Sequencing Annotation and Functional Analysis in Risk of Intracerebral Hemorrhage

脑出血(ICH)是最致命的中风形式，那些幸存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，这种情况 共同导致脑出血和小血管(SV)缺血性中风、认知衰退、晚年抑郁和步态 恶化。因为我们在ICH和其他CSVD中发现了共同的流行病学和遗传风险因素 了解脑出血的生物学基础为开发有效的治疗方法提供了机会 整个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富含基因的基因座，1q22，13q34和16q24，与脑出血和脑出血有关 SV冲程。这些基因座由一个共同的主题联系在一起，在这个主题中，相关的变异位于富集区 对于非编码的调节作用，而不是蛋白质编码的功能。因果功能变异体的鉴定 在将这一知识应用于改善中风护理之前，它们的调节机制必须出现。我们的 建议的动机是(A)脑出血和小血管卒中的良好GWA以及初步目标 测序数据表明，这些基因座上的脑出血相关变异具有显著的调控作用，(B) 全基因组测序(WGS)数据在大量脑出血和缺血性卒中患者中的可用性 对这些基因座进行关联测试，以及(C)积累了翻译基因组方法方面的专业知识 这可以将遗传变异与功能生物学效应联系起来，弥合疾病关联结果之间的差距 以及生物后果。 这一建议符合我们的中心假设，即探索遗传关联在脑出血中的功能影响 将产生生物学见解，将确定新的治疗靶点，并推进治疗方法的探索 床边应用的策略。我们的提案，题为《序列注释和功能分析》 非物质文化遗产的风险“，或Safari-ICH，将利用NIH支持的来自NHLBI TOPMed和NHGRI的WGS努力 常见病基因组学中心将全面确定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 利用相关的细胞模型，推测因果变异对这些和其他基因座上的基因转录有影响。我们的 该方法利用了NIH对WGS的投资，而不会对该提案产生任何成本，从而使资源能够专门用于 确定脑出血和室性心动过速卒中的因果变异及其功能分支。因为我们的方法是 这项建议旨在描述在细胞水平上对基因调控产生影响的变异的特征，该提议提供了一种 提供独一无二的机会深入了解脑出血的病理生物学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.