Dataset Information

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 P_TWAS values 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.

SUBMITTER: Wu C

PROVIDER: S-EPMC7821659 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Transcriptome-wide association study identifies susceptibility genes for rheumatoid arthritis.

Wu Cuiyan C Tan Sijian S Liu Li L Cheng Shiqiang S Li Peilin P Li Wenyu W Liu Huan H Zhang Feng'e F Wang Sen S Ning Yujie Y Wen Yan Y Zhang Feng F

Arthritis research & therapy 20210122 1

<h4>Objective</h4>To identify rheumatoid arthritis (RA)-associated susceptibility genes and pathways through integrating genome-wide association study (GWAS) and gene expression profile data.<h4>Methods</h4>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 autoantibod ...[more]

PMID: 33482886

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Project description:AimsDegenerative cervical spondylosis (DCS) is a common musculoskeletal disease that encompasses a wide range of progressive degenerative changes and affects all components of the cervical spine. DCS imposes very large social and economic burdens. However, its genetic basis remains elusive.MethodsPredicted whole-blood and skeletal muscle gene expression and genome-wide association study (GWAS) data from a DCS database were integrated, and functional summary-based imputation (FUSION) software was used on the integrated data. A transcriptome-wide association study (TWAS) was conducted using FUSION software to assess the association between predicted gene expression and DCS risk. The TWAS-identified genes were verified via comparison with differentially expressed genes (DEGs) in DCS RNA expression profiles in the Gene Expression Omnibus (GEO) (Accession Number: GSE153761). The Functional Mapping and Annotation (FUMA) tool for genome-wide association studies and Meta tools were used for gene functional enrichment and annotation analysis.ResultsThe TWAS detected 420 DCS genes with p < 0.05 in skeletal muscle, such as ribosomal protein S15A (RPS15A) (PTWAS = 0.001), and 110 genes in whole blood, such as selectin L (SELL) (PTWAS = 0.001). Comparison with the DCS RNA expression profile identified 12 common genes, including Apelin Receptor (APLNR) (PTWAS = 0.001, PDEG = 0.025). In total, 148 DCS-enriched Gene Ontology (GO) terms were identified, such as mast cell degranulation (GO:0043303); 15 DCS-enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were identified, such as the sphingolipid signalling pathway (ko04071). Nine terms, such as degradation of the extracellular matrix (R-HSA-1474228), were common to the TWAS enrichment results and the RNA expression profile.ConclusionOur results identify putative susceptibility genes; these findings provide new ideas for exploration of the genetic mechanism of DCS development and new targets for preclinical intervention and clinical treatment.Cite this article: Bone Joint Res 2023;12(1):80-90.

Project description:IntroductionCataract is the leading cause of blindness among the elderly worldwide. Twin and family studies support an important role for genetic factors in cataract susceptibility with heritability estimates up to 58%. To date, 55 loci for cataract have been identified by genome-wide association studies (GWAS), however, much work remains to identify the causal genes. Here, we conducted a transcriptome-wide association study (TWAS) of cataract to prioritize causal genes and identify novel ones, and examine the impact of their expression.MethodsWe performed tissue-specific and multi-tissue TWAS analyses to assess associations between imputed gene expression from 54 tissues (including 49 from the Genotype Tissue Expression (GTEx) Project v8) with cataract using FUSION software. Meta-analyzed GWAS summary statistics from 59,944 cataract cases and 478,571 controls, all of European ancestry and from two cohorts (GERA and UK Biobank) were used. We then examined the expression of the novel genes in the lens tissue using the iSyTE database.ResultsAcross tissue-specific and multi-tissue analyses, we identified 99 genes for which genetically predicted gene expression was associated with cataract after correcting for multiple testing. Of these 99 genes, 20 (AC007773.1, ANKH, ASIP, ATP13A2, CAPZB, CEP95, COQ6, CREB1, CROCC, DDX5, EFEMP1, EIF2S2, ESRRB, GOSR2, HERC4, INSRR, NIPSNAP2, PICALM, SENP3, and SH3YL1) did not overlap with previously reported cataract-associated loci. Tissue-specific analysis identified 202 significant gene-tissue associations for cataract, of which 166 (82.2%), representing 9 unique genes, were attributed to the previously reported 11q13.3 locus. Tissue-enrichment analysis revealed that gastrointestinal tissues represented one of the highest proportions of the Bonferroni-significant gene-tissue associations (21.3%). Moreover, this gastrointestinal tissue type was the only anatomical category significantly enriched in our results, after correcting for the number of tissue donors and imputable genes for each reference panel. Finally, most of the novel cataract genes (e.g., Capzb) were robustly expressed in iSyTE lens data.DiscussionOur results provide evidence of the utility of imputation-based TWAS approaches to characterize known GWAS risk loci and identify novel candidate genes that may increase our understanding of cataract etiology. Our findings also highlight the fact that expression of genes associated with cataract susceptibility is not necessarily restricted to lens tissue.

Dataset Information

Transcriptome-wide association study identifies susceptibility genes for rheumatoid arthritis.

Objective

Methods

Results

Publications

Transcriptome-wide association study identifies susceptibility genes for rheumatoid arthritis.

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