Transcriptome-wide association study identifies susceptibility genes for rheumatoid arthritis

Cuiyan Wu,Shiqiang Cheng,Li Liu,Wenyu Li,Peilin Li,Feng’E Zhang,Yujie Ning,Sijian Tan,Feng Zhang,Huan Liu,Sen Wang,Yan Wen

doi:10.1186/s13075-021-02419-9

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 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.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. Eighteen genes, including ANXA5, AP4B1, ATIC (PTWAS = 0.0113, downregulated expression), C12orf65, CMAH, PDHB, RUNX3 (PTWAS = 0.0346, downregulated expression), SBF1, SH2B3, STK38, TMEM43, XPNPEP1, KIAA1530, NUFIP2, PPP2R3C, RAB24, STX6, and TLR5 (PTWAS = 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.ConclusionWe identified multiple candidate genes and pathways, providing novel clues for the genetic mechanism of RA.

Highlights

Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease primarily affecting the joints, even probably leading to accumulating joint damage and irreversible disability
The genome-wide summary data was collected from six genome-wide association study (GWAS) collections, 5539 cases and 20,169 controls in total, per-collection: Brigham Rheumatoid Arthritis Sequential Study (483 cases, 1449 controls), Canada (589 cases, 1472 controls), Epidemiological Investigation of Rheumatoid Arthritis (1173 cases, 1089 controls), North American Rheumatoid Arthritis Consortium I (867 cases, 1041 controls) and III (902 cases, 4510 controls), and Wellcome Trust Case Control Consortium (1525 cases, 10,608 controls); typed at 2,556,272 single nucleotide polymorphism (SNP)
transcriptome-wide association study (TWAS) FUSION software was applied to the RA GWAS summary data for cell/tissue-related TWAS analysis, including EBV-transformed lymphocytes (EL), transformed fibroblasts (TF), NBL, and YBL

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease primarily affecting the joints, even probably leading to accumulating joint damage and irreversible disability. Epidemiological studies in RA show that it affects up to 0.5–1% of the general adult population worldwide. Two thirds of cases are characterized by rheumatoid factor or autoantibodies that target various molecules including modified selfepitopes [1]. Some strong genetic components are known to be involved in the development of RA. Twins and family studies offered a strong suggestion that the risk of RA increased in individuals with an RA family history by shared genetic factors [2,3,4].

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Results

Conclusion