Sequencing Annotation and Functional Analysis in Risk of Intracerebral Hemorrhage

脑出血风险的测序注释和功能分析

基本信息

批准号：
10066375
负责人：
Christopher David Anderson
金额：
$ 65.29万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2018-01-15 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10066375
关键词：
13q34 1q22 Acute Animals Arteries Binding Sites Bioinformatics Biological Biological Assay Biology Brain hemorrhage Caring Catalogs Cell model Cellular Assay Cerebral hemisphere hemorrhage Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Code Collection Complex Data Deterioration Disease Distant Epidemiology Expression Library Foundations Functional disorder Funding Future Gait Gene Expression Regulation Genes Genetic Risk Genetic Transcription Genetic study Genome Genomic approach Genomics Genotype Impaired cognition Investments Ischemic Stroke Knowledge Link Maps Meta-Analysis Microvascular Dysfunction Morbidity - disease rate Mutagenesis National Heart, Lung, and Blood Institute National Human Genome Research Institute National Institute of Neurological Disorders and Stroke Nerve Pathologic Pathway interactions Phenotype Population Prevention strategy Process Promoter Regions Proteins Reporter Resolution Resources Risk Role Single Nucleotide Polymorphism Site Source Stroke Structure Testing Therapeutic Tissues Trans-Omics for Precision Medicine United States National Institutes of Health Untranslated RNA Variant bioinformatics pipeline bioinformatics tool case control causal variant cell type cost design disability effective therapy genetic analysis genetic association genetic risk factor genetic variant genome sequencing genome wide association study geriatric depression human disease hypertension control improved in silico innovation insertion/deletion mutation insight mortality novel novel strategies pleiotropism programs promoter protein structure risk variant screening sex targeted sequencing tool trait transcription factor translational approach translational genomics treatment strategy whole genome

项目摘要

Intracerebral hemorrhage (ICH) is the most deadly form of stroke, and those that survive carry a high burden of long-term disability. ICH is an acute manifestation of progressive small vessel disease (CSVD), a condition that collectively causes ICH and small vessel (SV) ischemic stroke, cognitive decline, late-life depression, and gait deterioration. Because we have found shared epidemiologic and genetic risk factors among ICH and other CSVD manifestations, understanding the biological foundations of ICH offers the opportunity to develop effective treatment and prevention strategies across CSVD. Through prior genome-wide association studies (GWAS), we have identified three promising gene-rich loci, 1q22, 13q34, and 16q24, carrying associations with both ICH and SV stroke. These loci are united by a common theme in which associated variants are located in regions enriched for non-coding regulatory roles, rather than protein-coding function. Identification of causal functional variants and their regulatory mechanisms must occur before this knowledge can be applied to improve stroke care. Our proposal is motivated by (A) well-powered GWAS of ICH and small vessel stroke as well as preliminary targeted sequencing data suggesting a prominent regulatory role for ICH-associated variants at these loci, (B) the availability of whole genome sequencing (WGS) data on large populations with ICH and ischemic stroke for well- powered association testing at these loci, and (C) accumulated expertise in translational genomic approaches that can link genetic variants to functional biological effects, bridging the gap between disease association results and biological consequence. This proposal serves our central hypothesis that exploring the functional impact of genetic associations in ICH will yield biological insights that will identify novel treatment targets and advance the search for therapeutic strategies with bedside applications. Our proposal, entitled “Sequencing Annotation and Functional Analysis of Risk in ICH”, or SAFARI-ICH, will leverage NIH-supported WGS efforts from NHLBI TOPMed and the NHGRI Centers for Common Disease Genomics to comprehensively determine 1) which particular sequence and structural variants at 1q22, 13q34, and 16q24 predispose to CSVD, 2) which of these associated variants, using annotation and cross-phenotype analyses, are most likely to reflect causal biology, and 3) what effect these putative causal variants have on gene transcription at these and other loci using relevant cellular models. Our approach leverages NIH investment in WGS at no cost to this proposal, allowing resources to be devoted to identifying the causal variants and their functional ramifications in ICH and SV stroke. Because our approach is designed to characterize variants with an impact on gene regulation at the cellular level, this proposal offers a unique opportunity to deliver insight into ICH pathobiology and highlight potential targets for future treatment of ICH and other adverse and highly prevalent CSVD manifestations.

脑出血 (ICH) 是最致命的中风形式，幸存者承受着沉重的负担长期残疾是进行性小血管病 (CSVD) 的一种急性表现，这种疾病会导致共同导致 ICH 和小血管 (SV) 缺血性中风、认知能力下降、晚年抑郁和步态因为我们发现 ICH 和其他脑小血管病有共同的流行病学和遗传危险因素。了解 ICH 的生物学基础为提高有效性提供了机会通过之前的全基因组关联研究 (GWAS)，我们发现了 CSVD 的治疗和预防策略。已经确定了三个有希望的富含基因位点：1q22、13q34 和 16q24，它们与 ICH 和 SV 中风。这些基因座由一个共同的主题联合起来，其中相关的变异位于丰富的区域。用于非编码调节作用，而不是蛋白质编码功能的因果功能变异的识别。在应用这些知识来改善中风护理之前，必须建立它们的调节机制。该提案的动机是 (A) ICH 和小血管行程的强大 GWAS 以及初步目标测序数据表明 ICH 相关变异在这些位点具有显着的调节作用，(B) 大量患有 ICH 和缺血性中风的人群的全基因组测序 (WGS) 数据的可用性在这些位点进行强力关联测试，并且 (C) 积累了转化基因组方法方面的专业知识可以将遗传变异与功能性生物效应联系起来，缩小疾病关联结果之间的差距和生物学后果。该提案服务于我们的中心假设，即探索 ICH 中遗传关联的功能影响将产生生物学见解，从而确定新的治疗靶点并推进治疗方法的探索我们的提案题为“测序注释和功能分析”。 ICH 中的风险”或 SAFARI-ICH 将利用 NIH 支持的 NHLBI TOPMed 和 NHGRI 的 WGS 工作常见疾病基因组学中心全面确定 1) 哪些特定序列和 1q22、13q34 和 16q24 的结构变异易患 CSVD，2) 这些相关变异中的哪一个，使用注释和交叉表型分析最有可能反映因果生物学，以及 3）这些影响是什么使用相关的细胞模型，推定的因果变异对这些和其他位点的基因转录有影响。该方法利用 NIH 对 WGS 的投资，无需为此提案付出任何成本，从而使资源能够投入到识别 ICH 和 SV 中风的因果变异及其功能后果，因为我们的方法是。该提案旨在表征在细胞水平上影响基因调控的变异，提供了深入了解 ICH 病理学并强调未来治疗的潜在目标的独特机会 ICH 和其他不良且高度流行的 CSVD 表现。