Mendelian randomization analysis identifies druggable genes for 7 types of osteoarthritis

Abstract

Objective Osteoarthritis (OA) is a common joint disease marked by cartilage degeneration, particularly in the elderly and obese. Current treatments mainly provide symptomatic relief, emphasizing the need for new therapies targeting the disease's root causes. This study aims to identify novel druggable genes for OA treatment using drug-targeted Mendelian randomization (MR) study.

Method The study utilized a druggable genome-wide Mendelian Randomization (MR) approach, leveraging summary-level data from genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL) studies. SMR analysis was conducted to evaluate the causal association of druggable genes on 7 types of OA and 4 OA-related traits. Colocalization analysis was conducted to deepen the understanding and identify potential therapeutic targets of OA. Two-sample MR and protein quantitative trait loci (pQTL) analyses were used for further validation. Identified genes were categorized based on their potential as drug targets, and a phenome-wide association study (PheWAS) assessed the safety of these targets. In addition, drug prediction, and molecular docking were performed to provide valuable guidance for the development of more effective and targeted therapeutic drugs.

Results The SMR analysis identified multiple druggable genes associated with 7 types of OA and 4 OA-related traits. Key genes such as MAPK3 and CSK were consistently associated with multiple OA traits. Colocalization analysis provided strong evidence for 35 genes, suggesting their potential as therapeutic targets. Two-sample MR and pQTL analysis further supported these findings, identifying MAPK3, CSK, IFNGR2, MVD, FES, and ITGA2 as tier 3 targets. PheWAS indicated potential side effects for these targets.

Conclusions The study identified several potential druggable genes for OA treatment, with MAPK3, CSK, IFNGR2, MVD, FES, and ITGA2 showing the most promise. These findings provide a foundation for prioritizing drug treatment for OA.

Keywords Druggable genes, Osteoarthritis, Summary-data-based Mendelian randomization