Background:　Ischemic　stroke　(IS)　is　an　important　disease　causing　death　and　disability　worldwide,　and　further　investigation　of　IS-related　genes　through　genome-wide　association　study　(GWAS)　data　is　valuable.　Methods:　The　study　included　GWAS　data　from　62,100　IS　patients　of　European　origin　and　1,234,808　controls　in　a　cross-tissue　transcriptome　association　study　(TWAS).　A　joint　analysis　was　first　performed　by　the　Unified　Test　for　Molecular　Markers　(UTMOST)　and　FUSION　methods.　The　results　of　the　joint　analysis　were　also　validated　by　fine-　mapping　through　FOCUS.　Mendelian　randomisation　analysis　was　performed　to　determine　whether　the　obtained　genes　were　causally　related　to　IS.　Genome　Annotated　Multiple　Marker　Analysis　(MAGMA)　explored　which　biological　functions　the　genes　associated　with　IS.　We　used　Coloc　to　co-localise　GWAS　and　eQTL　of　the　genes.　We　also　biologically　validated　the　results　by　Western　blotting　and　immunofluorescence　staining　in　the　middle　cerebral　artery　occlusion/reperfusion　(MCAO/R)　mouse　model.　Results:　Four　TWAS　methods　identified　only　one　new　susceptibility　gene　(USP38)　associated　with　IS　risk.　Mendelian　randomization　and　colocalization　analysis　found　that　USP38　may　be　protective　against　IS　development.　Functional　enrichment　analysis　indicated　IS-related　genes　were　mainly　associated　with　the　intrinsic　fibrinogen　activation,　acute　myocardial　infarction,　exogenous　fibrinogen　activation,　coagulation　cascade　response,　TNF　signalling　pathway　and　GRB2　signalling　pathway.　Western　blotting　and　immunofluorescence　staining　demonstrated　a　reduction　in　USP38　expression　in　MCAO/R　mice.　Conclusion:　Our　research　indicates　that　USP38　is　an　essential　gene　related　to　IS,　with　its　expression　strongly　connected　with　IS　risk,　thus　providing　new　perspectives　on　the　genetic　framework　of　IS.