Transcriptome-wide association study identifies susceptibility genes for rheumatoid arthritis
Abstract ObjectiveTo identify rheumatoid arthritis (RA) associated susceptibility genes and pathways through integrating genome-wide association study (GWAS) and gene expression profile data. MethodsA 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. ResultsTWAS identified 692 genes with PTWAS values < 0.05 for RA. CRIPAK (PEL = 0.01293, PTF = 0.00038, PNBL = 0.02839, PYBL = 0.0978), MUT (PEL = 0.00377, PTF = 0.00076, PNBL = 0.00778, PYBL = 0.00096), FOXRED1 (PEL = 0.03834, PTF = 0.01120, PNBL = 0.01280, PYBL = 0.00583) and EBPL (PEL = 0.00806, PTF = 0.03761, PNBL = 0.03540, PYBL = 0.04254) were collectively expressed in all the four tissues/cells. 18 genes, including ANXA5, AP4B1, ATIC (PTWAS = 0.0113, down-regulated expression), C12orf65, CMAH, PDHB, RUNX3 (PTWAS = 0.0346, down-regulated expression), SBF1, SH2B3, STK38, TMEM43, XPNPEP1, KIAA1530, NUFIP2, PPP2R3C, RAB24, STX6, TLR5 (PTWAS = 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. ConclusionWe identified multiple candidate genes and pathways, providing novel clues for the genetic mechanism of RA.