Skip to main content

ORIGINAL RESEARCH article

Front. Med.
Sec. Translational Medicine
Volume 11 - 2024 | doi: 10.3389/fmed.2024.1426261

Proteome-wide mendelian randomization provides novel insights into the pathogenesis and druggable targets of osteoporosis

Provisionally accepted
Jingchuan Yan Jingchuan Yan Ying Huai Ying Huai Qi Liang Qi Liang Li Lin Li Lin Bo Liao Bo Liao *
  • Tangdu Hospital, Air Force Medical University, Xi'an, China

The final, formatted version of the article will be published soon.

    With the aging population, the prevalence and impact of osteoporosis are expected to rise, and existing anti-osteoporosis agents have limitations due to adverse events. This study aims to discover novel drug targets for osteoporosis.The protein data were obtained from the latest proteome-wide association studies (PWAS) including 54, 219 participants. The osteoporosis data were extracted from a GWAS meta-analysis, characterized by heel bone mineral density (HBMD) comprising 426,824 individuals. Mendelian randomization (MR) was the primary approach used to establish genetic causality between specific traits. Summary-data-based MR (SMR), colocalization analysis, heterogeneity test, and external validation were applied to ensure the findings were reliable. The underlying mechanisms behind these causal associations were investigated by additional analyses. Finally, the druggability of the identified proteins was assessed.After Bonferroni correction, a total of 84 proteins were found to have a genetic association with osteoporosis. With strong colocalization evidence, proteins such as ACHE, HS6ST1, LRIG1, and LRRC37A2 were found to negatively influence HBMD, whereas CELSR2, CPE, FN1, FOXO1, and FSHB exhibited a positive association with HBMD. No significant heterogeneity was found. Additionally, CELSR2, FN1, FSHB, HS6ST1, LRIG1, and LRRC37A2 were replicated in the external validation. The effect of FSHB on HBMD was more pronounced in females compared to males. Interestingly, ACHE, LRIG1, FN1, and FOXO1 were observed to partially act on HBMD through BMI. Phewas analysis indicated that CPE and FOXO1 did not have genetic associations with any phenotypes other than osteoporosis. FN1 was highlighted as the most significant protein by protein-protein interaction network analysis.In conclusion, this study offers valuable insights into the role of specific proteins in the development of osteoporosis, and underscores potential therapeutic targets. Future studies should emphasize exploring these causal relationships and elucidating their underlying mechanisms.

    Keywords: Mendelian randomization, Osteoporosis, bone mineral density, proteomic, Colocalization analysis, druggability evaluation

    Received: 01 May 2024; Accepted: 14 Oct 2024.

    Copyright: © 2024 Yan, Huai, Liang, Lin and Liao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Bo Liao, Tangdu Hospital, Air Force Medical University, Xi'an, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.