Transcriptome-wide association study identifies susceptibility genes for rheumatoid arthritis

OBJECTIVE: To identify rheumatoid arthritis (RA)-associated susceptibility genes and pathways through integrating genome-wide association study (GWAS) and gene expression profile data. METHODS: A transcriptome-wide association study (TWAS) was conducted by the FUSION software for RA considering EBV-transformed lymphocytes (EL), transformed fibroblasts (TF), peripheral blood (NBL), and whole blood (YBL). GWAS summary data was driven from a large-scale GWAS, involving 5539 autoantibody-positive RA patients and 20,169 controls. The TWAS-identified genes were further validated using the mRNA expression profiles and made a functional exploration. RESULTS: TWAS identified 692 genes with P(TWAS) values < 0.05 for RA. CRIPAK (P(EL) = 0.01293, P(TF) = 0.00038, P(NBL) = 0.02839, P(YBL) = 0.0978), MUT (P(EL) = 0.00377, P(TF) = 0.00076, P(NBL) = 0.00778, P(YBL) = 0.00096), FOXRED1 (P(EL) = 0.03834, P(TF) = 0.01120, P(NBL) = 0.01280, P(YBL) = 0.00583), and EBPL (P(EL) = 0.00806, P(TF) = 0.03761, P(NBL) = 0.03540, P(YBL) = 0.04254) were collectively expressed in all the four tissues/cells. Eighteen genes, including ANXA5, AP4B1, ATIC (P(TWAS) = 0.0113, downregulated expression), C12orf65, CMAH, PDHB, RUNX3 (P(TWAS) = 0.0346, downregulated expression), SBF1, SH2B3, STK38, TMEM43, XPNPEP1, KIAA1530, NUFIP2, PPP2R3C, RAB24, STX6, and TLR5 (P(TWAS) = 0.04665, upregulated expression), were validated with integrative analysis of TWAS and mRNA expression profiles. TWAS-identified genes functionally involved in endoplasmic reticulum organization, regulation of cytokine production, TNF signaling pathway, immune response-regulating signaling pathway, regulation of autophagy, etc. CONCLUSION: We identified multiple candidate genes and pathways, providing novel clues for the genetic mechanism of RA. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13075-021-02419-9.