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Proteome-Wide Mendelian Randomization and Colocalization Analysis Identify Therapeutic Targets for Knee and Hip
Mingrui Zou1,2, Zhenxing Shao1,2
1Department of Sports Medicine, Peking University Third Hospital, Institute of Sports Medicine of Peking University, Beijing 100191, China.
Abstract:
Osteoarthritis (OA) is a common degenerative disease. Although some biomarkers and drug targets of OA have been discovered and employed, limitations and challenges still exist in the targeted therapy of OA. Mendelian randomization (MR) analysis has been regarded as a reliable analytic method to identify effective therapeutic targets. Thus, we aimed to identify novel therapeutic targets for OA and investigate their potential side effects based on MR analysis. In this study, two-sample MR, colocalization analysis, summary-data-based Mendelian randomization (SMR) and Mendelian randomization phenome-wide association study (MR-PheWAS) were conducted. We firstly analyzed data from 4907 plasma proteins to identify potential therapeutic targets associated with OA. In addition, blood expression quantitative trait loci (eQTLs) data sources were used to perform additional validation. A protein-protein interaction (PPI) network was also constructed to delve into the interactions among identified proteins. Then, MR-PheWASs were utilized to assess the potential side effects of core therapeutic targets. After MR analysis and FDR correction, we identified twelve proteins as potential therapeutic targets for knee OA or hip OA. Colocalization analysis and additional validation supported our findings, and PPI networks revealed the interactions among identified proteins. Finally, we identified MAPK3 (OR = 0.855, 95% CI: 0.791-0.923, p = 6.88 × 10-5) and GZMK (OR = 1.278, 95% CI: 1.131-1.444, p = 8.58 × 10-5) as the core therapeutic targets for knee OA, and ITIH1 (OR = 0.847, 95% CI: 0.784-0.915, p = 2.44 × 10-5) for hip OA. A further MR phenome-wide association study revealed the potential side effects of treatments targeting MAPK3, GZMK, and ITIH1. This comprehensive study indicates twelve plasma proteins with potential roles in knee and hip OA as therapeutic targets. This advancement holds promise for the progression of OA drug development, and paves the way for more efficacious treatments of OA.
Insights
Mendelian randomization identified twelve plasma proteins as potential therapeutic targets for osteoarthritis (OA). Key targets include MAPK3 and GZMK for knee OA, and ITIH1 for hip OA, offering new avenues for drug development.
Area of Science:
- Genetics
- Biochemistry
- Epidemiology
Background:
- Osteoarthritis (OA) is a prevalent degenerative joint disease with existing therapeutic challenges.
- Current biomarkers and drug targets for OA have limitations, necessitating novel approaches.
- Mendelian randomization (MR) analysis is a robust method for identifying effective therapeutic targets.
Purpose of the Study:
- To identify novel plasma protein targets for osteoarthritis (OA) using Mendelian randomization (MR).
- To investigate potential side effects of these therapeutic targets through MR-phenome-wide association studies (MR-PheWAS).
- To explore interactions among identified protein targets via protein-protein interaction (PPI) networks.
Main Methods:
- Two-sample MR, colocalization analysis, summary-data-based Mendelian randomization (SMR), and MR-PheWAS were employed.
- Analysis of 4907 plasma proteins and validation using blood expression quantitative trait loci (eQTLs) data.
- Construction of a protein-protein interaction (PPI) network to understand target relationships.
Main Results:
- Twelve plasma proteins were identified as potential therapeutic targets for knee or hip OA after MR analysis and FDR correction.
- MAPK3 and GZMK were identified as core targets for knee OA, while ITIH1 was identified for hip OA.
- MR-PheWAS revealed potential side effects associated with targeting MAPK3, GZMK, and ITIH1.
Conclusions:
- This study identifies twelve plasma proteins as promising therapeutic targets for knee and hip osteoarthritis.
- The findings advance OA drug development by providing novel targets and insights into potential side effects.
- The identified targets, including MAPK3, GZMK, and ITIH1, hold promise for developing more efficacious OA treatments.
