Identification of Potential Therapeutic targets for Stroke and Its Subtypes by Integrating Proteomes and Genetics from Human Plasma

Background 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. Method We systematically integrated the latest stroke GWAS database (73,652 patients and 1,234,808 controls) with human plasma proteomes (N=7,213) and performed proteome-wide association studies (PWAS), Mendelian randomization (MR), Bayesian colocalization analysis, and transcriptome-wide association study (TWAS) to prioritize genes that associate the risk of stroke and its subtypes with their expression and protein abundance in plasma. Cell-type specificity and functional enrichment analysis using single-cell RNA sequencing (scRNA-seq) and Gene Ontology (GO) databases were then performed to select target genes. A two-step MR analysis was followed to explore the potential mechanisms. Results We found that the protein abundance of seven genes ( MMP12, F11, SH3BGRL3, ENGASE, SCARA5, SWAP70, and SPATA20 ) in the plasma was associated with stroke and its subtypes, with six genes ( MMP12, F11, SH3BGRL3, SCARA5, SWAP70, and SPATA20 ) causally related with stroke and its subtypes (P < 0.05/proteins identified for PWAS; P < 0.05/8 for MR; posterior probability of hypothesis 4 ≥ 75 % for Bayesian colocalization). The effect of F11, SH3BGRL, SPATA20, and SWAP70 on each subtype was mediated by Factor XI inhibitors (FXI), atrial fibrillation, T2D, and SBP respectively (p<0.05). We also found that SCARA5 and SWAP70 were related to stroke and ischemic stroke at the transcriptome level. Conclusions Our present proteomic findings have identified new causal genes in the pathogenesis of stroke, which may offer potential future therapeutic targets for stroke prevention. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was partially supported by grants from the National Natural Science Foundation of China (No. 81400979 and 81870931), the SanHang Program of the Naval Medical University, and the ?Climbing? program of Changhai Hospital. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: NONE I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data in the manuscript is truly usable