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

Background Osteoarthritis (OA) is a common skeletal system disease which proven partly related to genetic factors. The hand is a frequently affected part, which seriously affects the quality of life. But pathogenesis mechanism of hand osteoarthritis (hand OA) is still elusive. Methods The Genome-wide association study (GWAS)summary of hand OA was derived from the UK Biobank, which contains 452,264 White British individuals with 37782 osteoarthritis patients. The transcriptome-wide association study (TWAS)of hand OA was carried out using the Functional Summary-based Imputation (FUSION) using the gene expression references of muscle skeleton and blood. The significant genes identified by TWAS were further subjected to gene sets enrichment analysis (GSEA) by the Database for Annotation, Visualization and Integrated Discovery (DAVID) tool. Furthermore, we compared the identified genes and gene sets of TWAS with that of an OA mRNA expression profile to detect the genes and gene sets shared by TWAS and mRNA expression profiles of OA. Results TWAS identified 177 genes with P value < 0.05 for muscle skeleton, such as ANKRD44 (P = 0.0001), RIC3(P = 0.0003), AC005154.6 (P = 0.0004). TWAS identified 423 genes with P value < 0.05 for blood, such as CRIM1(P = 0.0002), ZNF880 (P = 0.0002), NCKIPSD (P = 0.0003).After comparing these results of TWAS to those of mRNA expression profile, we identified 5 common genes, such as DHRS3 (log2fold=-1.85, P = 3.31 × 10− 9), SKP2(log2fold = 1.36, P = 1.62 × 10− 8). GSEA of TWAS identified genes detected 51 gene ontology (GO) terms for hand OA, for example, protein binding (P = 0.0003), cytosol (P = 0.0020). We also detected 6 common GO terms shared by TWAS and mRNA expression profiling of OA, such as protein binding (PTWAS = 2.54 × 10− 4, PmRNA = 3.42 × 10− 8), extracellular exosome (PTWAS =0.02, PmRNA = 1.18 × 10− 4), cytoplasm(PTWAS =0.0183, PmRNA = 0.0048). Conclusion In this study, we selected 5 sensitive genes(DHRS3, SKP2, IRS2, TOB1, PPP1R15A)and 6 GO terms(protein binding, extracellular exosome, cytoplasm, oxidoreductase, cellular response to mechanical stimulus, oxidation-reduction process) related to the hand osteoarthritis, which may help to uncover the pathogenesis of hand osteoarthritis at the genetic and molecular levels.