The CHARGE Study Phase II: A Multifactorial Approach to Autism Etiology

CHARGE 研究第二阶段：自闭症病因学的多因素方法

• 批准号: 10343808
• 负责人: Deborah Hall Bennett
• 金额: $ 162万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10343808
• 关键词: Address; Affect; Air Pollutants; Air Pollution; Behavioral; Biochemical; Biological; Case-Control Studies; Chemicals; Child; Data; Databases; Developmental Delay Disorders; Diabetes Mellitus; Diagnosis; Discipline of obstetrics; Enrollment; Environment; Environmental Epidemiology; Environmental Exposure; Environmental Risk Factor; Epilepsy; Etiology; Exposure to; Family; Fever; Folic Acid; Fragile X Syndrome; Gene-Modified; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genome; Genomics; Haplotypes; Immune; Immunity; Individual; Industrial fungicide; Inherited; Intellectual functioning disability; Intervention; Ion Channel; Knowledge; Lead; Life; Link; Literature; Maternal Health; Measures; Medical; Metabolic; Methods; Mothers; Neurofibromatoses; Neurologic; Nutritional; Odds Ratio; Ontology; Organophosphates; Outcome; Paper; Parental Ages; Pathogenicity; Pathway interactions; Pesticides; Pharmacology; Placental Insufficiency; Population Control; Positioning Attribute; Pre-Eclampsia; Predisposition; Pregnancy Complications; Prevalence; Public Health; Reporting; Research; Research Project Grants; Risk; Risk Factors; Sample Size; Sampling; Science; Seminal; Severities; Solid; Specimen; Subgroup; Sum; Symptoms; Syndrome; Toxic effect; Variant; WNT Signaling Pathway; Work; associated symptom; autism spectrum disorder; autistic; base; blood glucose regulation; case control; disability; disorder risk; environmental chemical; exposure pathway; gene environment interaction; genetic variant; genome wide association study; genome-wide analysis; improved; interest; intrauterine environment; lens; maternal risk; mitochondrial dysfunction; neuroinflammation; non-genetic; nutrition; personalized intervention; pesticide exposure; phase 2 study; population based; postnatal; postnatal period; power analysis; precision medicine; prenatal; prenatal environmental exposure; prevent; proband; public health relevance; pyrethroid; rare variant; recruit; sex; synaptogenesis; transcriptomics

Abstract: This project builds upon 15 years of the CHARGE Study, which identified numerous environmental chemicals, nutritional factors, and maternal health conditions that are associated with altered risk for autism spectrum disorder (ASD). This work provided clues about potential pathogenic mechanisms and also produced the first evidence of gene-by-environment (GxE) interaction. In this renewal, CHARGE study will continue to enroll in order to achieve a solid sample size for statistically powerful analyses of both chemical mixtures and GxE interactions. Risk factors of concern are preeclampsia, air pollution, and pesticides, each having replicated evidence of association with ASD. This application departs from the focus on single exposures in isolate, and instead emphasizes multifactorial causation: the focus is on mixtures and interactions. In aim 1, state-of-the-art methods will be applied to understand the impact of exposure mixtures on risk for ASD and if feasible, to identify which component(s) of the mixture most contributes to the overall effects. Aims 2 and 3 address interactions between genes and non-genetic factors (GxE). Aim 2 is to identify common gene variants carried by the mother, which, in combination with early life environmental or medical factors, amplify the risk for ASD, more so than when either factor is assessed separately. The Precision Medicine Array from the Affymetrix platform will be used to generate over 800,000 SNPs that draw heavily from metabolic, pharmacologic, and immune-related regions of the genome. This project then pre-selects subsets of genes biologically relevant to the activity or mechanism of toxicity of each exposure, using annotated gene ontology databases. The resulting GxE analyses are expected to identify common variants that act synergistically with environmental insults, which may have been unremarkable in gene-only studies, or gene studies that emphasized rare variants. Aim 3 examines GxE interactions as in Aim 2, for the child's gene variants. To our knowledge, this will be the first study to evaluate GxE interaction utilizing omics-scale genetics data in a sufficiently powered analysis for detecting interactions. The proposed work moves autism etiologic research into a new direction that bridges separate silos of genetic and environmental research, creating a dynamic interdisciplinary and integrative science. Given shared biologic pathways between some genes and certain environmental exposures, the proposed project has potential to advance etiologic research towards targeted interventions that could reduce risk for ASD or ASD-associated disabilities and improve lives of affected individuals and their families. Additional significance may derive from identification of common variants that have hitherto eluded the traditional genetics enterprise. The long-term impacts may therefore be the emergence of a shift in etiologic research that unifies fragmented disciplinary approaches; major advancement in understanding common variants; and the possibility for public health precision interventions that expand notions of genetic susceptibility to encompass the biochemical milieu of the intrauterine and broader postnatal environment.

摘要： 该项目建立在15年的CHARGE研究的基础上，该研究确定了许多环境化学品， 与自闭症谱系风险改变相关的营养因素和孕产妇健康状况 自闭症（ASD）这项工作提供了关于潜在致病机制的线索，也产生了第一个 基因与环境（GxE）相互作用的证据。在本次更新中，CHARGE研究将继续入组 为了实现固体样本量，以便对化学混合物和GxE进行统计学上强大的分析， 交互.令人担忧的风险因素是先兆子痫，空气污染和杀虫剂，每一个都复制了 与ASD相关的证据。该应用程序不再关注孤立的单次暴露，并且 相反，强调多因素因果关系：重点是混合和相互作用。在目标1中， 方法将用于了解接触混合物对ASD风险的影响，如果可行， 确定混合物的哪些成分对整体效果贡献最大。目标2和3地址 基因与非遗传因素之间的相互作用（GxE）。目的2是确定携带的常见基因变异 由母亲造成，再加上早期的环境或医学因素，会放大ASD的风险， 这比单独评估任何一个因素都要重要。第一千一百零六章Affyphire的精准医疗阵列 该平台将用于生成超过80万个SNP，这些SNP大量来自代谢、药理学和生物学领域。 基因组的免疫相关区域。然后，该项目预先选择生物学相关的基因子集， 使用注释的基因本体数据库，研究每次暴露的活性或毒性机制。的 由此产生的GxE分析预计将确定与环境协同作用的常见变异， 侮辱，这可能在仅基因研究中并不显著，或者强调罕见的基因研究 变体。目标3检查GxE相互作用，如目标2所示，用于儿童的基因变异。据我们所知，这将 是第一项利用组学规模的遗传学数据在一个足够有力的研究中评估GxE相互作用的研究。 用于检测交互的分析。这项拟议中的工作将自闭症病因学研究推向了一个新的方向 它将遗传和环境研究的孤岛连接起来，创造了一个充满活力的跨学科， 综合科学鉴于某些基因和某些环境因素之间共享的生物学途径， 暴露，拟议的项目有可能推进病原学研究，以有针对性的干预措施 这可以降低ASD或ASD相关残疾的风险，并改善受影响的个人及其 家庭另外的重要性可能来自于迄今为止一直回避的常见变异的鉴定。 传统的基因工程因此，长期的影响可能是出现了病因学的转变， 统一分散的学科方法的研究;在理解共同 变异;以及扩大遗传概念的公共卫生精确干预的可能性 易感性包括子宫内和更广泛的产后环境的生化环境。