5/5 - Elucidating the Genetic Architecture of Autism by Deep Genomic Sequencing

5/5 - 通过深度基因组测序阐明自闭症的遗传结构

基本信息

批准号：
7844428
负责人：
JAMES S SUTCLIFFE
金额：
$ 247.88万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7844428
关键词：
Architecture Attention Autistic Disorder Biocompatible Materials Biological Biological Process Biology Candidate Disease Gene Cell Line Clinical Data Collaborations Collection Commit Communities DNA DNA Library DNA Sequence Data Data Analyses Diagnosis Disease Employee Strikes Epidemiology Etiology Evaluation Family Family member Frequencies Future Gene Family Genes Genetic Genetic Polymorphism Genetic Research Genome Genomics Genotype Goals Heritability Heterogeneity Individual Inherited Institutes Knowledge Large-Scale Sequencing Medical Genetics Medicine Methodology Modeling Molecular Mutation National Institute of Mental Health Neurologic Parents Pathogenesis Pathway interactions Patients Performance Phenotype Plant Roots Play Population Process Production Research Resources Role Sampling Solid Splice-Site Mutation Staging Technology Testing Translating Validation Variant Work abstracting autism spectrum disorder base college design exome experience follow-up gene discovery genome sequencing genome-wide innovation insight meetings novel prevent proband public health relevance repository research study response success therapeutic development tool

项目摘要

DESCRIPTION (provided by applicant): This collaborative application is submitted in response to RFA MH-09-171. The root causes of autism remain unknown, limiting efforts to understand disease heterogeneity, diagnose cases, and prevent and treat disease. Epidemiological findings have repeatedly and unequivocally determined that heritable variation in DNA plays a substantial role in the etiology of autism and autism spectrum disorders, yet traditional efforts to identify the genetic basis of this striking heritability have met with very limited success to date and have therefore provided limited insight into disease biology. We propose here an unprecedented partnership between expert large- scale sequencing centers (at the Baylor College of Medicine and the Broad Institute of MIT and Harvard) and a collaborative network of research labs focused on the genetics of autism (brought together by the Autism Genome Project and the Autism Consortium). These groups will work together to utilize dramatic new advances in DNA sequencing technology to reveal the genetic architecture of autism, first through a detailed examination of 1000 genes implicated by previous genetic studies or postulated to be functionally relevant, and later, as the technology continues to advance, through unbiased whole-genome sequencing. The goal is to conclusively identify which genes harbor individual or collections of rare DNA variants that predispose to autism, and thus translate the abstract heritability into solid biological clues to disease pathogenesis that can be studied molecularly and approached therapeutically. These efforts and their follow-up, which will be performed on thousands of autism families collected by the autism research groups and being provided with phenotype data to NIMH repositories, will form the cornerstone of autism genetic research going forward. PUBLIC HEALTH RELEVANCE: We propose a partnership between expert large-scale sequencing centers and a collaborative network of research labs focused on the genetics of autism to utilize novel high-throughput genome sequencing to discover specific genes underlying the significant heritability of autism. Without knowledge of the specific genes and DNA variants that predispose to disease, we lack the basic starting point with which we might understand the biological processes of disease. By combining large, well-characterized patient samples, experienced DNA sequencing teams and a collaborative, expert analysis and follow-up network, this study will provide novel insight into disease biology and will expose genes and pathways that constitute high priority targets for therapeutic development.

描述（由申请人提供）：此协作申请是根据RFA MH-09-171提交的。自闭症的根本原因仍然未知，限制了理解疾病异质性，诊断病例以及预防和治疗疾病的努力。流行病学的发现反复且明确地确定，DNA的可遗传差异在自闭症和自闭症谱系障碍的病因中起着重要作用，但是传统的努力确定这种引人注目的遗传力的遗传基础已经达到了迄今为止非常有限的成功，并因此为疾病生物学提供了有限的洞察力。我们在这里提出了专家大规模测序中心（位于贝勒医学院和麻省理工学院和哈佛大学广泛研究所）与研究实验室的协作网络（由自闭症基因组项目和自闭症联盟汇集在一起）之间的前所未有的伙伴关系。这些群体将共同利用DNA测序技术中的巨大新进步来揭示自闭症的遗传结构，首先是通过对先前遗传学研究所涉及的1000个基因或假定在功能上相关的1000个基因的详细检查，然后随着技术的继续，随着技术的继续发展，通过无偏见的全基因组测序来推进。目的是最终确定哪些基因具有易于自闭症的稀有DNA变异的个体或集合，从而将抽象的遗传力转化为固体生物学线索，为疾病发病机理，可以分子研究并接受治疗。这些努力及其后续行动将对自闭症研究小组收集的数千个自闭症家庭进行，并向NIMH存储库提供表型数据，这将构成自闭症基因研究的基石。公共卫生相关性：我们提出了专家大规模测序中心与关注自闭症遗传学的研究实验室的合作网络之间的合作伙伴关系，以利用新颖的高通量基因组测序，以发现自闭症的重要遗传性的基本基因。如果不了解易感疾病的特定基因和DNA变异，我们缺乏可能理解疾病生物学过程的基本起点。通过结合大型，良好的患者样本，经历了DNA测序团队以及协作，专家分析和随访网络，这项研究将提供对疾病生物学的新见解，并将揭示构成治疗发展的高优先级目标的基因和途径。