Genetic Architecture of Autisms without Intellectual Disability

摘要 鉴于自闭症谱系障碍(ASD)的发病率越来越高，迫切需要更好地了解其病因。通过关联和测序研究发现的遗传变异为ASD的生物学基础提供了有价值的线索，ASD具有高度的遗传性。我们的目标是将目前在宾夕法尼亚大学(Penn Aspe)自闭症谱系卓越计划(Aspe)进行的基于家庭的自闭症遗传学研究与Simons Simplex Collection(SSC)和Spark遗传学数据相结合，以研究导致自闭症风险的基本机制，特别是在无智力残疾的自闭症受试者(ASD w/o ID)及其家人中。新的数据集，如SSC、SRARK和我们自己的ASPE集合，将使我们能够从基因上剖析多基因风险负担，并解决长期存在但尚未探索的假设，即分类交配可能导致ASD易感性。如果存在分类交配，这将影响对ASD遗传学的广泛研究，在重新分析现有数据和设计未来研究时将是重要的。拥有支持或驳斥这些理论的科学证据可能对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)从基因上剖析区分有无ID的ASD的基因组特征。对已知与ASD相关的多基因风险分数和罕见或低频变异的遗传解剖将进一步与大量ASD家系的祖先和特征相关的分类交配的分析相结合(目标2)。目的2)研究自闭症先证者父母的配型交配特征。我们假设，在性状水平和基因组水平上，分类交配在无ID先证者的自闭症患者的父母中更为普遍。在具有丰富表型和性状(Spark、SSC和Aspe)的家系中，PR与分类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。 这一建议的重点在于ASD w/o ID，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。类似地，祖先和基于特征的配对在ASD家族中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自闭症相关特征的分类交配，这对自闭症遗传学的广泛研究具有意义。

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.