Genome-wide Mendelian Randomization Identifies Potential Drug Targets for Dorsopathies

Abstract

AbstractBackgroundDorsopathies 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, andRNF212. Mendelian randomization (MR) analysis revealed a potential causal link between these genes and dorsopathies. Elevated transcription levels ofNLRC4,CGREF1, andKHKcorrelated with reduced dorsopathies risk, while increased levels ofRNF212were associated with heightened risk of dorsopathies. Regarding methylation sites, an increase incg04686953fully mediated the decreased risk of dorsopathies byRNF212. Similarly, the risk effect ofcg26638505andcg18948125was entirely mediated byNLRC4, whileCGREF1predominantly mediated the risk-increasing effect ofcg06112415and the decrease effect ofcg22740783.ConclusionDorsopathies were associated with four pivotal genes:NLRC4,CGREF1,KHK, andRNF212. Methylation analysis identified cg04686953 andcg22740783as protective against dorsopathies risk, whilecg26638505,cg18948125, andcg06112415exhibited a risk-increasing impact.