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

表型谱基础遗传机制的全基因组剖析 自闭症 公认自闭症谱系障碍（ASD）的遗传病因是多因素的， 有多种因素的影响，包括新生突变，罕见的遗传变异， 多基因风险评分（PRS）和性别。遗传研究已确定> 100种ASD易感性 基因.然而，研究已经每次进行一种模式（GWAS，外显子组或外显子组）。 基因组）。因此，我们对遗传机制的理解存在重大差距 潜在的ASD例如，ASD的遗传性解释尚未得到系统的研究。 所有形式的罕见和常见变异风险，包括结构变异（SV） 和串联重复序列（TRs）。罕见和常见变异的非加性效应尚未得到证实。 系统地探索。此外，还不清楚在这些情况下， 基因和神经发育途径，影响ASD症状领域，并最终 都能诊断为自闭症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， 并且每个遗传因子具有不同的表型相关性。这些结果突出了知识 可以从ASD基因组和表型数据集的综合分析中获得 家庭随着样本量的大幅增加，我们有足够的能力来解决这些问题。 （1）完成基因组和表型数据的组装， 62，328个ASD家族（N = 204，428名受试者），并对这些家族进行全基因组分析。 由常见和罕见SNV、SV和TR解释的遗传力;（2）研究新的遗传学 可以解释遗传性缺失的机制，包括基因x基因和基因x性别， （3）分析分子和细胞途径对认知功能的遗传影响。 性状对不同频率范围内的变异类型进行综合分析可以设定一个新的标准 对于ASD的遗传性解释，可以产生线索的性质无法解释， 可以为基因对认知的影响提供机制基础

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