Phenotypic profiling of ASD risk

ASD 风险的表型分析

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要自闭症谱系障碍（ASD）是一组神经精神病疾病，具有大量表型可变性。新兴的遗传分析明确证明了多种遗传因素 ASD风险，包括常见的多基因变化，从头差异，稀有遗传变化和拷贝数变化。为了了解这些不同的遗传因素如何影响ASD的风险，我们将评估完整在ASD病例和一般人群中，与与之相关的表型的光谱。在因此，我们将确定与ASD相关的遗传变异的类型，在表型方面看起来相似撞击并批判性地突出了不同的类型。表征ASD遗传风险之间的关系以及在ASD案件中的表型异质性，我们将利用13,000多个ASD案件的新资源丹麦国家精神病学注册表。我们将研究常见的多基因变异和稀有蛋白截断变化（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的亚组，使我们能够将ASD种群分层用于研究和最终治疗开发。使用来自两个队列研究的数据，我们还将表征ASD的遗传风险与行为和认知变异之间的关联在一般人群中。我们将对整个现象的关联研究费城的ASD和行为，认知和医学差异的常见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，蛋白质截断变化的速率与智力的一般人口关系：类似自闭症的特征，精神病般的特征和注意力缺陷障碍的特征。重要的遗传关联使用一般人群表型将有助于解释ASD风险变体，并告知我们了解临床阈值。本提案中描述的项目将大大改善了解ASD的异质性和遗传影响。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genetic contributions to autism spectrum disorder.

DOI：
10.1017/s0033291721000192
发表时间：
2021-10
期刊：
Psychological medicine
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

DOI：
10.1038/s41467-019-11039-6
发表时间：
2019-07-10
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Taylor, Jacob L.;Debost, Jean-Christophe P. G.;Robinson, Elise B.
通讯作者：
Robinson, Elise B.

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.

DOI：
10.1001/jamapediatrics.2022.2423
发表时间：
2022-09-01
期刊：
JAMA PEDIATRICS
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.

The female protective effect against autism spectrum disorder.

DOI：
10.1016/j.xgen.2022.100134
发表时间：
2022-06-08
期刊：
CELL GENOMICS
影响因子：
0
作者：
Wigdor, Emilie M.;Weiner, Daniel J.;Grovo, Jako;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;iPSYCH Consortium, David M.;Hougaard, David M.;Mortensen, Preben Bo;Daily, Mark J.;Talkowski, Michael E.;Sanders, Stephan J.;Bishop, Somer L.;Borglum, Anders D.;Robinson, Elise B.
通讯作者：
Robinson, Elise B.