Identification of potential therapeutic targets for stroke and its subtypes by integrating proteomes and genetics from human plasma

Previous genome-wide association studies (GWAS) have identified several risk genes for stroke; however, it remains unclear how they confer risk for the disease. We conducted an integrative analysis to identify candidate genes for stroke and stroke subtypes by integrating blood-derived multi-omics data with genetic data. We systematically integrated the latest stroke GWAS database with human plasma proteomes and performed proteome-wide association studies, Mendelian randomization (MR), Bayesian colocalization analysis and transcriptome-wide association study to prioritize genes that associate the risk of stroke and its subtypes with their expression and protein abundance in plasma. The target genes were verified by performing tissue and cell type specificity, and functional analysis using the Genotype-Tissue Expression database, single-cell RNA sequencing and Gene Ontology databases. A two-step MR analysis was followed to explore the potential mechanisms. We found that the protein abundance of seven genes (<i>MMP12, F11, SH3BGRL3, ENGASE, SCARA5, SWAP70</i> and <i>SPATA20</i>) in the plasma was associated with stroke and its subtypes, and six genes (<i>MMP12, F11, SH3BGRL3, SCARA5, SWAP70</i> and <i>SPATA20</i>) causally related with stroke and its subtypes. The effect of <i>F11, SH3BGRL3, SPATA20</i> and <i>SWAP70</i> on each subtype was mediated by Factor XI inhibitors, atrial fibrillation, type 2 diabetes and systolic blood pressure, respectively (<i>P</i> < 0.05). We also found that <i>SCARA5</i> and <i>SWAP70</i> were related to stroke and ischemic stroke at the transcriptome level. Our present proteomic findings may offer potential future therapeutic targets for stroke prevention.