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（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 年自闭症谱系障碍研究战略计划中确定的研究重点，但由于在大量流行病学样本中获取相关数据的挑战，快速进展受到阻碍。当前提案的目标是审查：(1) 关于家庭和环境对 ASD 风险影响的基本争议； (2) 风险代际传递； (3) 研究 ASD 中与妊娠相关的环境因素，(4) 表观遗传变化在这些因素中的潜在作用。我们将建立一个现有的研究网络，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。研究数据将基于超过 450 万新生儿（1998-2007 年）、超过 20,000 个自闭症谱系障碍病例以及三代以上的家庭联系（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，我们提出了一个关于 ASD 风险的新颖的多代视角，涵盖四个综合目标： 目标 1：建立家庭复发风险模型以及共同环境因素对 ASD 责任的贡献，建立在使用大家庭关系的高级建模方法的基础上。目标 2：确定 ASD 风险的父母因素是否会跨代传播，特别是父母/祖父母年龄的增长以及少数群体父母/祖父母的移民。目标 3：检查产前接触具有潜在不良神经发育影响的药物导致的自闭症谱系障碍 (ASD) 风险：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； 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，检查在前一目标中产前暴露于母体药物的 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准确地确定家庭和环境因素对自闭症病因的影响，特别是孕期针对孕产妇慢性和急性疾病的药物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。从公共卫生的角度来看，这项研究将加速对高风险人群、可改变风险因素的描述，并阐明自闭症病因学机制，最终有助于预防措施或干预和治疗。

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