Genome-wide Mendelian Randomization Identifies Potential Drug Targets for Dorsopathies

Abstract

BackgroundDorsopathies are a group of musculoskeletal disorders affecting the spinal column and related structures, contributing significantly to global disability rates and healthcare costs. Despite their prevalence, the genetic and biological mechanisms underlying dorsopathies are not fully understood. MethodSummary-data-based Mendelian Randomization (SMR) and colocalization analysis were employed, using data from genome-wide association studies (GWAS) and cis-expression quantitative trait loci (cis-eQTLs) databases. Genes with a colocalization posterior probability (PP.H4) above 0.7 in SMR results were selected for additional analysis. These selected genes underwent MR analysis to examine possible causal connections with dorsopathies, and sensitivity analyses were carried out to ensure robustness. Additionally, two transcriptome-wide association studies (TWAS) were utilized to confirm and screen for potential drug targets. ResultWe identified four essential genes linked to dorsopathies: NLRC4, CGREF1, KHK, and RNF212. Mendelian randomization (MR) analysis revealed a potential causal link between these genes and dorsopathies. Elevated transcription levels of NLRC4, CGREF1, and KHK correlated with reduced dorsopathies risk, while increased levels of RNF212 were associated with heightened risk of dorsopathies. Regarding methylation sites, an increase in cg04686953 fully mediated the decreased risk of dorsopathies by RNF212. Similarly, the risk effect of cg26638505 and cg18948125 was entirely mediated by NLRC4, while CGREF1 predominantly mediated the risk-increasing effect of cg06112415 and the decrease effect of cg22740783. ConclusionDorsopathies were associated with four pivotal genes: NLRC4, CGREF1, KHK, and RNF212. Methylation analysis identified cg04686953 and cg22740783 as protective against dorsopathies risk, while cg26638505, cg18948125, and cg06112415 exhibited a risk-increasing impact.