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: 9121391
• 负责人: ABRAHAM REICHENBERG
• 金额: $ 98.99万
• 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 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9121391
• 关键词: Acute; Address; Adrenergic Agonists; Age; Antibiotics; Antiepileptic Agents; Archives; Australia; Autistic Disorder; Biological; Birth; Blood; California; Characteristics; Child; Chronic; Country; 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; Genomic DNA; Goals; Immigration; Individual; Israel; Link; Maternal Exposure; Mediating; Medical; Minority Groups; Modeling; Moods; Neonatal; Norway; Parental Ages; Parents; Pattern; Perinatal; Pharmaceutical Preparations; Pregnancy; Preventive Intervention; Preventive measure; 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.

描述（适用提供）：自闭症谱系障碍（ASD）中，对家族史，产前环境因素和潜在生物学机制（例如表观遗传变化）的病因学作用（ASD）的潜在生物学机制（ASD）的研究优先级是自闭症协调委员会在2011年自闭症委员会的研究优先级中确定的2011年自闭症谱系研究的策略性进展，对Acciqu的较大的数据是，在自闭症协调的委员会中，对自闭症谱系的研究优先确定。当前提案的目标是研究：（1）有关家庭和环境对ASD风险的贡献的基本争议； （2）跨几代人的风险传播； （3）研究ASD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。我们将建立在现有的研究网络的基础上，该网络利用了来自七个国家（美国 - 加利福尼亚，澳大利亚，丹麦，芬兰，以色列，以色列，瑞典）的基于人群的流行病学资源，其中包括个人级别的围产期医疗信息，人口统计信息和存档的生物素。研究数据将基于超过450万的出生（1998-2007），超过20,000例ASD和三代人的家庭联系（祖父母，父母/阿姨/叔叔，兄弟姐妹/堂兄）。使用这种无与伦比的资源，我们提出了四个综合目的的ASD风险中新型的多代元观点：AIM 1：模型家庭复发风险以及共同环境因素对ASD责任的贡献，使用扩展的家庭关系在先进的建模方法上构建高级建模方法。 AIM 2：确定ASD风险的父母组成部分是否在各个世代传播，特别是推动了父母/祖父母的年龄以及少数群体的父母/祖父母移民。目标3：检查具有潜在不良神经发育作用的药物的ASD风险：a）丙丙酸酯； b）2-肾上腺素能受体激动剂； c）选择性5-羟色胺再摄取抑制剂；或d）阻碍叶酸代谢的抗生素，即磺酰胺和甲氧苄啶。 AIM 4：使用从存档的新生儿血液点样品中提取的基因组DNA，检查先前目标中ASD儿童在产前暴露于母体药物的儿童的表观遗传变化。密涅瓦网络建立的资源将允许对家庭和环境因素对自闭症病因的贡献的贡献更加准确，精确，特别是如果在怀孕对ASD风险中规定的孕产妇慢性和急性状况的药物对ASD风险的贡献，以及表观遗传过程是否构成了与自闭症相关的生物学异常。从公共卫生的角度来看，这项研究将加速高风险群体的表征，可修改的危险因素以及自闭症病因中机制的阐明，这些机制最终可能有助于预防测量或干预措施和治疗。

项目成果

Elevated polygenic burden for autism is associated with differential DNA methylation at birth.

• DOI: 10.1186/s13073-018-0527-4
• 发表时间: 2018-03-28
• 期刊: Genome medicine
• 影响因子: 12.3
• 作者: Hannon E;Schendel D;Ladd-Acosta C;Grove J;iPSYCH-Broad ASD Group;Hansen CS;Andrews SV;Hougaard DM;Bresnahan M;Mors O;Hollegaard MV;Bækvad-Hansen M;Hornig M;Mortensen PB;Børglum AD;Werge T;Pedersen MG;Nordentoft M;Buxbaum J;Daniele Fallin M;Bybjerg-Grauholm J;Reichenberg A;Mill J
• 通讯作者: Mill J