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Background  Osteoarthritis (OA) is a common skeletal system disease that has been partially attributed to genetic factors. The hand is frequently affected, which seriously affects the patient’s quality of life. However, the pathogenetic mechanism of hand osteoarthritis (hand OA) is still elusive.    Methods  A genome-wide association study (GWAS) summary of hand OA was obtained from the UK Biobank dataset, which contains data from a total of 452,264 White British individuals, including 37,782 OA patients. The transcriptome-wide association study (TWAS) of hand OA was performed using FUnctional Summary-based ImputatiON (FUSION) with the skeletal muscle and blood as gene expression references. The significant genes identified by TWAS were further subjected to gene set enrichment analysis (GSEA) with the Database for Annotation, Visualization and Integrated Discovery (DAVID) tool. Furthermore, we compared the genes and gene sets identified by our TWAS with that of a knee OA mRNA expression profile to detect the genes and gene sets shared by TWAS and mRNA expression profiles in OA. The mRNA expression profiles of 18 normal knee cartilages and 20 OA knee cartilages were acquired from the Gene Expression Omnibus database (accession number: GSE114007).    Results  TWAS identified 177 genes with  P  < 0.05 for the skeletal muscle, including ANKRD44 ( P  = 0.0001), RIC3 ( P  = 0.0003), and AC005154.6 ( P  = 0.0004). TWAS identified 423 genes with  P  < 0.05 for the blood, including CRIM1 ( P  = 0.0002), ZNF880 ( P  = 0.0002), and NCKIPSD ( P  = 0.0003). After comparing the results of the TWAS to those of the mRNA expression profiling of OA, we identified 5 common genes, including DHRS3 (log2fold = − 1.85,  P  = 3.31 × 10 − 9 ) and SKP2 (log2fold = 1.36,  P  = 1.62 × 10 − 8 ). GSEA of TWAS identified 51 gene ontology (GO) terms for hand OA, for example, protein binding ( P  = 0.0003) and cytosol ( P  = 0.0020). We also detected 6 common GO terms shared by TWAS and mRNA expression profiling, including protein binding ( P  TWAS  = 2.54 × 10 − 4 ,  P  mRNA  = 3.42 × 10 − 8 ), extracellular exosome ( P  TWAS  = 0.02,  P  mRNA  = 1.18 × 10 − 4 ), and cytoplasm ( P  TWAS  = 0.0183,  P  mRNA  = 0.0048).    Conclusion  In this study, we identified 5 candidate genes and 6 GO terms related to hand OA, which may help to uncover the pathogenesis of hand OA. It should be noted that the possible difference in the gene expression profiles between hand OA and knee OA may affect our study results, which should be interpreted with caution.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13075-021-02458-2.

Integrating transcriptome-wide association study and mRNA expression profile identified candidate genes related to hand osteoarthritis