Clinical implications of bone marrow adiposity identified by phenome-wide association and Mendelian randomization in the UK Biobank

Wei Xu, Ines Mesa-Eguiagaray, David M. Morris, Chengjia Wang, Calum D. Gray, Samuel Sjöström, Giorgos Papanastasiou, Sammy Badr, Julien Paccou, Lijuan Wang, Xue Li, Paul R. H. J. Timmers, Maria Timofeeva, Scott IK Semple, Tom MacGillivray, Evropi Theodoratou () and William P. Cawthorn ()
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Wei Xu: University of Edinburgh
Ines Mesa-Eguiagaray: University of Edinburgh
David M. Morris: The University of Edinburgh
Chengjia Wang: 47 Little France Crescent
Calum D. Gray: 47 Little France Crescent
Samuel Sjöström: The University of Edinburgh
Giorgos Papanastasiou: 47 Little France Crescent
Sammy Badr: Department of Rheumatology
Julien Paccou: Department of Rheumatology
Lijuan Wang: University of Edinburgh
Xue Li: Zhejiang University School of Medicine
Paul R. H. J. Timmers: University of Edinburgh
Maria Timofeeva: University of Edinburgh
Scott IK Semple: The University of Edinburgh
Tom MacGillivray: 47 Little France Crescent
Evropi Theodoratou: University of Edinburgh
William P. Cawthorn: The University of Edinburgh

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract Bone marrow adiposity changes in diverse diseases, but the full scope of these, and whether they are directly influenced by marrow adiposity, remains unknown. To address this, we previously measured the bone marrow fat fraction of the femoral head, total hip, femoral diaphysis, and spine of over 48,000 UK Biobank participants. Here, we first use these data for PheWAS to identify diseases associated with marrow adiposity at each site. This reveals associations with 47 incident diseases across 12 disease categories, including osteoporosis, fracture, type 2 diabetes, cardiovascular diseases, cancers, and other conditions that burden public health worldwide. Intriguingly, type 2 diabetes associates positively with spine bone marrow adiposity but negatively with marrow adiposity at femoral sites. We then establish PRSs based on bone-marrow-fat-fraction-associated SNPs and use PRS-PheWAS and Mendelian randomization to explore causal associations between marrow adiposity and disease. PRS-PheWAS reveals that genetic predisposition to increased marrow adiposity is positively associated with osteoporosis and fractures. Mendelian randomization further suggests that increased marrow adiposity at the diaphysis and total hip is causally associated with osteoporosis. Our findings substantially advance understanding of how marrow adiposity impacts human health and highlight its potential as a biomarker and/or therapeutic target for diverse human diseases.

Date: 2025
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DOI: 10.1038/s41467-025-63395-1

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