Phenotypic profiling of ASD risk

项目总结 自闭症谱系障碍(ASD)是一组具有大量表型的神经精神疾病 可变性。新出现的遗传分析明确地证明，各种遗传因素会导致 ASD风险，包括常见的多基因变异、从头变异、罕见的遗传变异和拷贝数 变种。为了了解这些不同的遗传因素如何影响自闭症的风险，我们将全面评估 在ASD病例和普通人群中，与它们相关的表型谱。在……里面 这样做，我们将确定在表型方面看起来相似的与ASD相关的遗传变异类型 影响，关键是突出不同的类型。描述ASD遗传风险之间的关系 ASD病例的表型异质性，我们将利用超过13,000例ASD病例的新资源 丹麦国家精神病学登记处。我们将研究常见的多基因变异和稀有蛋白质 截断变异(点突变和CNV)与ASD病例的表型差异有关。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，用于研究和最终的治疗开发。使用来自两个队列研究的数据， 我们还将描述自闭症的遗传风险与行为和认知变异之间的联系。 在普通人群中。我们将对两者之间的关系进行一项全现象的关联研究 费城自闭症与行为、认知和医学变异的共同多基因风险 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 稀有蛋白质截断变异率与以下各项之间的总体群体关系：智力， 孤独症样特征、精神病样特征和注意力缺陷障碍特征。显著的遗传关联 与普通人群的表型将有助于解释ASD风险变量，并告知我们 对临床阈值的理解。这份提案中描述的项目将显著改善 了解自闭症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.