Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry^1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis³, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach⁴, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry⁵. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

此前针对中风（全球第二大死因）的全基因组关联研究 (GWAS) 主要在欧洲血统人群中进行^1,2 。在这里，在对 110,182 名中风患者（5 个血统，33% 非欧洲人）和 1,503,898 名对照个体进行的跨血统 GWAS 荟萃分析中，我们在 89 个（61 个新的）独立位点识别出中风及其亚型的关联信号：主要逆方差加权分析为 60，次要元回归和多性状分析为 29。根据内部跨血统验证和对另外 89,084 例中风病例（30% 非欧洲）和 1,013,843 名对照个体的独立随访，87% 的主要中风风险位点和 60% 的继发中风风险位点重复（ P < 0.05）。不同血统的效应大小高度相关。跨祖先精细作图、计算机诱变分析³以及全转录组和全蛋白质组关联分析揭示了假定的因果基因（例如SH3PXD2A和FURIN ）和变异（例如GRK5和NOS3 ）。我们采用三管齐下的方法⁴ ，为假定的药物效应提供遗传证据，强调 F11、KLKB1、PROC、GP1BA、LAMC2 和 VCAM1 作为可能的靶标，并且已经在研究针对 F11 和 PROC 的中风药物。将跨血统和血统特异性中风 GWAS 与血管危险因素 GWAS（综合多基因评分）相结合的多基因评分强烈预测欧洲、东亚和非洲血统人群中的缺血性中风⁵ 。 在 52,600 名患有心脏代谢疾病的临床试验参与者中，中风遗传风险评分可预测缺血性中风，与临床危险因素无关。我们的研究结果为生物学提供了见解，揭示了潜在的药物靶点，并得出跨祖先的遗传风险预测工具。