Transcriptome-wide association study identifies new susceptibility genes and pathways for spondyloarthritis

BackgroundSpondyloarthritis (SpA) is a group of multifactorial bone diseases influenced by genetic factors, the environment and lifestyle. However, current studies have found a limited number of SpA-related genes, and the genetic and pathogenic mechanisms of SpA are still unclear.MethodsA tissue-specific transcriptome-wide association study (TWAS) of SpA was performed using GWAS (including 3966 SpA patients and 448,298 controls) summary data and gene expression weights of whole blood and skeletal muscle. The SpA-associated genes identified by TWAS were further compared with the differentially expressed genes (DEGs) identified in the SpA gene expression profile acquired from the Gene Expression Omnibus database (GEO, GSE58667). Finally, functional enrichment and annotation analyses of the identified genes were performed.ResultsThe TWAS detected 499 suggestive genes associated with SpA in whole blood and skeletal muscle, such as CTNNAL1 (PSM = 3.04 x 10-2, PWB = 9.58 x 10-3). The gene expression profile of SpA identified 20 candidate genes that overlapped in the TWAS data, such as MCM4 (PTWAS = 1.32 x 10-2, PDEG = 2.75 x 10-2) and KIAA1109 (PTWAS = 3.71 x 10-2, PDEG = 4.67 x 10-2). Enrichment analysis of the genes identified by TWAS identified 93 significant GO terms and 33 KEGG pathways, such as mitochondrion organization (GO: 0007005) and axon guidance (hsa04360).ConclusionWe identified multiple candidate genes that were genetically related to SpA. Our study may provide novel clues regarding the genetic mechanism, diagnosis, and treatment of SpA. This is the first study to identify susceptibility genes associated with spondyloarthritis (SpA), revealing 499 suggestive genes by TWAS analysis.The TWAS results were further verified by comparing the gene expression profiles.This study provides novel clues for understanding the genetic mechanism of SpA, especially focusing on aberrant gene expression in the pathogenesis of SpA.

Automated summary

This study identified multiple candidate genes associated with spondyloarthritis (SpA) using a tissue-specific transcriptome-wide association study (TWAS) approach. These findings may provide novel insights into the genetic mechanism, diagnosis, and treatment of SpA.