Genetic insight into the putative causal proteins and druggable targets of osteoporosis: a large-scale proteome-wide mendelian randomization study

Zhichong Wu; Kenneth Guangpu Yang; Tsz-Ping Lam; Jack Chun Yiu Cheng; Zezhang Zhu; Wayne Yuk-Wai Lee

doi:10.3389/fgene.2023.1161817

Genetic insight into the putative causal proteins and druggable targets of osteoporosis: a large-scale proteome-wide mendelian randomization study

Front Genet. 2023 Jun 28:14:1161817. doi: 10.3389/fgene.2023.1161817. eCollection 2023.

Authors

Zhichong Wu^{1

2

3}, Kenneth Guangpu Yang^{2

3

4

5

6}, Tsz-Ping Lam³, Jack Chun Yiu Cheng³, Zezhang Zhu^{1

2

3}, Wayne Yuk-Wai Lee^{2

3

4

5

6}

Affiliations

¹ Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
² Musculoskeletal Research Laboratory, SH Ho Scoliosis Research Laboratory, Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
³ Joint Scoliosis Research Centre of the Chinese University of Hong Kong and Nanjing University, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
⁴ Prince of Wales Hospital, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
⁵ Center for Neuromusculoskeletal Restorative Medicine, CUHK InnoHK Centres, Shatin, Hong Kong SAR, China.
⁶ Key Laboratory for Regenerative Medicine, School of Biomedical Sciences, Faculty of Medicine, Ministry of Education, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.

Abstract

Background: Osteoporosis is a major causative factor of the global burden of disease and disability, characterized by low bone mineral density (BMD) and high risks of fracture. We aimed to identify putative causal proteins and druggable targets of osteoporosis. Methods: This study utilized the largest GWAS summary statistics on plasma proteins and estimated heel BMD (eBMD) to identify causal proteins of osteoporosis by mendelian randomization (MR) analysis. Different GWAS datasets were used to validate the results. Multiple sensitivity analyses were conducted to evaluate the robustness of primary MR findings. We have also performed an enrichment analysis for the identified causal proteins and evaluated their druggability. Results: After Bonferroni correction, 67 proteins were identified to be causally associated with estimated BMD (eBMD) (p < 4 × 10^-5). We further replicated 38 of the 67 proteins to be associated with total body BMD, lumbar spine BMD, femoral neck BMD as well as fractures, such as RSPO3, IDUA, SMOC2, and LRP4. The findings were supported by sensitivity analyses. Enrichment analysis identified multiple Gene Ontology items, including collagen-containing extracellular matrix (GO:0062023, p = 1.6 × 10^-10), collagen binding (GO:0005518, p = 8.6 × 10^-5), and extracellular matrix structural constituent (GO:0005201, p = 2.7 × 10^-5). Conclusion: The study identified novel putative causal proteins for osteoporosis which may serve as potential early screening biomarkers and druggable targets. Furthermore, the role of plasma proteins involved in collagen binding and extracellular matrix in the development of osteoporosis was highlighted. Further studies are warranted to validate our findings and investigate the underlying mechanism.

Keywords: BMD; drug; genetic; mendelian randomization; osteoporosis.

Grants and funding

This work was supported by the Start-up grant from Chinese University of Hong Kong (Ref. Nos. 4930991 and 4930992); 2020 Rising Star Award from American Society for Bone and Mineral Research; General Research Fund (Ref. No. 14104620) and Research Matching Grant Scheme, University Grants Committee; Area of Excellence (Ref. No. AoE/M-402/20), University Grants Committee; Center for Neuromusculoskeletal Restorative Medicine (Ref. No. CT1.1), Health@InnoHK program, Innovation Technology Commission, Hong Kong SAR, China.