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 5,539 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. 18 genes, including ANXA5, AP4B1, ATIC ( P TWAS = 0.0113, down-regulated expression), C12orf65, CMAH, PDHB, RUNX3 ( P TWAS = 0.0346, down-regulated expression), SBF1, SH2B3, STK38, TMEM43, XPNPEP1, KIAA1530, NUFIP2, PPP2R3C, RAB24, STX6, TLR5 ( P TWAS = 0.04665, up-regulated expression), were validated with integrative analysis of TWAS and mRNA expression profiles. TWAS-identified genes functionally involved in endomembrane system organization, endoplasmic reticulum organization, regulation of cytokine production, TNF signaling pathway, etc. Conclusion: We identified multiple candidate genes and pathways, providing novel clues for the genetic mechanism of RA.