Integrative proteogenomic analyses discover novel plasma proteins that impact risk of ischemic stroke

Understanding the proteins implicated in the pathogenesis of ischemic stroke is essential for developing novel prevention strategies. In this study, we compiled the largest available data sources for proteins and stroke to conduct Mendelian randomization (MR) using cis protein quantitative trait loci of over 3,500 proteins across two proteomic platforms and assess their causal relationship with ischemic stroke and its risk factors. We identified 21 potentially causal associations between proteins and ischemic stroke or its subtypes at 5% false discovery rate, with 16 supported by co-localisation. Four proteins (CEP85, KNG1, MMUT, SPATA20) represented novel findings not previously implicated in ischemic stroke through MR or genome-wide association studies. Integration of evidence from phenome-wide MR, animal models and tissue-specific gene expression highlighted agonists of MMUT, CEP85 and GRK5, and inhibitors of F11 and KNG1 as the most promising targets for prevention of ischemic stroke. Our study provides the most comprehensive data integration to date supporting the identification and causal relevance of plasma proteins for ischemic stroke.