Whole genome dissection of genetic mechanisms that underlie the phenotypic spectrum of autism

表型谱背后的遗传机制的全基因组解剖 自闭症 自闭症谱系障碍(ASD)的遗传病因是多因素的， 有多种因素的作用，包括从头突变，罕见的遗传变异， 多基因风险评分(PR)和性别。遗传学研究发现&gt；100自闭症易感性 基因。然而，每项研究都是一次进行一种模式(GWAS、EXOME或 基因组)。因此，我们对遗传机制的理解存在很大差距 潜在的ASD。例如，ASD的遗传性还没有得到系统的解释 具有各种形式的罕见和常见变异风险的特征，包括结构变异(SVS) 和串联重复序列(TRs)。稀有和常见变种的非相加效应还没有 系统地探索。此外，人们还不知道稀有和常见的变体是如何在 基因和神经发育途径，影响ASD症状领域并最终 会聚为ASD的诊断。我们实验室的最新研究(PMID：35654974,33442040) 已经表明多种因素在个体中共同作用，以确定ASD的风险， 而且每个遗传因素都有不同的表型相关。这些结果突出了知识 这可以从ASD的基因组和表型数据集的综合分析中获得 家人。随着样本数量的大幅增加，我们有足够的能力解决这些问题 以下目标中的问题(1)完成基因组和表型数据的组装 62,328个ASD家系(N=204,428名受试者)，并进行全基因组分析 遗传力由常见和罕见的SNV、SVS和TRs解释；(2)研究新的遗传 可以解释缺失遗传性的机制，包括基因x基因和基因x性别， 以及(3)剖析分子和细胞通路对认知的遗传效应。 特征。对一系列频率的变异类型的综合分析可能会设定一个新的标杆 对于ASD的遗传性解释，可以为不明原因的本质提供线索，以及 可以为基因对认知的影响提供机械基础的洞察

Whole genome dissection of genetic mechanisms that underlie the phenotypic spectrum of autism It is recognized that the genetic etiology of Autism Spectrum Disorder (ASD) is multifactorial, with contributions from multiple factors including de novo mutations, rare inherited variants, polygenic risk scores (PRS) and sex. Genetic studies have identified >100 ASD susceptibility genes. However, studies have each been carried out one modality at a time (GWAS, exome or genome). Consequently, there are major gaps in our understanding of the genetic mechanisms underlying ASD. For instance, the heritability of ASD explained has not been systematically characterized for all forms of rare and common variant risk, including structural variant (SVs) and tandem repeats (TRs). Non-additive effects of rare and common variants have not been systematically explored. Furthermore, it is not understood how rare and common variants, in genes and neurodevelopmental pathways, influence ASD symptom domains and ultimately converge to a diagnosis of ASD. Recent studies from our labs (PMID: 35654974, 33442040) have shown that multiple factors act in combination in the individual to determine risk for ASD, and each genetic factor has distinct phenotypic correlates. These results highlight knowledge that can be gained from an integrated analysis of genomic and phenotypic datasets in ASD families. With a vast increase in sample size, we have sufficient power to address these questions in the following aims (1) Complete assembly of genomic and phenotypic data on 62,328 ASD families (N = 204,428 subjects) and perform a whole genome analysis of the heritability explained by common and rare SNVs, SVs, and TRs; (2) Investigate novel genetic mechanisms that could explain missing heritability, including gene x gene and gene x sex, interactions; and (3) Dissect the genetic effects of molecular and cellular pathways on cognitive traits. An integrated analysis of variant types across a range of frequencies could set a new bar for the heritability of ASD explained, could yield clues to the nature of the unexplained, and could provide mechanistic basis insights into the effects of genes on cognition