Multigenerational FamIlial and Environmental Risk for Autism (MINERvA) Network

自闭症多代家庭和环境风险 (MINERvA) 网络

• 批准号: 8386420
• 负责人: ABRAHAM REICHENBERG
• 金额: $ 100万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-04 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8386420
• 关键词: Acute; Address; Adrenergic Agonists; Age; Antibiotics; Antiepileptic Agents; Archives; Australia; Autistic Disorder; Biological; Birth; Blood; California; Characteristics; Child; Chronic; Country; DNA; DNA Methylation; Data; Databases; Denmark; Diagnostic; Environment; Environmental Risk Factor; Epidemiologic Studies; Epidemiology; Epigenetic Process; Etiology; Exposure to; Extended Family; Family; Family Relationship; Family history of; Finland; Generations; Genomics; Goals; Immigration; Individual; Intervention; Israel; Link; Maternal Exposure; Measures; Mediating; Medical; Minority Groups; Modeling; Moods; Neonatal; Norway; Parental Ages; Parents; Pattern; Perinatal; Pharmaceutical Preparations; Pregnancy; Preventive; Public Health; Recurrence; Reporting; Research; Research Priority; Resources; Risk; Risk Factors; Role; Sampling; Selective Serotonin Reuptake Inhibitor; Siblings; Spottings; Strategic Planning; Sulfonamides; Sweden; Testing; Trimethoprim; autism spectrum disorder; base; disorder risk; folic acid metabolism; genome-wide; grandparent; high risk; modifiable risk; named group; novel; offspring; population based; postnatal; prenatal; prenatal exposure; transmission process; valproate

DESCRIPTION (provided by applicant): Better understanding of the etiologic roles of family history, prenatal environmental factors, and potential biologic mechanisms, such as epigenetic changes, in autism spectrum disorders (ASD) are research priorities identified in the Autism Coordinating Committee 2011 Strategic Plan for Autism Spectrum Disorder Research, but rapid progress is hampered by the challenges of acquiring relevant data in large epidemiologic samples. The goals of the current proposal are to examine: (1) fundamental controversies concerning familial and environmental contributions to risk for ASD; (2) transmission of risk across generations; (3) investigate pregnancy-related environmental factors in ASD, and (4) the potential role of epigenetic changes in those factors. We will build on an existing research network leveraging established population-based epidemiologic resources from seven countries (USA-California, Australia, Denmark, Finland, Israel, Norway, Sweden) that include individual-level perinatal medical, and demographic information and archived biospecimens. Study data will be based on over 4.5 million births (1998-2007), over 20,000 cases of ASD, and family linkages over three generations (grandparents, parents/aunts/uncles, siblings/cousins). Using this unparalleled resource, we propose a novel multigenerational perspective in ASD risk across four integrated aims: Aim 1: Model familial recurrence risk and the contributions of shared environmental factors to ASD liability, building on advanced modeling approaches using extended family relations. Aim 2: Determine if parental components of ASD risk are transmitted across generations, specifically, advancing parental/grandparental age and parental/grandparental immigration of minority groups. Aim 3: Examine ASD risk from prenatal exposure to medications with potential adverse neurodevelopmental effects: a) valproate; b) ¿2-adrenergic receptor agonists; c) selective serotonin reuptake inhibitors; or d) antibiotics that impede folate metabolism, i.e., sulfonamides and Trimethoprim. Aim 4: Using genomic DNA extracted from archived neonatal blood-spot samples, examine epigenetic changes in children with ASD exposed prenatally to the maternal medications in the previous aim. The resource established by the MINERvA Network will allow more accurate and precise determination of the contributions of familial and environmental factors to the etiology of autism, in particular if medications for maternal chronic and acute conditions prescribed in pregnancy contribute to ASD risk, and whether epigenetic processes underlie a biological abnormality linked to autism. From a public health perspective the study will accelerate the characterization of high risk groups, modifiable risk factors and the elucidation of mechanisms in autism etiology that could ultimately contribute to preventive measures or interventions and treatments. PUBLIC HEALTH RELEVANCE: Using existing population-based epidemiologic resources, our goal is to examine how familial and environmental risks for autism may track through families and across generations, from grandparents, parents and to their children. This approach will set a new bar for epidemiologic investigation and accelerate our understanding of the contribution of the environment to the etiology of autism.

描述（由申请人提供）：更好地了解自闭症谱系障碍 (ASD) 中家族史、产前环境因素和潜在生物学机制（例如表观遗传变化）的病因作用是自闭症协调委员会 2011 年战略计划中确定的研究重点自闭症谱系障碍研究，但快速进展受到获取大量流行病学样本相关数据的挑战的阻碍。当前提案的目标是检查：（1）基本原理。关于家庭和环境对自闭症谱系障碍风险影响的争议；(2) 代际传播风险；(3) 调查自闭症谱系障碍中与妊娠相关的环境因素，以及 (4) 表观遗传变化在这些因素中的潜在作用。现有的研究网络利用来自七个国家（美国-加利福尼亚、澳大利亚、丹麦、芬兰、以色列、挪威、瑞典）的已建立的基于人群的流行病学资源，其中包括个人水平的围产期医疗和人口统计信息以及存档的生物样本。数据将基于超过 450 万个新生儿（1998-2007 年）、超过 20,000 个自闭症谱系障碍病例以及三代人的家庭联系（祖父母、父母/阿姨/叔叔、兄弟姐妹/表兄弟姐妹）。利用这一无与伦比的资源，我们提出了一部小说。跨四个综合目标的 ASD 风险的多代视角： 目标 1：基于高级模型，建立家族复发风险模型以及共同环境因素对 ASD 责任的贡献目标 2：确定 ASD 风险的父母因素是否会代代相传，特别是父母/祖父母年龄的增长和少数群体的父母/祖父母移民。 目标 3：检查产前接触潜在药物的 ASD 风险。不良神经发育影响：a) 丙戊酸；b) ¿ 2-肾上腺素受体激动剂；c) 选择性血清素再摄取抑制剂；或 d) 阻碍叶酸代谢的抗生素，即磺胺类药物和甲氧苄啶 目标 4：使用从存档的新生儿血斑样本中提取的基因组 DNA，检查 ASD 儿童的表观遗传变化。 MINERvA 网络建立的资源将有助于更准确和精确地确定先前目标中产前接触过的母亲药物。家庭和环境因素对自闭症病因的影响，特别是孕期慢性和急性疾病的药物治疗是否会导致自闭症风险，以及表观遗传过程是否是与自闭症相关的生物学异常的基础。将加速高风险群体的特征、可改变的风险因素以及自闭症病因学机制的阐明，最终有助于预防措施或干预和治疗。 公共卫生相关性：利用现有的基于人群的流行病学资源，我们的目标是研究自闭症的家庭和环境风险如何在家庭和代际之间进行追踪，从祖父母、父母到他们的孩子。这种方法将为流行病学树立新的标准。调查并加速我们对环境对自闭症病因的贡献的理解。