Genetic Architecture of Autisms without Intellectual Disability

摘要 鉴于自闭症谱系障碍（ASD）的日益普遍，迫切需要更好地了解其病因。通过关联和测序研究确定的遗传变异为ASD的生物学基础提供了有价值的线索，ASD具有高度遗传性。我们的目标是结合联合收割机ASD的遗传学研究，目前正在进行的自闭症谱系卓越计划在宾夕法尼亚大学（Penn ASPE）与Simons Simplex Collection（SSC）和SPARK遗传数据，调查的基本机制，有助于ASD的风险，特别是在ASD受试者无智力残疾（ASD w/o ID）和他们的家庭。新的数据集，如SSC，SRARK和我们自己的ASPE收集，将使我们能够从遗传学上剖析多基因风险负担，并解决一个长期存在但未探索的假设，即交配可能导致ASD的责任。如果存在选择性交配，这将影响广泛的ASD遗传学研究，并且在重新分析现有数据和设计未来研究时将是重要的。拥有科学证据来支持或反驳这些理论可能对ASD社区具有直接和直接的价值。我们提出了以下具体目标：目标1）从遗传学上剖析区分ASD伴和不伴ID的基因组特征。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学剖析将进一步与大量ASD家族的祖先和性状相关的重复交配分析相结合（目标2）。目的2）研究ASD先证者父母的择偶行为。我们假设，在性状水平和基因组水平上，选择性交配在ASD w/o ID先证者的父母中更为普遍。相关的PRS和家庭的表型和性状（在SPARK，SSC和ASPE）的丰富集合的排斥性交配的程度将揭示多基因结构的重要见解，并可能提供关键的机械线程。 该提案对ASD w/o ID的关注是新颖的，因为大多数先前的ASD遗传学发现都是在招募患有ID的ASD先证者的研究中发现的。同样，ASD家族中祖先和基于性状的替代性交配的作用可能揭示一些ASD家族中遗传结构的独特方面，从而有助于解释遗传学发现。由于大多数标准的遗传分析方法假设随机交配，如果存在基于社会反应或其他ASD相关性状的选择性交配，这对ASD遗传学的广泛研究具有影响。

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.