Genome-wide Environment Interaction Study for Autism: The SEED study

自闭症全基因组环境相互作用研究：SEED 研究

• 批准号: 7845816
• 负责人: M Daniele Fallin
• 金额: $ 72.4万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7845816
• 关键词: 5 year old; Address; Alcohol consumption; Autistic Disorder; Candidate Disease Gene; Case-Control Studies; Categories; Centers for Disease Control and Prevention (U.S.); Child; Controlled Study; DNA; Data; Data Collection; Data Set; Detection; Development; Disease; Dose; Environment; Environmental Exposure; Face; Funding; Future; Gene Targeting; Genes; Genetic; Genome; Genotype; Grant; Heterogeneity; Human; Impairment; Infection; Infectious Pregnancy Complications; Interview; Investigation; Maternal Behavior; Methods; Paper; Parents; Participant; Perinatal; Pharmaceutical Preparations; Population; Pregnancy; Probability; Publishing; Questionnaires; Recruitment Activity; Reporting; Research; Research Priority; Risk; Sample Size; Sampling; Series; Smoke; Smoking; Specificity; Statistical Methods; Strategic Planning; Techniques; Testing; United States National Institutes of Health; Variant; Venous blood sampling; Work; Writing; autism spectrum disorder; base; case control; disorder risk; drinking; gene environment interaction; genetic association; genome wide association study; genome-wide; improved; in vivo; interest; neonatal exposure; novel; population based; prenatal exposure; public health relevance; response

DESCRIPTION (provided by applicant): Improving our understanding of gene-environment interaction (GxE) as an etiologic mechanism in autism has been identified as a research priority in the NIH Inter-Agency Autism Coordinating Committee's (IACC's) Strategic Plan for Autism Spectrum Disorders (ASD) Research as well as in the IOM's recent Report on Autism and the Environment. However, empirical investigations of GxE in autism remain scarce. Although several lines of evidence support its general plausibility, GxE research in autism faces several key obstacles: 1) lack of epidemiologic datasets uniting genetic and exposure data; 2) absence of mechanistic data/hypotheses on GxE in vivo to guide epidemiologic analyses (such data increases the prior probability that tested GxE associations are real); and 3) low statistical power for testing GxE using conventional methods. Here we propose a case-control analysis of GxE aimed at surmounting these obstacles. The Study to Explore Early Development (SEED) is a multisite ASD case-control investigation recruiting 900 3-5 year old children with ASDs, 900 typically developing controls, and 900 children with non-autism developmental impairments. Biosamples for DNA and exposure information across a wide range of hypotheses are available. SEED therefore brings together genetic and environmental data in a large epidemiologic sample. To surmount the other obstacles highlighted above, we propose extending the GWAS approach to consider GxE in what has been referred to as a gene-environment-wide interaction study (GEWIS). To do this we will complete GEWIS genotyping on the first 500 cases and 500 typically developing controls with data available during this 2-year grant timetable, develop summary exposure variables related to prenatal exposures, and use recently proposed novel statistical techniques to search for genes in the context of heterogeneity by environment. Our specific aims include: (1) identify SNPs whose effects on ASD may vary across exposure categories related to maternal behaviors (smoking and alcohol use during pregnancy), infection, and maternal medication use using the Illumina 1M-Duo SNP panel and two complementary analysis methods: a 2-df test for genetic association in the context of heterogeneity, an empirical Bayes approach to efficiently estimate GxE interaction effects by exploiting GxE independence in controls. (2) Integrate SNP findings from the above approaches, further characterize exposure interactions via dose-response and specificity analyses, and pursue replication analyses in other ASD data sets. This work will accelerate future efforts centered around gene-environment interaction both in our full set of SEED participants and in other data sets for autism. PUBLIC HEALTH RELEVANCE: We plan to carry out a multi-center case-control study of 500 cases and 500 controls from the SEED study to identify genes whose effects on ASD may vary across exposure categories related to pre-natal infection, maternal medication use, or smoking and drinking during pregnancy.

描述（由申请人提供）：提高我们对基因-环境相互作用（GxE）作为自闭症病因机制的理解已被NIH机构间自闭症协调委员会（IACC）自闭症谱系障碍（ASD）研究战略计划以及IOM最近的自闭症与环境报告确定为研究重点。然而，GxE在自闭症的实证研究仍然很少。虽然有几条证据支持其普遍的可验证性，但自闭症的GxE研究面临几个关键障碍：1）缺乏统一遗传和暴露数据的流行病学数据集; 2）缺乏体内GxE的机制数据/假设来指导流行病学分析（这些数据增加了测试的GxE关联是真实的的先验概率）; 3）使用传统方法测试GxE的统计功效较低。在这里，我们提出了一个病例对照分析的GxE，旨在克服这些障碍。探索早期发育研究（SEED）是一项多地点ASD病例对照研究，招募了900名3-5岁ASD儿童，900名典型发育对照儿童和900名非自闭症发育障碍儿童。可获得DNA生物样本和各种假设的接触信息。因此，SEED在一个大的流行病学样本中汇集了遗传和环境数据。为了克服上面强调的其他障碍，我们建议扩展GWAS方法，在被称为基因-环境-全相互作用研究（GEWIS）的研究中考虑GxE。要做到这一点，我们将完成GEWIS基因分型的第一个500例和500个典型的开发控制与数据在这2年的补助时间表，制定总结暴露变量相关的产前暴露，并使用最近提出的新的统计技术来搜索基因的异质性环境的背景下。我们的具体目标包括：（1）识别SNP，其对ASD的影响可能因与孕产妇行为相关的暴露类别而异使用Illumina 1 M-Duo SNP组和两种互补分析方法，对妊娠期间吸烟和饮酒、感染和母体药物使用进行分析：异质性背景下遗传关联的2-DF检验，一种经验贝叶斯方法，通过利用控制中的GxE独立性来有效估计GxE相互作用效应。(2)整合上述方法的SNP结果，通过剂量-反应和特异性分析进一步表征暴露相互作用，并在其他ASD数据集中进行复制分析。这项工作将加速未来围绕基因-环境相互作用的努力，无论是在我们的全套SEED参与者还是在其他自闭症数据集中。 公共卫生关系：我们计划对来自SEED研究的500例病例和500例对照进行多中心病例对照研究，以确定其对ASD的影响可能在与产前感染，母体药物使用或怀孕期间吸烟和饮酒相关的暴露类别中有所不同的基因。