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• 11 overlapping genes associated with AAD were identified by integrative analysis. • Dysregulated gene expression plays an important role in AAD risk. • Extracellular matrix organization plays a vital role in AAD development. Aortic aneurysm and dissection (AAD) are a set of life-threatening diseases. This study aimed to investigate the genetic mechanisms of AAD by integrating transcriptome-wide association study (TWAS) and mRNA expression profile. The genome-wide association study (GWAS) summary data of AAD was obtained from the UK Biobank, which contains 452,264 White British individuals, including 1470 AAD patients. The TWAS analysis was performed by integrating expression quantitative trait loci (eQTL) data of aorta and the GWAS dataset of AAD using the FUSION software. The TWAS significant genes and differentially expressed genes (DEGs) identified by mRNA expression profile of aortic dissection were integrated to find common genes and biological process. For TWAS significant genes, protein–protein interaction (PPI) network analysis was further conducted based on STRING database. TWAS identified 423 genes with P < 0.05. After comparing the results of TWAS and mRNA expression profile, 11 overlapping genes (PDE8B, IKBKE, HMGA1, PKM, CHST1, DUS3L, S100A16, PTGS1, RAB38, PDLIM5, NOL6) and 15 common gene ontology (GO) terms (including extracellular matrix organization, external encapsulating structure organization, cell-substrate adhesion, actin filament-based process, focal adhesion, protein kinase activity) were identified. 9 hub genes of the TWAS results were identified via PPI network analysis, including RPS9, RPS18, RSRC1, DNAJC3, HBS1L, PRKCA, NCAM1, ITGB3, FTSJ3. Multiple candidate genes and biological processes associated with AAD were identified by the present integrative study of TWAS and mRNA expression profile. Further studies are needed to elucidate the genetic mechanisms of AAD. [ABSTRACT FROM AUTHOR]