Genetic Architecture of Autisms without Intellectual Disability

摘要 鉴于自闭症谱系障碍（ASD）的患病率不断上升，迫切需要更好地了解其病因。通过关联和测序研究鉴定出的遗传变异为自闭症谱系障碍的生物学基础提供了宝贵的线索，而自闭症谱系障碍具有高度遗传性。我们的目标是将宾夕法尼亚大学 (Penn ASPE) 自闭症谱系卓越计划目前正在进行的基于家庭的 ASD 遗传学研究与 Simons Simplex Collection (SSC) 和 SPARK 遗传数据相结合，以研究导致 ASD 风险的基本机制，特别是在无智力障碍的 ASD 受试者（ASD w/o ID）及其家庭中。新的数据集，例如 SSC、SRARK 和我们自己的 ASPE 数据集，将使我们能够从基因角度剖析多基因风险负担，并解决一个长期存在但未经探索的假设，即选型交配可能导致 ASD 责任。如果存在选型交配，这会影响自闭症谱系障碍遗传学的广泛研究，并且在重新分析现有数据和设计未来研究时需要考虑这一点。拥有支持或反驳这些理论的科学证据可能对自闭症谱系障碍社区具有直接价值。我们提出以下具体目标： 目标 1) 从基因角度剖析区分 ASD 与 ID 的基因组特征。对已知与 ASD 相关的多基因风险评分和罕见或低频变异的遗传剖析将进一步与大量 ASD 家族的血统和性状相关选型交配分析相结合（目标 2）。目标 2) 描述自闭症谱系障碍先证者父母的选型交配特征。我们假设，在性状水平和基因组水平上，选型交配在无 ID 先证者的自闭症谱系障碍的父母中将更为普遍。 PRS 与具有丰富表型和性状的家族（SPARK、SSC 和 ASPE）中选型交配程度的相关性将揭示对多基因结构的重要见解，并可能提供关键的机制线索。 这项提案的重点是无智力障碍的自闭症谱系障碍（ASD），这是新颖的，因为之前大多数自闭症谱系障碍遗传学发现都是在招募患有智力障碍的自闭症谱系障碍先证者的研究中进行的。同样，自闭症谱系障碍家族中血统和基于性状的选型交配的作用可能揭示一些自闭症谱系障碍家族遗传结构的独特方面，从而有助于解释遗传发现。由于大多数标准遗传分析方法都假设随机交配，如果存在基于社会反应或其他 ASD 相关特征的选型交配，这将对 ASD 遗传学的广泛研究产生影响。

ABSTRACT Given the growing prevalence of autism spectrum disorder (ASD), there is an urgent need to better understand its etiology. Genetic variation identified through association and sequencing studies has provided valuable clues about the biological underpinnings of ASD, which is highly heritable. Our objective is to combine family-based genetic studies of ASD currently ongoing at the Autism Spectrum Program of Excellence at the University of Pennsylvania (Penn ASPE) with the Simons Simplex Collection (SSC) and SPARK genetic data to investigate fundamental mechanisms contributing to ASD risk, specifically in ASD subjects without intellectual disability (ASD w/o ID) and their families. New datasets, such as SSC, SRARK and our own ASPE collection, will allow us to genetically dissect polygenic risk burden and address a longstanding but unexplored hypothesis that assortative mating may contribute to ASD liability. If assortative mating is present, this affects a broad range of studies of genetics of ASD and will be important to consider in re-analysis of existing data and design of future studies. Having scientific evidence to support or refute these theories may be of immediate and direct value to the ASD community. We propose the following Specific Aims: Aim 1) To genetically dissect genomic features that differentiate ASD with and without ID. Genetic dissection of polygenic risk scores and rare or low frequency variants known to be associated with ASD will be further combined with the analysis of ancestry and trait-related assortative mating across a large number of ASD families (Aim 2). Aim 2) To characterize assortative mating in parents of probands with ASD. We hypothesize that assortative mating, at a trait-level and a genomic level, will be more prevalent in parents of ASD w/o ID probands. Correlation of the PRS and the degree of assortative mating in families with a rich collection of phenotypes and traits (in SPARK, SSC and ASPE) will reveal important insights into polygenic architecture and may provide critical mechanistic threads. The focus of this proposal on ASD w/o ID is novel because most previous ASD genetics findings have been in studies that recruited ASD probands with ID. Similarly, the role of ancestry and trait- based assortative mating in ASD families may reveal unique aspects of genetic architecture in some ASD families and thereby facilitate interpretation genetic findings. As most standard genetic analysis approaches assume random mating, if assortative mating on the basis of social responsiveness or other ASD-related traits is present, this has implications for a wide range of studies of ASD genetics.