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

AimsDegenerative cervical spondylosis (DCS) is a common musculoskeletal disease that encom-passes 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 as-sociation study (TWAS) was conducted using FUSION software to assess the association be-tween 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 pro-tein 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) path-ways 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 ex-ploration of the genetic mechanism of DCS development and new targets for preclinical intervention and clinical treatment.

Automated summary

This study integrated gene expression and genome-wide association study data to identify potential susceptibility genes and functional pathways associated with degenerative cervical spondylosis (DCS). The findings provide new insights into the genetic mechanism of DCS development and potential targets for intervention and treatment.