脑卒中遗传学有助于药物发现和跨血统风险预测
Aniket Mishra1, Rainer Malik2, Tsuyoshi Hachiya3
1Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France.
Nature
|September 30, 2022
概括
这项研究在不同祖先中发现了89个新的脑卒中风险基因位点,改善了对脑卒中原因的理解,并为所有人群提供了更好的遗传风险预测工具.
科学领域:
- 遗传学
- 基因组学
- 流行病学
- 心血管疾病研究
背景情况:
- 脑卒中是全球主要的死亡原因, 之前的遗传研究主要集中在欧洲人群.
- 这种祖先偏见限制了研究结果的概括性和公平风险预测工具的发展.
- 了解不同祖先的遗传风险因素对于全球中风预防和治疗至关重要.
研究的目的:
- 进行大规模的跨祖先全基因组关联研究 (GWAS) 的元分析,以确定与中风相关的新遗传位点.
- 在多种人群中验证已识别的位置并调查潜在的因果基因和变异.
- 探索新药点的遗传证据,并开发综合性多基因评分来预测中风风险.
主要方法:
- 涉及超过11万名中风病例和150万名来自五个祖先的对照群体的交叉祖先GWAS元分析.
- 确定中风风险位置的内部验证和独立复制.
- 交叉祖先精细映射,基突变,全转录组和全蛋白组关联研究 (TWAS/PWAS) 以确定因果基因/变异.
- 整合血管风险因子GWAS以制定整合性多基因分数.
主要成果:
- 确定了89个独立的中风关联信号及其子类型 (61个新的位置).
- 87%的初级和60%的二次中风风险基因在祖先之间复制,效果大小的相关性很高.
- 假定原因基因 (例如,SH3PXD2A,FURIN) 和变体 (例如,在GRK5,NOS3) 的鉴定.
- 基因证据支持F11,KLKB1,PROC,GP1BA,LAMC2和VCAM1作为潜在的药物标.
- 综合性多基因评分准确预测了欧洲,东亚和非洲祖先的缺血性中风,独立于临床风险因素.
结论:
- 这种跨血统的大规模GWAS提供了关于中风遗传结构的重要见解.
- 这项研究确定了新的风险位置,潜在的因果机制以及适用于不同人群的有希望的药物标.
- 开发的多基因风险评分证明了对预测缺血性中风的有用性,为改进和公平的基因风险评估工具铺平了道路.
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