的样本， 世代家族谱系，严格协调和可重复的暴露（CMC诊断， 处方），结局（ASD（25，000例），共病ID，2016年前的ADHD诊断;按儿童性别划分的ASD） 和协变量数据;以及来自丹麦全国iPSYCH研究的30，000例ASD病例的基因型数据， 对照我们的创新包括第一次，严格的，多方面的调查CMC作为一类 普遍存在的，潜在的可改变的ASD风险;家族和遗传CMC贡献的关键综合， ASD风险;对多种暴露和多变量结局进行独特的大规模综合分析， 创建母体CMC作为ASD风险因素的整体图，以及CMC-ASD遗传 使用创新的遗传建模方法的系谱和基因组数据的相互关系。我们 综合的方法，严谨的方法和前所未有的研究力量在我们的专家团队手中， 为发现潜在可改变的风险因素、高风险亚组、关键风险途径铺平道路， 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.