Prenatal SSRI Exposure, Maternal and Child Genotype, and Autism Spectrum Disorders

产前 SSRI 暴露、母婴基因型和自闭症谱系障碍

• 批准号: 9246557
• 负责人: LISA A CROEN
• 金额: $ 66.63万
• 依托单位: KAISER FOUNDATION RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9246557
• 关键词: Address; Affect; Antidepressive Agents; Autistic Disorder; Behavior; Biological; Birth; Caring; Case-Control Studies; Child; Child Care; Complex; Data; Data Collection; Development; Developmental Delay Disorders; Environmental Exposure; Environmental Risk Factor; Evaluation; Evidence based treatment; Exposure to; First Pregnancy Trimester; Funding; Genetic; Genetic Predisposition to Disease; Genotype; Health Status; Individual; Investigation; Joints; Life; Light; Long-Term Effects; Measurement; Measures; Mediating; Mental Depression; Mental Health; Mental disorders; Mothers; Neurodevelopmental Disorder; Outcome; Pattern; Perinatal; Perinatal Exposure; Pharmaceutical Preparations; Phenotype; Population; Positioning Attribute; Predisposition; Pregnancy; Pregnant Women; Prevalence; Public Health; Publications; Recording of previous events; Reporting; Research; Risk; Role; Sampling; Selective Serotonin Reuptake Inhibitor; Site; Social Interaction; Targeted Research; Therapeutic Intervention; Time; United States; antidepressant effect; autism spectrum disorder; comparison group; cost; disorder risk; early life exposure; gene environment interaction; genome-wide; high risk; maternal depression; peripartum depression; phenotypic data; population based; postnatal; prenatal; prenatal exposure; public health relevance; social communication

 DESCRIPTION (provided by applicant): Autism Spectrum Disorders (ASDs) are complex neurodevelopmental disorders that occur in approximately 1 in 68 children today, an increase from 1 in 2,000 just 50 years ago. The causes of ASD are unknown, but a growing body of evidence supports a critical role for both genetic and environmental factors, particularly during gestation and the early postnatal period. Among numerous environmental exposures that have increased in prevalence over the past decades is perinatal exposure to antidepressant medications, which are currently used by 7%-13% of pregnant women in the United States. In the first study to examine risk of autism following prenatal exposure to antidepressants, we found a significant 3-fold increased risk associated with first trimester SSRI exposure. Subsequent studies in other populations have reported increased risk of ASD associated with in utero exposure to SSRIs, although not all studies have found such evidence. The interpretation of these collective findings is limited by exposure and outcome misclassification and confounding by indication, and lack of integration of underlying genetic susceptibility. The proposed study will overcome these limitations by utilizing data and biospecimens already collected in the SEED study (Study to Explore Early Development, www.cdc.gov/ ncbddd/autism/caddre.html), the largest, multi-site, population-based case- control study of autism in the United States. We will explore main and joint effects of maternal antidepressant use, maternal psychiatric disease history, and maternal and child genetic susceptibility. We seek funds to generate genome-wide SNP data and perform targeted genotyping on 1608 SEED mothers and to support analyses of these perinatal environmental, maternal and child genetic, and ASD phenotypic data to 1) examine the effect of perinatal exposure to SSRI antidepressants on risk of ASD; 2) evaluate the role of perinatal SSRI exposure in ASD risk in the context of maternal mental health status; and 3) examine whether perinatal SSRI exposure and child or maternal genotype interact to impact risk of ASD. This study leverages the extensive data already assembled by SEED, which provide comprehensive information on several important confounders not previously measured, robust and valid measurement of child phenotype, genome-wide SNP data on children, and maternal genetic samples. Since SEED data collection focused on the preconception through early postnatal period, the proposed study has the ability to identify developmental time periods of greatest vulnerability to SSRI exposure and aid clinicians and mothers in making informed decisions about the management of perinatal depression. Our study may identify specific maternal or child profiles that indicate heightened susceptibility to perinatal SSRI exposure and shed light on potential biological mechanisms underlying ASD development. Finally, since early life exposure to antidepressants is common and modifiable, the proposed research has the potential to make a large public health impact and guide research targeting ASD interventions and therapies.

 描述（由申请人提供）：自闭症谱系障碍 (ASD) 是一种复杂的神经发育障碍，目前每 68 名儿童中就有 1 人患有自闭症谱系障碍，而 50 年前这一比例为 2,000 人中就有 1 人。自闭症谱系障碍的原因尚不清楚，但越来越多的证据支持遗传和环境因素的关键作用，特别是在妊娠期和产后早期。过去几十年来，众多环境暴露的患病率有所增加，其中包括围产期抗抑郁药物的暴露，目前美国有 7%-13% 的孕妇使用这种药物。在第一项检查产前接触抗抑郁药物后患自闭症风险的研究中，我们发现与妊娠早期接触 SSRI 相关的风险显着增加了 3 倍。随后对其他人群的研究报告称，在子宫内接触 SSRIs 会增加患自闭症谱系障碍 (ASD) 的风险，但并非所有研究都发现了此类证据。对这些集体发现的解释受到暴露和结果的错误分类和适应症的混淆以及缺乏对潜在遗传易感性的整合的限制。拟议的研究将利用 SEED 研究（探索早期发展的研究，www.cdc.gov/ncbddd/autism/caddre.html）中已收集的数据和生物样本来克服这些限制，SEED 研究是美国最大的、多地点、基于人群的自闭症病例对照研究。我们将探讨母亲抗抑郁药物使用、母亲精神疾病史以及母婴遗传易感性的主要影响和联合影响。我们寻求资金来生成全基因组 SNP 数据，对 1608 位 SEED 母亲进行有针对性的基因分型，并支持对这些围产期环境、母婴遗传和 ASD 表型数据的分析，以 1) 检查围产期接触 SSRI 抗抑郁药对 ASD 风险的影响； 2) 在孕产妇心理健康状况的背景下，评估围产期 SSRI 暴露在 ASD 风险中的作用； 3) 检查围产期 SSRI 暴露与儿童或母亲基因型是否相互作用，从而影响 ASD 风险。这项研究利用了 SEED 已经收集的大量数据，这些数据提供了有关先前未测量的几个重要混杂因素的全面信息、儿童表型的稳健且有效的测量、儿童全基因组 SNP 数据以及母亲遗传样本。由于 SEED 数据收集的重点是从孕前到产后早期，因此拟议的研究能够确定最容易暴露于 SSRI 的发育时期，并帮助临床医生和母亲就围产期抑郁症的管理做出明智的决定。我们的研究可能会确定特定的母亲或儿童概况，这些概况表明对围产期 SSRI 暴露的易感性较高，并揭示 ASD 发展的潜在生物学机制。最后，由于生命早期接触抗抑郁药物很常见且可以改变，因此拟议的研究有可能对公共卫生产生巨大影响，并指导针对 ASD 干预和治疗的研究。