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（由适用提供）：自闭症谱系障碍（ASDS）是复杂的神经发育障碍，当今大约有68名儿童中有1个发生在50年前的2,000名儿童中有1个增加。 ASD的原因是未知的，但是越来越多的证据支持遗传和环境因素的关键作用，尤其是在妊娠和产后早期。在过去几十年中，患病率增加的众多环境暴露是围产期暴露于抗抑郁药，目前，美国有7％-13％的孕妇使用它们。在首次研究产前暴露于抗抑郁药后自闭症风险的研究中，我们发现与第一学期SSRI暴露有关的风险显着增加了3倍。随后在其他人群中进行的研究报告说，与子宫内的SSRI相关的ASD风险增加，尽管并非所有研究都发现了这种证据。这些集体发现的解释受到暴露和结果错误分类的限制，并因迹象而混淆，并且缺乏基本遗传易感性的整合。拟议的研究将通过利用种子研究中已经收集的数据和生物测量来克服这些局限性（探索早期发展的研究，www.cdc.gov/ncbddd/ ncbddd/autism/caddre.html），最大的，多层，基于人群的基于人群的基于人口的病例对照研究，是美国裔美国自动抗体的。我们将探讨产妇抗抑郁药，母体精神病史以及母亲和儿童遗传敏感性的主要和关节作用。我们寻求资金来生成全基因组SNP数据并对1608个种子母亲进行靶向基因分型，并支持对这些围产期环境，母体和儿童遗传的分析，以及ASD表型数据对1）检查围产期暴露于SSRI抗抑郁药对ASD风险的影响； 2）评估围产期SSRI暴露在母亲心理健康状况下的ASD风险中的作用； 3）检查围产期SSRI暴露以及儿童或母体基因型是否相互作用以影响ASD的风险。这项研究利用了已经由种子组装的大量数据，该数据提供了有关以前未测量的几个重要混杂因素，儿童表型的稳健和有效测量，对儿童全基因组SNP数据的稳健和有效测量的全面信息，以及孕产妇的遗传样本。由于种子数据收集着重于产后早期的观念，因此拟议的研究能够确定对SSRI暴露的最大脆弱性的发育时期，并在对围产期抑郁症的管理方面做出明智的决定方面遇到了最大的脆弱性。我们的研究可能会确定特定的母亲或儿童特征，表明对围产期SSRI暴露的敏感性增强，并阐明ASD发育中潜在的生物学机制。最后，由于早期生命暴露于抗抑郁药是常见和可修改的，因此拟议的研究有可能产生巨大的公共卫生影响，并指导针对ASD干预措施和疗法的研究。