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

 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，今天约有68名儿童中有1名发生，比50年前的2,000名儿童中有1名增加。ASD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。在过去几十年中，在众多的环境暴露中，抗抑郁药物的使用率有所增加，目前美国有7%-13%的孕妇使用抗抑郁药物。在第一项研究中，检查产前暴露于抗抑郁药后自闭症的风险，我们发现与妊娠早期SSRI暴露相关的风险显著增加3倍。在其他人群中的后续研究报告了与宫内暴露于SSRIs相关的ASD风险增加，尽管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错误分类以及适应症混淆以及缺乏潜在遗传易感性整合的限制。拟议的研究将通过利用SEED研究（探索早期发育的研究，www.cdc.gov/ ncbddd/autism/caddre.html）中已经收集的数据和生物标本来克服这些限制，该研究是美国最大的、多地点的、基于人群的自闭症病例对照研究。我们将探讨母亲使用抗抑郁药、母亲精神疾病史以及母亲和儿童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，并对1608名SEED母亲进行靶向基因分型，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暴露在母体心理健康状况下ASD风险中的作用;以及3）检查围产期SSRI暴露和儿童或母亲基因型是否相互作用以影响ASD的风险。这项研究利用了SEED已经收集的大量数据，这些数据提供了关于先前未测量的几个重要混杂因素的全面信息，儿童表型的稳健和有效测量，儿童的全基因组SNP数据和母体遗传样本。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受到SSRI暴露影响的发育时间段，并帮助临床医生和母亲做出有关围产期抑郁症管理的明智决定。我们的研究可能会确定特定的母亲或儿童的配置文件，表明围产期SSRI暴露的易感性增加，并阐明ASD发展的潜在生物学机制。最后，由于早期接触抗抑郁药是常见的和可改变的，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干预和治疗的研究。

 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.