Autistic Traits: Life Course & Genetic Structure

描述（由申请人提供）：这是一项持续5年的竞争性延续的兄弟姐妹对自闭症社交障碍纵向（R 01）研究的申请。鉴于最近关于自闭症遗传和神经生物学结构的研究结果，很明显，对自闭症表型的遗传定量成分进行更精确的表征可能会加速发现自闭症的特定遗传和神经生物学原因。这项研究将涉及5576名受试者的定量表型（来自1295个临床确定的患有和不患有自闭症谱系障碍（ASD）的儿童家庭）。它将包括：评估父母和受影响的个人在扩展的谱系;检查数量自闭症性状在家庭中的分布模式是否作为性别，种族，单纯与多重与“复杂”自闭症或其他表型协变量的函数而变化;对现有的纵向研究对象进行长期随访，以更好地阐明自闭症社会障碍随时间的发展过程;以及检查自闭症患者的数量特征。 新的定量内表型（运动、躯体感觉和电生理）的同胞对，可能与自闭症社交障碍的严重程度和自闭症的核心遗传和神经生物学决定因素有关。在这个应用程序中，我们试图响应的问题，以前的自闭症的家族遗传学研究往往代表性不足的少数民族和弱势群体，对他们来说，特定的责任自闭症（如果存在）将被忽略在现有的研究和数据集。除了增强这一大型临床确定的兄弟姐妹样本的表型特征外，还将通过两项正在进行的自闭症国家连锁研究（自闭症遗传资源交换和Simons Simplex Collection）中的任何一项对475个家庭进行基因分型（父母和兄弟姐妹集）。除了对自闭症的遗传学和神经生物学的影响外，这项研究的发现还将增强测量治疗微妙效果的方法，将确定干预措施可能对社会发展产生特殊影响的生命周期，并将阐明各种非ASD儿童精神疾病引起的功能障碍的方式，包括ADHD可以加剧时，叠加（因为是常见的）， 亚临床自闭症特征的共同出现。公共卫生相关性：自闭症和相关疾病影响美国每150名儿童中就有1名，并导致终身严重的社会障碍。这项研究探讨了自闭症的社会障碍如何改变的过程中， 儿童时期，它们如何在几代人之间传播，以及它们破坏了哪些正常的发育过程。这项研究的结果将有助于寻找导致自闭症的基因和神经异常，将加强测量干预措施的微妙但重要影响的方法，并将确定干预措施可能对受影响儿童的社会发展产生最大影响的生命周期。

DESCRIPTION (provided by applicant): This is an application for a 5-year competing continuation of an ongoing longitudinal (R01) study of autistic social impairment in sibling pairs. Given recent findings regarding the genetic and neurobiologic architecture of autism, it has become clear that a more precise characterization of heritable quantitative components of the autism phenome might accelerate the discovery of specific genetic and neurobiologic causes of autism. This study will involve quantitative phenotyping of 5576 subjects (from 1295 clinically ascertained families of children with and without autism spectrum disorders (ASD). It will include: assessment of parents and affected individuals in extended pedigrees; examination of whether patterns of distribution of quantitative autistic traits in families vary as a function of gender, ethnicity, simplex versus multiplex versus "complex" autism, or other phenotypic covariates; longer-term follow-up of existing longitudinal study subjects to better elucidate the developmental course of autistic social impairment over time; and examination among sib-pairs of novel quantitative endophenotypes (motor, somatosensory, and electrophysiologic) that may relate both to severity of autistic social impairment and to core genetic and neurobiologic determinants of autism. In this application, we have attempted to be responsive to the problem that previous family-genetic studies of autism have often under-represented minority and disadvantaged populations, for whom specific liabilities to autism (if present) would be overlooked in existing studies and data sets. In addition to enhanced phenotypic characterization of this large clinically-ascertained sibling sample, 475 of the families will be genotyped (parents and sibling sets) by either of two ongoing national linkage studies of autism (the Autism Genetic Resource Exchange and the Simons Simplex Collection). In addition to implications for the genetics and neurobiology of autism, the findings from the study will enhance methods for measuring subtle effects of treatment, will identify intervals in the lifespan when interventions might have particular influence on social development, and will elucidate the manner in which functional disability incurred by a wide range of non-ASD child psychiatric conditions, including ADHD can be exacerbated when superimposed (as is common) by the co-occurrence of sub clinical autistic traits. PUBLIC HEALTH RELEVANCE: Autism and related disorders affect 1 out of every 150 children in the US and result in profound social impairment throughout life. This study examines how autistic social impairments change over the course of childhood, how they are transmitted across generations, and which normal developmental processes they disrupt. The results of the study will aid in the search for the genes and neural abnormalities that cause autism, will enhance methods for measuring subtle but important effects of intervention, and will identify intervals in the lifespan when interventions might have their greatest impact on social development in affected children.