Sequencing Annotation and Functional Analysis in Risk of Intracerebral Hemorrhage

脑出血（ICH）是最致命的中风形式，那些存活下来的人携带着很高的负担， 长期残疾。ICH是进行性小血管疾病（CSVD）的急性表现， 共同导致ICH和小血管（SV）缺血性卒中、认知能力下降、晚年抑郁和步态不稳 恶化因为我们发现ICH和其他CSVD之间有共同的流行病学和遗传危险因素， 通过了解非物质文化遗产的生物学基础， CSVD的治疗和预防策略通过先前的全基因组关联研究（GWAS），我们 已经确定了三个有希望的基因丰富的位点，1 q22，13 q34和16 q24，携带与ICH和 SV中风。这些基因座由一个共同的主题联合在一起，其中相关的变体位于富集的区域， 而不是蛋白质编码功能。因果功能变体的鉴定 并且它们的调节机制必须在这些知识可以应用于改善中风护理之前发生。我们 该提案的动机是（A）ICH和小血管卒中的有效GWAS以及初步目标 测序数据表明在这些基因座上ICH相关变体的显著调节作用，（B） 全基因组测序（WGS）数据在大规模ICH和缺血性卒中人群中的可用性， 在这些基因座上进行有力的关联测试，以及（C）积累了翻译基因组方法的专业知识 可以将遗传变异与功能性生物效应联系起来，弥合疾病关联结果之间的差距， 和生物学后果。 这一建议符合我们的中心假设，即探索ICH中遗传关联的功能影响 将产生生物学的见解，将确定新的治疗目标，并推进治疗的研究 战略与床边应用。我们的建议，题为“测序注释和功能分析的 ICH中的风险”，或SAFARI-ICH，将利用NIH支持的来自NHLBI TOPMed和NHGRI的WGS工作 常见疾病基因组中心全面确定1）哪个特定序列和 1 q22、13 q34和16 q24的结构变异易患CSVD，2）这些相关变异中，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 使用相关的细胞模型，推定的致病变体在这些和其他基因座上具有基因转录。我们 这种方法利用NIH在WGS中的投资，而不需要本提案的成本，允许将资源用于 确定ICH和SV卒中中的因果变异及其功能分支。因为我们的方法是 旨在表征在细胞水平上对基因调控有影响的变体，该提案提供了一个 提供深入了解ICH病理生物学的独特机会，并强调未来治疗的潜在靶点。 ICH和其他不良和高度流行的CSVD表现。

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.