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: 10531594
• 负责人: MAGDALENA JANECKA
• 金额: $ 63.41万
• 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/10531594
• 关键词: Accounting; Affect; American; Birth; Brothers; California; Child; Circulation; 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; Infection; 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; Vertical Disease Transmission; Woman; Work; autism spectrum disorder; autistic children; 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; transmission process

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59名儿童中的1名1，由遗传和环境引起 因素尽管如此，这种疾病的可改变的风险因素仍然未知， 健康需要。由于ASD可能在产前发育早期出现，因此在识别这种ASD方面做出了相当大的努力。 可改变的风险因素主要集中在孕妇怀孕期间的暴露。其中一些研究表明 患有糖尿病、抑郁症或复发性感染等疾病的妇女的子女患ASD的比率较高。然而，在这方面， (1)妇女在怀孕期间经历许多其他情况，其中大多数尚未在背景下研究 后代ASD风险;（2）母亲诊断和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会直接影响 母亲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ASD都是由重叠的遗传因素引起的，从母亲传播到 那个孩子作为回应，我们建议的主要目标是（1）测试孕产妇健康与 和ASD系统地，在整个母亲诊断范围内，并考虑到它们的相关性， 和（2）阐明这些关联背后的遗传和/或非遗传机制。为了实现这一点， 我们提出独立的，但协同的，旨在增加我们的结果的可靠性和普遍性。 目的1：系统地识别与后代ASD相关的妊娠期母亲诊断。目标二： 确定母亲诊断和ASD之间的关联是否是由于遗传因素，使用 在丹麦提供有关家庭关系的信息。目的3：测试母亲诊断之间的关联 在怀孕和儿童的遗传易感性ASD使用分子遗传数据。我们将使用大型动力强劲的 来自丹麦的> 723，000例活产婴儿样本，包含完整的人口统计学、医学和谱系信息，以及 这些个体的子集的遗传数据（N~ 26 k）。所有重要的关联都将在 美国数据集（Kaiser Permanente北方加州），约32万例出生，确保我们的外部有效性 结果该项目的创新有三个方面：（1）它有可能识别新的风险因素（见 我们的初步数据），（2）它引入了ASD流行病学的方法学转变，大规模暴露- 广泛而严格的推理过程，类似于已经应用于遗传学领域的推理过程;以及（3）首次， 它整合了来自北欧登记处的国家数据与美国最大的队列之一（Kaiser Permanente）。 该项目将提供一个高置信度的系统列表，围绕妊娠相关的孕产妇诊断 在两个独立的队列中有ASD风险，关于遗传和非遗传的三角证据 将妊娠期诊断与后代患ASD风险联系起来的机制。这些产出合在一起将 为ASD病因学提供了新的见解，提出了潜在的预防因素，并有助于早期 确定高危家庭。