Multigenerational FamIlial and Environmental Risk for Autism (MINERvA) Network

描述（由申请人提供）：更好地了解家族史、产前环境因素和潜在的生物学机制（如表观遗传变化）在自闭症谱系障碍（ASD）中的病因学作用，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，但由于在大流行病学样本中获取相关数据的挑战，阻碍了快速进展。当前提案的目标是检查：(1)关于家庭和环境对ASD风险贡献的基本争议；(2)风险的代际传递；(3)探讨与妊娠相关的环境因素在ASD中的作用；(4)表观遗传变化在这些因素中的潜在作用。我们将以现有的研究网络为基础，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）已建立的基于人群的流行病学资源，包括个人层面的围产期医学、人口统计信息和存档的生物标本。研究数据将基于450多万名新生儿（1998-2007年）、2万多例自闭症患者，以及三代人的家庭关系（祖父母、父母/阿姨/叔叔、兄弟姐妹/表亲）。利用这一无与伦比的资源，我们提出了一种新的多代视角来研究ASD风险，包括四个综合目标：目标1：基于使用扩展家庭关系的先进建模方法，建模家族复发风险和共享环境因素对ASD责任的贡献。目的2：确定ASD风险的父母成分是否代代相传，特别是父母/祖父母年龄的增加和少数群体的父母/祖父母移民。目的3：检查产前暴露于具有潜在不良神经发育影响的药物的ASD风险：a)丙戊酸酯；2-肾上腺素能受体激动剂；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。目的4：利用从存档的新生儿血斑样本中提取的基因组DNA，研究前一目的中暴露于母体药物的ASD儿童的表观遗传变化。MINERvA网络建立的资源将允许更准确和精确地确定家族和环境因素对自闭症病因的贡献，特别是如果怀孕期间开具的用于母亲慢性和急性疾病的药物会增加ASD风险，以及表观遗传过程是否构成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，这项研究将加速高风险群体的特征，可改变的风险因素和自闭症病因机制的阐明，最终有助于预防措施或干预和治疗。

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.