Autism Risk and Maternal Cardiometabolic Health (ARCH) study

自闭症风险与母亲心脏代谢健康 (ARCH) 研究

• 批准号: 10178066
• 负责人: ABRAHAM REICHENBERG
• 金额: $ 65.17万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-09 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10178066
• 关键词: Address; Affect; Attention deficit hyperactivity disorder; Biometry; Birth; Brain; Child; Data; Data Analytics; Denmark; Detection; Development; Diabetes Mellitus; Diagnosis; Disease; Environmental Epidemiology; Environmental Risk Factor; Etiology; Exposure to; Family; Family member; Fetal Development; Fetal health; Future; Generations; Genetic; Genetic Diseases; Genetic Models; Genetic Risk; Genetic Variation; Genotype; Gestational Diabetes; Goals; Health; Hypertension; Individual; Intellectual functioning disability; Investigation; Knowledge; Link; Literature; Live Birth; Methodology; Methods; Modeling; Morbidity - disease rate; Mothers; Obesity; Outcome; Pathway interactions; Pattern; Pre-Eclampsia; Pregnancy; Pregnant Women; Prevalence; Prevention strategy; Primary Prevention; Psychiatric epidemiology; Reproducibility; Research Personnel; Resources; Risk; Risk Factors; Role; Sampling; Severities; Subgroup; Sweden; Universities; autism spectrum disorder; base; boys; cardiometabolic risk; cardiometabolism; case control; cohort; comorbidity; data registry; disorder risk; fetal; genetic epidemiology; genetic pedigree; genomic data; girls; high risk; innovation; insight; medical schools; modifiable risk; neurodevelopmental effect; non-genetic; offspring; population based; pregnancy disorder; prenatal exposure; prospective; risk sharing; sex; sex risk

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.

自闭症谱系障碍（ASD）现在影响美国59名儿童中的1个，并且无法治愈。遗传和 环境因素对ASD风险产生了重大贡献，但是这些因素在ASD病因中的整合 研究 - 初级预防的关键步骤 - 很少见。心脏代谢条件（CMCS：肥胖症， 怀孕/临时症状的高血压或糖尿病和高血压疾病 孕妇的妊娠糖尿病患有妊娠发作）很普遍，通常同时发生； 对怀孕和发育中的胎儿施加严重的并发症；并已证明 神经发育，包括智力残疾（ID）和注意力缺陷多动障碍（ADHD）。 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 协会的基础（CMC组合，严重性和计时； ID或ADHD合并症的ASD结果 或通过性别）的研究不足，可以增强风险检测。此外，没有研究 调查了母亲CMC是否通过母亲和她的后代的共同遗传学或 通过独立的机制。自闭症风险和母体心脏代谢健康（ARCH）的目标 研究是确定母体CMC和相关家族和遗传因素在ASD病因中的作用 三个特定目标（1）：严格评估矩阵CMC和ASD关联，合并， 发作和严重性的时间； （2）通过ASD合并症阐明Mater CMC-ASD风险模式 亚组和儿童性别； （3）通过共同的遗传因素量化CMC对ASD风险的影响； 将后代ASD遗传学和母体CMC效应结合在一起；和独立的CMC效应。我们使用一个 来自丹麦和瑞典的150万活节生（1998-2007）的强大，功能强大的样本 一代家庭的血统，严格统一和繁殖暴露（CMC诊断， 处方），结果（ASD（25,000例），合并ID，ADHD诊断至2016年；儿童性别ASD） 和协变量数据；以及来自丹麦全国ipsych研究的基因型数据，针对30,000例ASD病例和 控件。我们的创新包括CMC作为一类的首次严格，多方面的投资 ASD的普遍，可能改变的风险；家族和遗传CMC对批判性合成对 ASD风险；对多种暴露和多元结果的独特大规模综合分析 创建母体CMC作为ASD的风险因素以及CMC-ASD遗传的整体图片 使用谱系和基因组数据的创新遗传建模方法进行相互关系。我们的 综合方法，严格的方法和前所未有的研究能力在我们的专家团队手中 为发现潜在可修改的风险因素，高风险亚组，关键风险途径和 未来的ASD预防策略。