Transcriptome-wide association study identifies susceptibility genes for rheumatoid arthritis
Cuiyan Wu, Sijian Tan, Li Liu, Shiqiang Cheng, Peilin Li, Wenyu Li, Huan Liu, Feng’e Zhang, Sen Wang, Yujie Ning, Yan Wen, Feng Zhang
Abstract
Abstract 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.