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

基本信息

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
项目类别：
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

项目摘要

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.

目前，美国每 59 名儿童中就有 1 人患有自闭症谱系障碍 (ASD)，而且遗传和治愈方法均无法治愈。环境因素对 ASD 风险有重大影响，但将这些因素整合到 ASD 病因学中研究——一级预防的关键步骤——很少见。高血压，或妊娠前糖尿病和妊娠期高血压疾病/先兆子痫或妊娠期糖尿病（妊娠期发病）在孕妇中很常见，并且通常同时发生；对妊娠和发育中的胎儿造成严重并发症；神经发育，包括智力障碍（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，但关键风险模式关联的基础（CMC 组合、严重程度和时间；按 ID 或 ADHD 合并症划分的 ASD 结果或按性别）尚未得到充分调查，并且还没有研究可以加强风险检测。研究了母体 CMC 是否通过母亲及其后代的共同遗传影响自闭症谱系障碍 (ASD) 风险，或者通过独立机制实现自闭症风险和孕产妇心脏代谢健康 (ARCH) 的目标。研究旨在通过以下方式确定母体 CMC 以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)：通过组合严格评估孕产妇 CMC 和 ASD 关联，发病时间和严重程度； (2) 通过 ASD 共病阐明孕产妇 CMC-ASD 风险模式亚群体和儿童性别；(3) 通过共同的遗传因素量化 CMC 对 ASD 风险的影响；结合后代 ASD 遗传和母体 CMC 效应；以及独立 CMC 效应。来自丹麦和瑞典的 150 万活产婴儿（1998 年至 2007 年）的稳健、有力的样本，并将 3- 世代家族谱系、严格协调和可重复的暴露（CMC 诊断、处方）、结果（自闭症谱系障碍（ASD）（25,000 例）、共病 ID、2016 年 ADHD 诊断；按儿童性别划分的自闭症谱系障碍（ASD）和协变量数据；以及来自丹麦全国 iPSYCH 研究的 30,000 个 ASD 病例的基因型数据和我们的创新包括对 CMC 作为一类进行首次、严格、多方面的调查。自闭症谱系障碍（ASD）普遍存在的、潜在可改变的风险； ASD 风险；对多重风险和多变量结果进行独特的大规模综合分析全面了解母体 CMC 作为 ASD 危险因素以及 CMC-ASD 遗传使用谱系数据和基因组数据的创新遗传建模方法来研究相互关系。我们的专家团队手中的综合方法、严谨的方法和前所未有的研究能力将为发现潜在可改变的风险因素、高风险亚组、关键风险途径和未来的 ASD 预防策略。