Phenotypic profiling of ASD risk

ASD 风险的表型分析

• 批准号: 10202433
• 负责人: Elise B Robinson
• 金额: $ 50.52万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-05 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202433
• 关键词: Attention Deficit Disorder; Attention deficit hyperactivity disorder; Behavioral; Clinical; Cognitive; Cohort Studies; Congenital Abnormality; Copy Number Polymorphism; Data; Development; Epilepsy; General Population; Genetic; Genetic Heterogeneity; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Grant; Heterogeneity; Impairment; Individual; Inherited; Intellectual functioning disability; Intelligence; Link; Medical; Neurologic; Outcome; Phenotype; Philadelphia; Point Mutation; Population; Population Research; Proteins; Psychoses; Recording of previous events; Registries; Resources; Risk; Sampling Studies; Seizures; Subgroup; Twin Multiple Birth; Variant; Work; autism spectrum disorder; behavioral phenotyping; cohort; database of Genotypes and Phenotypes; de novo mutation; disorder risk; exome; exome sequencing; genetic analysis; genetic architecture; genetic association; genome wide association study; improved; insight; neuropsychiatry; novel; patient stratification; phenome; rare variant; risk variant; social; therapy development; trait

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.

项目概要 自闭症谱系障碍 (ASD) 是一组具有多种表型的神经精神疾病 可变性。新兴的遗传分析明确表明，多种遗传因素会产生 ASD 风险，包括常见的多基因变异、新发变异、罕见的遗传变异和拷贝数 变化。为了了解这些不同的遗传因素如何影响自闭症谱系障碍的风险，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，我们将识别出在表型方面相似的 ASD 相关遗传变异类型 影响，并且重要的是，突出不同的类型。描述 ASD 遗传风险之间的关系 以及 ASD 病例的表型异质性，我们将利用来自 13,000 多个 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 截短变异（点突变和 CNV）与 ASD 病例的表型差异有关。这些分析 将识别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， 我们还将描述自闭症谱系障碍的遗传风险与行为和认知变异之间的关联 在一般人群中。我们将对两者之间的关系进行全表组关联研究 费城常见的自闭症谱系障碍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，我们将检查 稀有蛋白质截短变异率与以下各项之间的总体人口关系：智力、 自闭症样特征、精神病样特征和注意力缺陷障碍特征。显着的遗传关联 与一般人群表型的比较将有助于解释 ASD 风险变异，并告知我们 了解临床阈值。本提案中描述的项目将显着改善 了解自闭症谱系障碍的异质性和遗传影响。

项目成果

Genetic contributions to autism spectrum disorder.

自闭症谱系障碍的遗传因素。

• 发表时间: 2021
• 影响因子: 6.9
• 作者: Havdahl, A;Niarchou, M;Starnawska, A;Uddin, M;van der Merwe, C;Warrier, V
• 通讯作者: Warrier, V

Polygenic risk for schizophrenia and measured domains of cognition in individuals with psychosis and controls.

精神分裂症的多基因风险以及精神病患者和对照组的认知领域的测量。

• 发表时间: 2018
• 影响因子: 6.8
• 作者: Shafee, Rebecca;Nanda, Pranav;Padmanabhan, Jaya L;Tandon, Neeraj;Alliey;Kalapurakkel, Sreeja;Weiner, Daniel J;Gur, Raquel E;Keefe, Richard S E;Hill, Scot K;Bishop, Jeffrey R;Clementz, Brett A;Tamminga, Carol A;Gershon, Elliot S
• 通讯作者: Gershon, Elliot S

The female protective effect against autism spectrum disorder.

女性对自闭症谱系障碍的保护作用。

• 发表时间: 2022-06-08
• 作者: Wigdor, Emilie M;Weiner, Daniel J;Grove, Jakob;Fu, Jack M;Thompson, Wesley K;Carey, Caitlin E;Baya, Nikolas;van der Merwe, Celia;Walters, Raymond K;Satterstrom, F Kyle;Palmer, Duncan S;Rosengren, Anders;Bybjerg;iPSYCH Consorti
• 通讯作者: iPSYCH Consorti

Paternal-age-related de novo mutations and risk for five disorders.

与父亲年龄相关的新生突变和五种疾病的风险。

• 发表时间: 2019
• 影响因子: 16.6
• 作者: Taylor, Jacob L;Debost, Jean;Morton, Sarah U;Wigdor, Emilie M;Heyne, Henrike O;Lal, Dennis;Howrigan, Daniel P;Bloemendal, Ale;Larsen, Janne T;Kosmicki, Jack A;Weiner, Daniel J;Homsy, Jason;Seidman, Jonathan G;Seidman, Christin
• 通讯作者: Seidman, Christin

Developmental Variability in Autism Across 17 000 Autistic Individuals and 4000 Siblings Without an Autism Diagnosis: Comparisons by Cohort, Intellectual Disability, Genetic Etiology, and Age at Diagnosis.

17-000 名自闭症患者和 4000 名没有自闭症诊断的兄弟姐妹的自闭症发育变异性：按队列、智力障碍、遗传病因和诊断年龄进行比较。

• 发表时间: 2022-09-01
• 影响因子: 26.1
• 作者: Kuo, Susan S;van der Merwe, Celia;Fu, Jack M;Carey, Caitlin E;Talkowski, Michael E;Bishop, Somer L;Robinson, Elise B
• 通讯作者: Robinson, Elise B