Uncovering the role of rare and low-frequency mutations in stroke using a polygenic risk score informed approach – implications for risk prediction

使用多基因风险评分知情方法揭示罕见和低频突变在中风中的作用 â 对风险预测的影响

• 批准号: 497256604
• 负责人: Professor Dr. Martin Dichgans
• 金额: --
• 依托单位: Institut für Schlaganfall- und Demenzforschung (ISD)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/497256604?language=en
• 关键词: Uncovering; role; rare; low; frequency

Stroke is the leading cause of long-term disability, the second most common cause of death, and a major cause of dementia worldwide and thus represents a major global health problem in need for novel therapeutic strategies. Genetics has started to transform vascular medicine by providing novel drug targets and insights into the etiology and pathophysiology of cardiovascular disease. Up to now, genome-wide association studies (GWAS) revealed 35 risk loci harboring common risk variants for stroke and stroke subtypes. However, these loci collectively only explain a small proportion of the phenotypic variance. Hence, there is a requirement for high-resolution fine-mapping studies of variants at and beyond previously established risk loci to identify high-impact risk variants for stroke and enable the functional exploration of such variants. The overarching goal of this proposal is to identify genes harboring rare and low-frequency variants with large effects on ischemic stroke risk. To this end, we have assembled a previously untapped sample of ~4,000 ischemic stroke cases with available GWAS data for whole exome sequencing (WES) and have access to ~6,000 WES controls. While many WES experiments suffer from low power for discovery, we will increase power through a polygenic risk score (PRS) informed approach. Specifically, sampling from an extreme phenotype distribution will increase power in our WES setting. We recently showed that individuals in the top 0.25% of a PRS distribution for ischemic stroke have a >3x increased risk for ischemic stroke. This enables us to calculate the PRS for each individual in our dataset, putting all individuals on a continuous risk spectrum. We will select cases at the lower half (2000 / 4000) of the polygenic risk distribution and controls at the upper half (3000 / 6000) of the polygenic risk distribution, thus enhancing the power to identify novel low-frequency and rare risk variants and genes. We will perform both single-variant and gene-based tests for enrichment of rare variants. To further increase power we will add external, publicly available controls to our analysis. Findings will be replicated in international large-scale sequencing studies (UK Biobank Exome Project, deCode Genetics, TOPMed) and integrated into a novel improved PRS for the prediction of ischemic stroke. Individual variants and genes will be selected for genome-editing in human induced pluripotent stem cells and functional exploration in relevant cellular models. The outputs of this project will define novel molecular targets and pathways, provide formidable starting points for functional studies, and facilitate the development of novel therapeutics for stroke as well as and improve risk prediction for stroke and cardiovascular disease based on polygenic scores.

中风是长期残疾的主要原因，是第二大最常见的死亡原因，也是全世界痴呆症的主要原因，因此是一个需要新的治疗策略的重大全球健康问题。遗传学已经开始通过提供新的药物靶点和对心血管疾病的病因和病理生理学的见解来改变血管医学。到目前为止，全基因组关联研究（GWAS）揭示了35个具有卒中和卒中亚型常见风险变异的风险位点。然而，这些基因座共同只能解释一小部分表型变异。因此，有必要对先前建立的风险位点及其以外的变异进行高分辨率精细测绘研究，以确定中风的高影响风险变异，并对这些变异进行功能探索。这一建议的总体目标是识别对缺血性卒中风险有重大影响的罕见和低频变异基因。为此，我们收集了以前未开发的约4000例缺血性卒中病例样本，其中包含可用的GWAS数据，用于全外显子组测序（WES），并获得了约6000例WES对照。虽然许多WES实验的发现能力较低，但我们将通过多基因风险评分（PRS）知情方法来提高能力。具体来说，从极端表型分布中取样将增加WES设置的功率。我们最近发现，PRS分布在缺血性中风前0.25%的个体患缺血性中风的风险增加了50倍。这使我们能够计算数据集中每个个体的PRS，将所有个体置于连续的风险谱上。我们将在多基因风险分布的下半部分（2000 / 4000）选择病例，在多基因风险分布的上半部分（3000 / 6000）选择对照，从而增强识别新的低频和罕见风险变异和基因的能力。我们将进行单变异和基于基因的检测，以丰富罕见的变异。为了进一步增强功能，我们将在分析中添加外部的、公开可用的控件。研究结果将在国际大规模测序研究（UK Biobank Exome Project, deCode Genetics, TOPMed）中得到重复，并整合到一种新的改进PRS中，用于预测缺血性卒中。将选择个体变异和基因对人类诱导多能干细胞进行基因组编辑，并在相关细胞模型中进行功能探索。该项目的成果将定义新的分子靶点和途径，为功能研究提供强大的起点，促进中风新疗法的发展，并改进基于多基因评分的中风和心血管疾病的风险预测。