Transcriptome-wide association study identifies susceptibility genes for rheumatoid arthritis

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 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. Conclusion We identified multiple candidate genes and pathways, providing novel clues for the genetic mechanism of RA.

Identification of EP300 as a Key Gene Involved in Antipsychotic-Induced Metabolic Dysregulation Based on Integrative Bioinformatics Analysis of Multi-Tissue Gene Expression Data

“…The imputed gene expression can then be used in place of genotypes to assess the effect of genes on a given phenotype (Gamazon et al, 2015). This strategy has been previously used to identify candidate genes associated with schizophrenia, attention deficit hyperactivity disorder and other complex traits (Gusev et al, 2018;Liao et al, 2019;Lindström et al, 2019;Wu et al, 2021). Here, we found that the predicted expression levels of EP300 in different metabolic-related tissues of patients with FEP receiving APs were significantly associated with increases in body weight, BMI, total cholesterol levels, LDL cholesterol levels and TG concentrations at the 6-months follow-up.…”

Transcriptome-wide association study identifies new susceptibility genes for degenerative cervical spondylosis

“…A large-scale GWAS summary data set of DCS was obtained from the published study [12]. In short, this summary data set contains 3739 diagnosed DCS and 382326 controls of European from the UK Biobank [12].…”

“…A large-scale GWAS summary data set of DCS was obtained from the published study [12]. In short, this summary data set contains 3739 diagnosed DCS and 382326 controls of European from the UK Biobank [12]. Information about various phenotypes has been collected from every participant, and blood samples were taken when the subjects visited a UK Biobank assessment center [12].…”

“…In short, this summary data set contains 3739 diagnosed DCS and 382326 controls of European from the UK Biobank [12]. Information about various phenotypes has been collected from every participant, and blood samples were taken when the subjects visited a UK Biobank assessment center [12]. DNA extraction and genotyping were performed in the Affymetrix Research Services Laboratory.…”

“…DNA extraction and genotyping were performed in the Affymetrix Research Services Laboratory. After ltering, the data set contains 9,113,133 imputed variants [12]. The IMPUTE4 program was used to perform the imputation (http://jmarchini.org/software/).…”