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Metabolomic Pathways to Osteoporosis in Middle-Aged Women: A Genome-Metabolome-Wide Mendelian Randomization Study

Moayyeri, A; Cheung, CL; Tan, KCB; Morris, JA; Cerani, A; Mohney, RP; Richards, JB; ... Menni, C; + view all (2018) Metabolomic Pathways to Osteoporosis in Middle-Aged Women: A Genome-Metabolome-Wide Mendelian Randomization Study. Journal of Bone and Mineral Research , 33 (4) pp. 643-650. 10.1002/jbmr.3358. Green open access

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Abstract

The metabolic state of the body can be a major determinant of bone health. We used a Mendelian randomization approach to identify metabolites causally associated with bone mass to better understand the biological mechanisms of osteoporosis. We tested bone phenotypes (femoral neck, total hip, and lumbar spine bone mineral density [BMD]) for association with 280 fasting blood metabolites in 6055 women from TwinsUK cohort with genomewide genotyping scans. Causal associations between metabolites and bone phenotypes were further assessed in a bidirectional Mendelian randomization study using genetic markers/scores as instrumental variables. Significant associations were replicated in 624 participants from the Hong Kong Osteoporosis Study (HKOS). Fifteen metabolites showed direct associations with bone phenotypes after adjusting for covariates and multiple testing. Using genetic instruments, four of these metabolites were found to be causally associated with hip or spine BMD. These included androsterone sulfate, epiandrosterone sulfate, 5alpha-androstan-3beta17beta-diol disulfate (encoded by CYP3A5), and 4-androsten-3beta17beta-diol disulfate (encoded by SULT2A1). In the HKOS population, all four metabolites showed significant associations with hip and spine BMD in the expected directions. No causal reverse association between BMD and any of the metabolites were found. In the first metabolome-genomewide Mendelian randomization study of human bone mineral density, we identified four novel biomarkers causally associated with BMD. Our findings reveal novel biological pathways involved in the pathogenesis of osteoporosis.

Type: Article
Title: Metabolomic Pathways to Osteoporosis in Middle-Aged Women: A Genome-Metabolome-Wide Mendelian Randomization Study
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/jbmr.3358
Publisher version: https://doi.org/10.1002/jbmr.3358
Language: English
Additional information: Copyright © 2017 The Authors. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: Metabolomics; Genomewide Association Studies; Mendelian Randomization; Instrumental Variables Analysis; Bone Mineral Density; Osteoporosis
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Population, Policy and Practice Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10050729
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