Genetic Architecture of Autisms without Intellectual Disability

无智力障碍的自闭症的遗传结构

基本信息

批准号：
9809509
负责人：
MAJA BUCAN
金额：
$ 25.1万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9809509
关键词：
Address Affect Architecture Biological Biology Collaborations Collection Communities Complex Data Data Set Disease Dissection Equilibrium Etiology Family Family Research Foundations Frequencies Future Generations Genetic Genetic Diseases Genetic Medicine Genetic Research Genetic Structures Genetic Variation Genetic study Genetics and Medicine Genomics Genotype Heritability Inherited Intellectual functioning disability Lead Link Linkage Disequilibrium Neurodevelopmental Disorder Parents Partner in relationship Pennsylvania Phenotype Prevalence Principal Component Analysis Research Risk Role SNP array Societies Spouses Testing Universities Variant autism spectrum disorder base design disorder risk exome genetic analysis genetic architecture insight novel proband programs recruit risk variant social study population theories trait whole genome

项目摘要

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.

抽象的鉴于自闭症谱系障碍（ASD）的患病率日益增长，因此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的生物基础提供了宝贵的线索，这是高度遗传的。我们的目标是将目前正在宾夕法尼亚大学（Penn ASPE）自闭症卓越计划中正在进行的ASD基于家庭的遗传研究与Simons Simplex Collection（SSC）和SPARD遗传数据相结合，以调查有助于ASD风险的基本机制，特别是在没有智力残疾的ASD受试者（ASD W/O ID）及其家人中。新的数据集，例如SSC，Srark和我们自己的ASPE收集，将使我们能够遗传剖析多基因风险负担，并解决一个长期但未开发的假设，即分类交配可能会导致ASD责任。如果存在分类交配，则会影响ASD遗传学的广泛研究，并且在重新分析现有数据和未来研究的设计时将非常重要。有科学证据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。我们提出以下特定目的：目标1）在具有和没有ID的情况下分化ASD的基因组特征进行基因剖析。多基因风险评分以及已知与ASD相关的稀有或低频变体的遗传解剖将进一步与祖先和与特质相关的分类交配的分析相结合（AIM 2）。目标2）在ASD的概率父母中表征分类交配。我们假设在特征级别和基因组水平上的分类交配将在ASD w/o ID概率的父母中更为普遍。 PRS的相关性以及具有丰富表型和特征（在Spark，SSC和ASPE中）的家族中的分类程度将揭示对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的重点是新颖的，因为大多数先前的ASD遗传学发现都在招募具有ID的ASD检验的研究中。同样，ASD家族中基于血统和基于特质的分类交配的作用可能会揭示某些ASD家族中遗传结构的独特方面，从而有助于解释遗传发现。由于大多数标准的遗传分析方法都会假设随机交配，如果存在基于社会反应或其他与ASD相关的特征的分类交配，这对ASD遗传学的广泛研究具有影响。