Genome-wide Mendelian Randomization Identifies Potential Drug Targets for Dorsopathies

Background Dorsopathies 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. Method Summary-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. Result We 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 . Conclusion Dorsopathies were associated with four pivotal genes: NLRC4 , CGREF1 , KHK , and RNF212 . Methylation analysis identified cg04686953 and cg22740783 as protective against NPs risk, while cg26638505 , cg18948125 , and cg06112415 exhibited a risk-increasing impact. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: N/A I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.