Transcriptome- wide association study reveals candidate causal genes for lumbar spinal stenosis

AimsLumbar spinal stenosis (LSS) is a common skeletal system disease that has been partly at-tributed to genetic variation. However, the correlation between genetic variation and patho-logical changes in LSS is insufficient, and it is difficult to provide a reference for the early diagnosis and treatment of the disease. MethodsWe conducted a transcriptome- wide association study (TWAS) of spinal canal stenosis by integrating genome- wide association study summary statistics (including 661 cases and 178,065 controls) derived from Biobank Japan, and pre-computed gene expression weights of skeletal muscle and whole blood implemented in FUSION software. To verify the TWAS results, the candidate genes were furthered compared with messenger RNA (mRNA) expres-sion profiles of LSS to screen for common genes. Finally, Metascape software was used to perform enrichment analysis of the candidate genes and common genes. ResultsTWAS identified 295 genes with permutation p-values < 0.05 for skeletal muscle and 79 genes associated for the whole blood, such as RCHY1 (PTWAS = 0.001). Those genes were en-riched in 112 gene ontology (GO) terms and five Kyoto Encyclopedia of Genes and Genomes pathways, such as 'chemical carcinogenesis -reactive oxygen species' (LogP value = -2.139). Further comparing the TWAS significant genes with the differentially expressed genes iden-tified by mRNA expression profiles of LSS found 18 overlapped genes, such as interleukin 15 receptor subunit alpha (IL15RA) (PTWAS = 0.040, PmRNA = 0.010). Moreover, 71 common GO terms were detected for the enrichment results of TWAS and mRNA expression profiles, such as negative regulation of cell differentiation (LogP value = -2.811). ConclusionThis study revealed the genetic mechanism behind the pathological changes in LSS, and may provide novel insights for the early diagnosis and intervention of LSS.

Automated summary

Through transcriptome-wide association study (TWAS), we identified 295 genes and 79 genes associated with lumbar spinal stenosis (LSS) in skeletal muscle and whole blood, respectively. Comparing with the mRNA expression profiles of LSS, 18 overlapped genes were found. This study revealed the genetic mechanism behind the pathological changes in LSS and provided new insights for early diagnosis and intervention.