Maternal health in pregnancy and autism risk - genetic and non-genetic mechanisms

怀孕期间的孕产妇健康和自闭症风险 - 遗传和非遗传机制

• 批准号: 10096699
• 负责人: MAGDALENA JANECKA
• 金额: $ 55.06万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10096699
• 关键词: Accounting; Affect; American; Birth; Blood Circulation; Brothers; California; Child; Coupled; Data; Data Set; Data Sources; Denmark; Development; Diabetes Mellitus; Diagnosis; Disease; Early identification; Ensure; Environmental Risk Factor; Epidemiology; Etiology; Exposure to; Extended Family; Family; Family Relationship; Female; Fetus; Genetic; Genetic Risk; Goals; Health Status; Individual; Intellectual functioning disability; International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10); Intervention; Knowledge; Link; Live Birth; Maps; Maternal Exposure; Maternal Health; Medical; Medical Records; Mental Depression; Methodology; Molecular Genetics; Mothers; Outcome; Output; Parents; Partner in relationship; Pathway interactions; Permeability; Pregnancy; Prevention; Preventive; Process; Public Health; Registries; Risk; Risk Factors; Sampling; Sister; Testing; Time; Woman; Work; autism spectrum disorder; autistic children; base; cohort; comorbidity; design; disorder risk; experience; family genetics; genetic pedigree; high risk; indexing; innovation; insight; male; modifiable risk; non-genetic; novel; offspring; polygenic risk score; population based; prenatal; recurrent infection; response; sex

Autism spectrum disorder (ASD) affects 1 in 59 children1, and is caused by both genetic and environmental factors. Nevertheless, the modifiable risk factors for this disorder remain unknown, creating a pressing public health need. As ASD likely arises early in prenatal development considerable efforts in identifying such modifiable risk factors have focused on maternal exposures in pregnancy. Some of those studies have shown higher rates of ASD among children of women with e.g. diabetes, depression or recurrent infections. However, (1) women experience many other conditions in pregnancy, most of which have not been studied in the context of offspring ASD risk; and (2) the mechanisms underlying the association between maternal diagnoses and ASD remain unknown. While placental permeability to multiple factors in maternal circulation renders direct effects of maternal health on fetus plausible, this explanation has not been rigorously evaluated against the possibility that both maternal diagnosis and child’s ASD are caused by overlapping genetic factors, transmitted from mother to the child. In response, the key objectives of our proposal are to (1) test the associations between maternal health and ASD systematically, across the full spectrum of maternal diagnoses, and accounting for their correlation, and (2) elucidate the genetic and/or non-genetic mechanisms underlying those associations. To achieve this, we propose independent, but synergistic, aims to increase the reliability and generalizability of our results. Aim 1: Systematically identify maternal diagnoses in pregnancy associated with ASD in offspring. Aim 2: Determine if the association between maternal diagnoses and ASD is due to transmitted genetic factors, using information on family relations available in Denmark. Aim 3: Test the association between maternal diagnoses in pregnancy and child’s genetic liability for ASD using molecular genetic data. We will use large, well-powered sample of >723k live births from Denmark with full demographic, medical and pedigree information, as well as genetic data for a subset of those individuals (N~26k). All significant associations will be replicated in an American dataset (Kaiser Permanente Northern California) with ~320k births, ensuring external validity of our results. The innovation of this project is three-fold: (1) it has a potential to identify novel risk factors (shown in our preliminary data), (2) it introduces a methodological shift in ASD epidemiology, with large-scale, exposure- wide and rigorous inference process, akin to that already applied in the field of genetics; and (3) for the first time, it integrates national data from Nordic registries with one of the largest US-based cohorts (Kaiser Permanente). This project will deliver a systematic list of high-confidence, maternal diagnoses around pregnancy associated with ASD risk in two, independent cohorts, and triangulated evidence regarding genetic and non-genetic mechanisms linking those diagnoses in pregnancy with risk of ASD in offspring. Collectively, these outputs will contribute new insights into ASD etiology, suggest potential preventive factors and aid the efforts towards early identification of high-risk families.

自闭症谱系障碍 (ASD) 影响每 59 名儿童中就有 1 名1，由遗传和环境共同造成 因素。然而，这种疾病的可改变的风险因素仍然未知，这引起了公众的紧迫关注 健康需要。由于自闭症谱系障碍 (ASD) 很可能在产前发育早期出现，因此需要付出巨大努力来识别此类现象。 可改变的危险因素主要集中于孕期母亲的暴露。其中一些研究表明 患有以下疾病的妇女的孩子患自闭症谱系障碍的比例较高糖尿病、抑郁症或反复感染。然而， (1) 女性在怀孕期间会经历许多其他状况，其中大部分尚未在背景下进行研究 后代 ASD 风险； (2) 孕产妇诊断与 ASD 之间关联的潜在机制 仍然未知。虽然胎盘对母体循环中多种因素的渗透性直接影响 孕产妇健康对胎儿的影响似乎是合理的，但这种解释尚未针对以下可能性进行严格评估： 母亲的诊断和孩子的自闭症谱系障碍都是由重叠的遗传因素引起的，从母亲传播给 孩子。作为回应，我们提案的主要目标是（1）测试孕产妇健康之间的关联 和自闭症谱系障碍（ASD），系统地涵盖所有孕产妇诊断，并解释它们的相关性， (2) 阐明这些关联背后的遗传和/或非遗传机制。为了实现这一目标， 我们建议独立但协同，旨在提高我们结果的可靠性和普遍性。 目标 1：系统地识别与后代 ASD 相关的妊娠期母亲诊断。目标 2： 使用以下方法确定孕产妇诊断与自闭症谱系障碍之间的关联是否是由于遗传因素造成的 丹麦提供有关家庭关系的信息。目标 3：测试孕产妇诊断之间的关联 使用分子遗传学数据研究怀孕和儿童对自闭症谱系障碍的遗传倾向。我们将使用大型、动力充足的 来自丹麦的超过 723,000 例活产样本，包含完整的人口统计、医疗和谱系信息，以及 这些个体的子集 (N~26k) 的遗传数据。所有重要的关联都将在一个 美国数据集（Kaiser Permanente Northern California）约有 32 万出生人口，确保我们的外部有效性 结果。该项目的创新之处在于三个方面：（1）它有可能识别新的风险因素（如图所示） 我们的初步数据），（2）它引入了 ASD 流行病学的方法论转变，大规模、暴露- 广泛而严格的推理过程，类似于遗传学领域已经应用的推理过程； (3) 第一次， 它将北欧登记处的国家数据与美国最大的队列之一（Kaiser Permanente）整合在一起。 该项目将提供一份关于妊娠相关的高置信度孕产妇诊断的系统列表 两个独立队列中存在自闭症谱系障碍（ASD）风险，以及关于遗传和非遗传的三角证据 将妊娠期诊断与后代自闭症谱系障碍风险联系起来的机制。总的来说，这些输出将 为自闭症谱系障碍 (ASD) 病因学提供新见解，提出潜在的预防因素，并帮助尽早采取措施 识别高危家庭。