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7/7-Collaborative genomic studies of Tourette Disorder

7/7-抽动秽语症的基因组合作研究

基本信息

批准号：
9925816
负责人：
BARBARA Jane COFFEY
金额：
$ 11.51万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-10 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9925816
关键词：
Affect Asians Attention deficit hyperactivity disorder Biocompatible Materials Biological Biology Brain C2 Domain Cell model Cells Child Clinical Clinical Data Code Communities Copy Number Polymorphism Data Data Analyses Development Dimensions Ensure Europe Family Family Study Foundations Funding Genes Genetic Genetic Risk Genome Genomics Genotype Gilles de la Tourette syndrome Goals Health Benefit Human In Vitro Individual International Investigation Journals Lead Link Methods Molecular Motor Tics National Institute of Mental Health Nature Neurites Neurons Obsessive-Compulsive Disorder Parents Pathologic Peptide Sequence Determination Phenotype Point Mutation Population Prevalence Process Public Health Publishing Recurrence Reporting Research Design Research Personnel Research Project Grants Rest Sampling Science Scientist Single Nucleotide Polymorphism Site Source South Korea Structure Supervision Testing Time Variant Vocal Tics Work autism spectrum disorder axonal pathfinding base biological systems clinical research site cohort comorbidity de novo mutation disorder risk effective therapy exome sequencing experience functional genomics gene discovery genomic data genomic locus human genomics in silico induced pluripotent stem cell insertion/deletion mutation multidimensional data neuropsychiatric disorder novel phenotypic data proband rare variant recruit risk variant stem cell technology success treatment strategy variant detection

项目摘要

PROJECT SUMMARY Despite strong evidence for a genetic contribution to Tourette disorder (TD), progress in the identification of specific risk genes has been, until quite recently, halting. However, building upon NIMH's support for our initial efforts to ascertain TD trios as well as our highly successful experience with genomic investigations of autism spectrum disorders (ASD), we have now demonstrated a clear path forward for reliable, systematic gene discovery in TD. Our TD work, recently published in the journal Neuron, identified one high confidence and three probable novel TD risk genes collectively pointing to neurite outgrowth and axon pathfinding as potential pathological mechanisms1. More importantly, however, our findings demonstrate, for the first time, a clear excess of de novo damaging point mutations in individuals with TD, with effect sizes that rival our recent findings in ASD. This discovery strongly suggests that sequencing of larger cohorts will reliably and rapidly lead to the identification of many more highly penetrant risk genes. Moreover, our recent work suggests an increased yield of highly penetrant damaging de novo variants in probands who are affected both with TD and obsessive compulsive disorder or attention deficit hyperactivity disorder, suggesting that our efforts may well also offer avenues to study the overlap in genetic risks for these often-comorbid conditions. Our current application proposes to: (1) expand our well characterized TD trio cohort by an additional 1,000 simplex trios and make the phenotypic data and biological materials widely and rapidly available to the broad scientific community; (2) accelerate gene discovery, via genotyping (for large de novo CNV identification) and whole exome sequencing (for de novo single nucleotide variant, insertion/deletion variant, and small CNV identification) of these additional TD trios, making these data rapidly and widely available as well; (3) extend the process of in silico and in vitro genomics investigations to elaborate the biology of TD with the long term goal of developing novel and more effective treatment strategies; and (4) begin biological characterization of TD variants using iPSC-derived neuronal cells. Given the potentially debilitating nature of TD alone, and a population prevalence of approximately 1 in 100 individuals, such advances would confer a significant public health benefit. The study design again rests heavily on the collaborative R01 mechanism that will bring together deep experience with the TD phenotype at multiple sites across the globe with scientists with a strong track record of success in rare variant human genomics and gene discovery. Specifically, the proposal includes seven primary US sites, four direct subcontracts (two USA sites for clinical supervision and data analysis and two foreign coordinating sites), and fourteen secondary clinical sites within Europe and South Korea.

项目总结