Integrative analysis of transcriptome-wide association study and gene expression profiling identifies candidate genes associated with stroke

Background. Stroke is a major public health burden worldwide. Although genetic variation is known to play a role in the pathogenesis of stroke, the specific pathogenic mechanisms are still unclear. Transcriptome-wide association studies (TWAS) is a powerful approach to prioritize candidate risk genes underlying complex traits. However, this approach has not been applied in stroke. Methods. We conducted an integrative analysis of TWAS using data from the MEGASTROKE Consortium and gene expression profiling to identify candidate genes for the pathogenesis of stroke. Gene ontology (GO) enrichment analysis was also conducted to detect functional gene sets. Results. The TWAS identified 515 transcriptome-wide significant tissue-specific genes, among which SLC25A44 (P = 5.46E-10) and LRCH1 (P = 1.54E-6) were significant by Bonferroni test for stroke. After validation with gene expression profiling, 19 unique genes were recognized. GO enrichment analysis identified eight significant GO func- tional gene sets, including regulation of cell shape (P = 0.0059), face morphogenesis (P = 0.0247), and positive regulation of ATPase activity (P = 0.0256). Conclusions. Our study identified multiple stroke-associated genes and gene sets, and this analysis provided novel insights into the genetic mechanisms underlying stroke.