Multigenerational FamIlial and Environmental Risk for Autism (MINERvA) Network

描述（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（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，但是，在大规模流行病学样本中获取相关数据的挑战阻碍了快速进展。目前的建议的目标是检查：（1）有关家庭和环境因素对ASD风险的影响的基本争议;（2）跨代风险的传递;（3）调查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上，利用来自七个国家（美国加利福尼亚州、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，包括个人水平的围产期医疗、人口统计学信息和存档的生物标本。研究数据将基于超过450万例出生（1998-2007年），超过20，000例ASD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/堂兄弟姐妹）。利用这一无与伦比的资源，我们提出了一个新的多代视角的ASD风险在四个综合目标：目标1：模型的家庭复发风险和共享的环境因素的贡献ASD责任，建立在先进的建模方法，使用扩展的家庭关系。目标二：确定ASD风险的父母组成部分是否跨代传递，特别是，提前父母/祖父母年龄和少数群体的父母/祖父母移民。目标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）丙戊酸盐; 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，磺胺和甲氧苄啶。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网络建立的资源将允许更准确和精确地确定家庭和环境因素对自闭症病因学的贡献，特别是如果怀孕期间为母亲慢性和急性疾病开具的药物会导致ASD风险，以及表观遗传过程是否是与自闭症相关的生物异常的基础。从公共卫生的角度来看，这项研究将加速高危人群的特征，可改变的风险因素和自闭症病因机制的阐明，最终可能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.