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优先研究重点，但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风险的贡献的根本争议；(2)风险的世代传递；(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。我们将在现有研究网络的基础上，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)的已建立的基于人口的流行病学资源，包括个人层面的围产期医疗、人口信息和存档的生物标本。研究数据将基于超过450万名新生儿(1998-2007年)、20,000多例自闭症病例以及三代人(祖父母、父母/阿姨/叔叔、兄弟姐妹/堂兄弟姐妹)的家庭关系。利用这一无与伦比的资源，我们提出了一个新的跨四个综合目标的自闭症风险的多代视角：目标1：建立在使用扩展家庭关系的先进建模方法的基础上，模拟家族性复发风险和共同环境因素对自闭症责任的贡献。目的2：确定自闭症风险的父母部分是否会在几代人之间传播，特别是提高父母/祖父母年龄和少数群体的父母/祖父母移民。目的3：检查产前接触具有潜在神经发育不良影响的药物的自闭症风险：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，即磺胺类和甲氧嘧啶。目的：利用从存档的新生儿血斑样本中提取的基因组DNA，检测产前接触母体药物的自闭症儿童的表观遗传学变化。Minerva网络建立的资源将能够更准确和准确地确定家庭和环境因素对自闭症病因的贡献，特别是在怀孕期间为产妇开出的慢性和急性疾病药物是否会增加自闭症的风险，以及表观遗传过程是否导致与自闭症有关的生物异常。从公共卫生的角度来看，这项研究将加速确定高危人群、可改变的危险因素的特征，并阐明自闭症病因学的机制，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.