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: 9916804
• 负责人: DANIEL H GESCHWIND
• 金额: $ 275.01万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916804
• 关键词: Adult; African; African American; Age; Awareness; Behavior; Biocompatible Materials; Bioinformatics; Biological; Biological Markers; Brain; Calendar; Child; Childhood; Chromatin Structure; Classification; Clinical; Code; Cohort Studies; Communities; Consensus; Data; Development; Developmental Gene; Diagnosis; Diagnostic; Diagnostic Services; Dideoxy Chain Termination DNA Sequencing; Early Diagnosis; Ethnic Origin; Etiology; European; Event; Family; Family member; Frequencies; Functional disorder; Funding Agency; Future; Gene Expression Profiling; Gene Expression Regulation; Genes; Genetic; Genetic Diseases; Genetic Enhancement; Genetic Research; Genetic Risk; Genetic Variation; Genetic study; Genome; Goals; Health Services Accessibility; Heritability; Human; Improve Access; Individual; Interview; Knowledge; Maps; Measures; Methods; MicroRNAs; National Institute of Mental Health; Network-based; Nucleotides; Outcome; Parents; Pathogenicity; Pathway Analysis; Pathway interactions; Patient Self-Report; Patients; Phase; Phenotype; Play; Population; Population Heterogeneity; Predisposition; Publishing; Quantitative Trait Loci; RNA Splicing; RNA analysis; Recording of previous events; Recurrence; Research; Research Personnel; Research Subject Recruitments; Resolution; Resources; Risk; Risk Factors; Role; Sample Size; Sampling; Services; Severities; Siblings; Single Nucleotide Polymorphism; Site; Structure; Susceptibility Gene; Symptoms; Syndrome; Testing; Time; Underrepresented Populations; Untranslated RNA; Update; Variant; Visual; Work; admixture mapping; autism spectrum disorder; base; clinical care; cohort; cost; data exchange; data pipeline; de novo mutation; disorder risk; endophenotype; follow-up; gene discovery; genetic analysis; genetic resource; genetic risk factor; genetic testing; genetic variant; genome sequencing; genome-wide; health disparity; improved; innovation; insertion/deletion mutation; instrument; lymphoblast; member; neuropsychiatry; novel; open data; polygenic risk score; population stratification; proband; rare variant; recruit; repository; risk sharing; risk variant; sex; social; standard measure; transcriptome sequencing; transmission process; variant detection; visual tracking; whole genome

ABSTRACT Autism Spectrum Disorder (ASD) is a common neuropsychiatric condition with largely unknown pathophysiology, but with a substantial genetic contribution. Over the last 8.5 years, the investigators in this highly successful Network have contributed significant advances in our understanding of ASD and enhanced open data and biomaterials resources for the research community via the NIMH Genetics Initiative and the AGRE resource. In our last renewal, we took an important new direction to fill a critical gap in ASD research by recruiting subjects of self-reported African ancestry (African-American; AA), a group not previously represented in ASD genetics research. We have made substantial progress on our aims and the project is in a critical phase: by obtaining a larger cohort via continued recruiting, we will be well powered to conduct the first comprehensive assessment of the coding and non-coding genome via whole genome sequencing (WGS). This proposal involving six research sites and the AGRE DCC, will systematically investigate the genetics of ASD to identify rare single nucleotide variation (SNV), structural variation (SV), and common variation contributing to ASD susceptibility in this population. Specifically, we will enrich existing resources by recruiting at least 700 AA probands and additional family members to bring our cohort to 1300 AA probands. We have successfully conducted a health disparities project that that confirms significant diagnostic delays despite well-articulated parental concerns. In the next phase, we propose to improve early diagnosis, facilitated by the application of a novel heritable, quantitative biomarker, which we hypothesize will improve access to care. We will leverage acquisition of WGS of all family members via other funding sources, at no cost to this proposal, to characterize the contributions of genetic risk for ASD in AA individuals, including novel rare risk variants for ASD, which will also benefit genetic studies outside of this population by improving classification of rare variation in ASD in European (EU) and other ethnicities. We will use innovative methods to define local ancestry to ascertain the background on which susceptibility alleles occur. We will perform analysis of rare de novo and transmitted variants, and perform gene-based burden tests, which are well powered in this cohort. Gene expression profiling, eQTL, and network analysis will be used to prioritize variants. Genetic risk factors identified in cohorts studied to date (EU) will be tested for association in the AA sample to determine whether these cohorts share the same genetic risk factors, using a sample size that provides power to replicate previous associations and identify rare, recurrent CNV and SNV. We will perform follow up GWA on ASD-related endophenotypes or covariates, such as sex and social responsiveness. The observation of new forms or different population frequencies of ASD-related variation in this sample, or alternatively, the sharing of most variation with other cohorts are both outcomes that will have great significance for future studies and clinical care. As has been our practice, all data will be shared on a rolling basis, further enhancing this genetic resource for the community. .

摘要 自闭症谱系障碍（ASD）是一种常见的神经精神疾病， 病理生理学，但具有实质性的遗传贡献。在过去的8.5年里，调查人员在这个 非常成功的网络为我们对ASD的理解做出了重大贡献， 通过NIMH遗传学倡议和 AGRE资源。在我们上次的更新中，我们采取了一个重要的新方向，以填补ASD研究的关键空白， 招募自我报告的非洲血统（非裔美国人; AA）的受试者，这是一个以前没有代表的群体 自闭症谱系障碍遗传学研究。我们在实现目标方面取得了重大进展，该项目正处于关键时期。 阶段：通过持续招募获得更大的队列，我们将有能力进行第一次 通过全基因组测序（WGS）对编码和非编码基因组进行全面评估。这 一项涉及六个研究中心和AGRE DCC的提案将系统地研究ASD的遗传学， 鉴定罕见单核苷酸变异（SNV）、结构变异（SV）和促成 ASD在这一人群中的易感性具体而言，我们将通过招聘至少700名AA来充实现有资源 先证者和其他家庭成员，使我们的队列达到1300 AA先证者。我们已经成功 进行了一项健康差异项目，该项目证实了尽管明确阐述了 父母的担忧。在下一阶段，我们建议通过应用一种 新的可遗传的定量生物标志物，我们假设这将改善获得护理的机会。我们将利用 通过其他资金来源获得所有家庭成员的WGS，本提案不承担任何费用， AA个体中ASD遗传风险的贡献，包括ASD的新型罕见风险变体， 通过改善ASD中罕见变异的分类， 欧洲（欧盟）和其他种族。我们将使用创新的方法来确定当地的祖先，以确定 易感性等位基因发生的背景。我们将对罕见的新发病例进行分析， 变异，并进行基于基因的负担测试，这在该队列中具有良好的功效。基因表达 分析、eQTL和网络分析将用于区分变体的优先级。队列中确定的遗传风险因素 将在AA样本中检测迄今为止研究（EU）的相关性，以确定这些队列是否共享 相同的遗传风险因素，使用样本量，提供力量复制以前的关联， 鉴别罕见、复发CNV和SNV。我们将对ASD相关内在表型进行随访GWA， 协变量，如性别和社会反应。观察新的形式或不同的人口 在这个样本中ASD相关变异的频率，或者，与其他样本共享大多数变异， 队列研究是对未来研究和临床护理具有重要意义的两种结果。就像我们的 在实践中，所有数据将滚动共享，进一步加强社区的遗传资源。 .