Autism Genetics, Phase II: Increasing Representation of Human Diversity

自闭症遗传学，第二阶段：增加人类多样性的代表性

• 批准号: 8386529
• 负责人: JOHN N. CONSTANTINO
• 金额: $ 300.59万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-25 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8386529
• 关键词: Admixture; Affect; African; African American; Alleles; Animals; Autistic Disorder; Biocompatible Materials; Bioinformatics; Biological; Brain; Cell Culture Techniques; Child; Childhood; Chromosome abnormality; Code; Communities; Complement; Confidential Information; Copy Number Polymorphism; Data; Databases; Development; Diagnosis; Dideoxy Chain Termination DNA Sequencing; Enrollment; Etiology; European; Event; Family; Family member; Frequencies; Functional disorder; Funding; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Predisposition to Disease; Genetic Research; Genetic Variation; Genotype; Goals; Haplotypes; Head circumference; Health; Health Services Accessibility; Human; Individual; Instruction; Internet; Investigation; Language; Language Delays; Maps; Measures; Methods; MicroRNAs; Mission; Modeling; Molecular; Molecular Profiling; Mutation; National Institute of Mental Health; Outcome; Parents; Pathogenicity; Pathway Analysis; Pathway interactions; Patient Self-Report; Patients; Phase; Phenotype; Play; Population; Population Control; Predisposition; Public Health; Publishing; RNA analysis; Recruitment Activity; Recurrence; Research; Research Design; Research Methodology; Research Personnel; Resolution; Resources; Role; SNP genotyping; Sample Size; Sampling; Sampling Studies; Sequence Analysis; Services; Severity of illness; Siblings; Site; Source; Stratification; Susceptibility Gene; Symptoms; Syndrome; Techniques; Testing; Time; Universities; Update; Validation; Variant; Washington; Work; abstracting; autism spectrum disorder; base; case control; clinical care; cohort; cost effective; data exchange; delay sex; density; design; endophenotype; exome sequencing; follow-up; gene discovery; genetic analysis; genetic resource; genetic risk factor; genome wide association study; genome-wide; health disparity; lymphoblast; meetings; member; neuropsychiatry; novel; proband; programs; public health relevance; repository; sex; social communication

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ ABSTRACT DESCRIPTION: See instructions. State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project (i.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe the rationale and techniques you will use to pursue these goals. In addition, in two or three sentences, describe in plain, lay language the relevance of this research to public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED. Autism Spectrum Disorder (ASD) is a common, often devastating neuropsychiatric condition with largely unknown pathophysiology. Although ASD has a multifactorial etiology, it encompasses a large genetic component. The investigators in this proposal aim to continue and enhance our collaborative effort that has produced significant advances in our understanding of ASD over the last four years and generated highly successful, open data and biomaterials resources for the research community, the NIMH Genetics Initiative and the Autism Genetic Resource Exchange (AGRE). Our Network has met or exceeded our original aims. We have built patient resources for research, identified rare and common ASD susceptibility alleles, defined models of ASD genetic susceptibility, provided evidence for convergent pathophysiology, and led development of animal and cell culture models. Here we propose to take a major new direction, filling a significant gap in ASD research, by recruiting underserved subjects of self-reported African ancestry (African-American; AA), an important population that has not previously been well-represented in ASD genetics research. Our Network involves six research sites and the AGRE DCC, collaborating in a systematic, comprehensive investigation of ASD genetics in order to identify rare mutations, chromosomal abnormalities, and common variation contributing to ASD susceptibility in the AA population. Specifically, we will enrich existing resources by recruiting at least 600 AA probands and additional family members. Our recruitment plan includes an embedded health disparities project that will evaluate access to care for AAs with ASD and clarify factors influencing participation of AA individuals in genetic research. We will employ novel methods to define the ancestral origin of specific chromosomal segments and ascertain the background on which susceptibility alleles occur. We will perform follow up GWA on ASD-related endophenotypes or co-variates, such as language delay, sex and head circumference. In parallel, we will conduct whole exome sequencing (WES) and analysis of copy number variation (CNV) using 2.5M SNP arrays yielding high resolution molecular karyotypes and providing a resource on genome-wide CNV and coding sequence variation (SNV) in ASD. Gene expression profiling and network analysis will be used to prioritize variants. Genetic risk factors identified in the mostly European samples will be tested for association in the AA sample to determine whether these cohorts share the same genetic risk factors, using a sample size providing power to replicate previous associations and to identify rare, recurrent CNV and SNV. The observation of new forms or different population frequencies of ASD-related variation in this sample as well as the sharing of most CNV and SNV with other cohorts are both outcomes that will have great significance for future studies and clinical care. As has been our practice, our Network will make all phenotypic and genotype data accessible via the internet on a rolling basis, further enhancing the value of this resource to the community.

描述(申请人提供)：项目总结/摘要描述：见说明书。说明申请的广泛、长期目标和具体目标，并提及项目与健康的相关性(即与机构使命的相关性)。简明扼要地描述实现这些目标的研究设计和方法。描述你将用来实现这些目标的基本原理和技术。此外，用两三句简单明了的话描述这项研究与公共卫生的相关性。如果申请得到资助，这一描述将成为公开信息。因此，不包括专有/机密信息。不要超过所提供的空间。自闭症谱系障碍(ASD)是一种常见的、往往具有破坏性的神经精神疾病，其病理生理机制基本上未知。虽然ASD的病因是多因素的，但它包含了很大的遗传成分。本提案中的研究人员旨在继续和加强我们的合作努力，在过去四年中，我们对ASD的理解取得了重大进展，并为研究界、NIMH遗传学倡议和自闭症遗传资源交换(AGRE)生成了非常成功的开放数据和生物材料资源。我们的网络已经达到或超过了我们最初的目标。我们建立了用于研究的患者资源，鉴定了罕见和常见的ASD易感基因，定义了ASD遗传易感性的模型，为趋同的病理生理学提供了证据，并领导了动物和细胞培养模型的发展。在这里，我们建议采取一个主要的新方向，通过招募自我报告的非洲血统(非洲裔美国人；AA)的服务不足的受试者来填补ASD研究中的一个重大空白，这是一个以前在ASD遗传学研究中没有得到很好代表的重要群体。我们的网络包括六个研究站点和AGRE DCC，合作对ASD遗传学进行系统、全面的研究，以确定导致AA人群ASD易感性的罕见突变、染色体异常和常见变异。具体地说，我们会增加现有资源，招募至少600名再生障碍症先驱和额外的家庭成员。我们的招募计划包括一个嵌入的健康差距项目，该项目将评估对患有自闭症的再生障碍性贫血的护理机会，并澄清影响再生障碍性贫血患者参与基因研究的因素。我们将使用新的方法来定义特定染色体片段的祖先起源，并确定易感等位基因发生的背景。我们将对ASD相关的内表型或协变量进行GWA随访，如语言延迟、性别和头围。同时，我们将使用2.5M个SNP阵列进行全外显子组测序(WES)和拷贝数变异(CNV)分析，产生高分辨率的分子核型，并提供全基因组CNV和ASD编码序列变异(SNV)的资源。基因表达谱分析和网络分析将被用来确定变异的优先顺序。在大多数欧洲样本中确定的遗传风险因素将在AA样本中进行相关性测试，以确定这些队列是否具有相同的遗传风险因素，使用提供复制先前关联的能力的样本大小，并识别罕见的、复发的CNV和SNV。在该样本中观察到ASD相关变异的新形式或不同人群频率，以及大多数CNV和SNV与其他队列共享，这两个结果都将对未来的研究和临床护理具有重要意义。按照我们的惯例，我们的网络将通过互联网滚动提供所有表型和基因数据，进一步提高这一资源对社区的价值。