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: 9035436
• 负责人: JOHN N. CONSTANTINO
• 金额: $ 249.88万
• 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/9035436
• 关键词: Affect; African; African American; 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; 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 array; 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; admixture mapping; autism spectrum disorder; base; case control; clinical care; cohort; comparative genomic hybridization; cost effective; data exchange; delay sex; density; design; endophenotype; exome sequencing; follow-up; gene discovery; genetic analysis; genetic resource; genetic risk factor; genetic variant; genome wide association study; genome-wide; health disparity; lymphoblast; meetings; member; neuropsychiatry; novel; open data; proband; programs; rare variant; repository; sex; social communication; transcriptome sequencing

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（由申请人提供）：项目总结/摘要描述：见说明。说明申请的广泛、长期目标和具体目标，并参考项目的健康相关性（即，与原子能机构的使命相关）。简要描述研究设计和实现这些目标的方法。描述你将用来实现这些目标的原理和技术。此外，用两三句话，用通俗的语言描述这项研究与公共卫生的相关性。如果申请获得资助，此描述将成为公共信息。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，往往是毁灭性的神经精神疾病，在很大程度上未知的病理生理学。虽然ASD具有多因素病因学，但它包含很大的遗传成分。本提案中的研究人员旨在继续并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遗传学计划和自闭症遗传资源交换（AGRE）产生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。我们已经建立了用于研究的患者资源，确定了罕见和常见的ASD易感性等位基因，定义了ASD遗传易感性模型，为收敛性病理生理学提供了证据，并领导了动物和细胞培养模型的开发。在这里，我们建议采取一个重大的新方向，填补ASD研究的重大空白，通过招募自我报告的非洲血统（非裔美国人; AA），一个重要的人口，以前没有很好地代表在ASD遗传学研究服务不足的主题。我们的网络涉及六个研究中心和AGRE DCC，合作对ASD遗传学进行系统，全面的调查，以确定AA人群中导致ASD易感性的罕见突变，染色体异常和常见变异。具体而言，我们将通过招募至少600名AA先证者和额外的家庭成员来丰富现有资源。我们的招募计划包括一个嵌入式健康差异项目，该项目将评估患有ASD的AA的护理机会，并澄清影响AA个体参与遗传研究的因素。我们将采用新的方法来确定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相关内在表型或协变量（如语言延迟、性别和头围）进行随访GWA。同时，我们将进行全外显子组测序（WES）和拷贝数变异（CNV）分析，使用2.5M SNP阵列产生高分辨率的分子核型，并提供全基因组CNV和编码序列变异（SNV）的资源在ASD。基因表达谱分析和网络分析将用于区分变体的优先级。将检测在大多数欧洲样本中鉴定的遗传风险因素与AA样本的相关性，以确定这些队列是否具有相同的遗传风险因素，使用样本量提供复制先前相关性的能力，并鉴定罕见的复发性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，以及与其他队列共享大多数CNV和SNV，这两个结果对未来的研究和临床护理具有重要意义。正如我们的做法一样，我们的网络将通过互联网滚动访问所有表型和基因型数据，进一步提高这一资源对社区的价值。