Phenotypic profiling of ASD risk

项目摘要 自闭症谱系障碍（ASD）是一组具有大量表型异常的神经精神疾病， 可变性新兴的遗传分析已经明确表明，各种遗传因素造成了 ASD风险，包括常见的多基因变异、新发变异、罕见遗传变异和拷贝数 变化量为了了解这些不同的遗传因素如何影响ASD的风险，我们将评估完整的 在ASD病例和一般人群中，与它们相关的表型谱。在 这样做，我们将确定与ASD相关的遗传变异类型，这些遗传变异在表型方面看起来相似， 影响力，并且关键的是，突出不同的类型。描述ASD遗传风险与 和表型异质性的ASD病例，我们将利用一个新的资源超过13,000 ASD病例， 丹麦国家精神病登记处我们将研究常见的多基因变异和罕见的蛋白质 截短变异（点突变和CNV）与ASD病例中的表型差异有关。这些分析 将确定具有相似遗传病因和表型表现的病例亚组，使我们能够 对ASD人群进行分层以进行研究和最终治疗开发。使用两项队列研究的数据， 我们还将描述ASD的遗传风险与行为和认知变异之间的关系 在一般人群中。我们将进行一个全表型关联研究， 在费城，ASD的常见多基因风险以及行为、认知和医学变异 神经发育队列（PNC; n=7500）。在双胞胎早期发展研究中，我们将研究 一般人群中罕见的蛋白质截短变异率与以下各项之间的关系：智力， 自闭症样特征、精神病样特征和注意力缺陷障碍的特征。重要的遗传关联 与一般人群表型将有助于解释ASD风险变异，并告知我们 了解临床阈值。本提案中所述的项目将大大改善 了解ASD的异质性和遗传影响。

PROJECT SUMMARY Autism spectrum disorders (ASDs) are a group of neuropsychiatric conditions with a great deal of phenotypic variability. Emerging genetic analyses have unequivocally demonstrated that a variety of genetic factors create ASD risk, including common polygenic variation, de novo variation, rare inherited variation, and copy number variation. To understand how these diverse genetic factors influence risk for ASDs, we will evaluate the full spectrum of phenotypes with which they are associated, both in ASD cases and in the general population. In so doing, we will identify types of ASD-associated genetic variation that appear similar in terms of phenotypic impact and, critically, highlight types that diverge. To characterize the relationship between ASD genetic risk and phenotypic heterogeneity in ASD cases, we will leverage a new resource of over 13,000 ASD cases from the Danish national psychiatric registry. We will examine how common polygenic variation and rare protein truncating variation (point mutations and CNVs) relate to phenotypic differences in ASD cases. These analyses will identify subgroups of cases that share similar genetic etiology and phenotypic presentation, allowing us to stratify ASD populations for research and eventual treatment development. Using data from two cohort studies, we will also characterize the association between genetic risk for ASDs and behavioral and cognitive variation in the general population. We will conduct a phenome-wide association study of the relationship between common polygenic risk for ASDs and behavioral, cognitive, and medical variation in the Philadelphia Neurodevelopmental Cohort (PNC; n=7500). In the Twins Early Development Study, we will examine the general population relationship between rate of rare, protein truncating variation and each of: intelligence, autism-like traits, psychosis-like traits, and traits of attention deficit disorder. Significant genetic associations with general population phenotypes will facilitate interpretation of ASD risk variants, and inform our understanding of clinical thresholds. The projects described in this proposal will significantly improve understanding of ASDs heterogeneity and genetic influences.