Clinical implications of bone marrow adiposity identified by phenome-wide association and Mendelian randomization in the UK Biobank
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.
Authors
- Xue Li (ORCID: https://orcid.org/0000-0001-6880-2577)
- Julien Paccou (ORCID: https://orcid.org/0000-0001-6599-8623)
- Scott Semple (ORCID: https://orcid.org/0000-0002-4008-7564)
- Samuel Sjöström (ORCID: https://orcid.org/0009-0001-3827-2218)
- Calum Gray (ORCID: https://orcid.org/0000-0002-2816-4707)
- Giorgos Papanastasiou (ORCID: https://orcid.org/0000-0002-1939-296X)
- Sammy Badr (ORCID: https://orcid.org/0000-0002-3485-6531)
- Evropi Τheodoratou (ORCID: https://orcid.org/0000-0001-5887-9132)
- Paul R. H. J. Timmers (ORCID: https://orcid.org/0000-0002-5197-1267)
- Tom MacGillivray (ORCID: https://orcid.org/0000-0001-5120-0086)
- Ines Mesa‐Eguiagaray (ORCID: https://orcid.org/0000-0002-6784-2419)
- Chengjia Wang (ORCID: https://orcid.org/0000-0003-2345-7364)
- Maria Timofeeva (ORCID: https://orcid.org/0000-0002-2503-4253)
- William P. Cawthorn (ORCID: https://orcid.org/0000-0001-7832-5057)
- Lijuan Wang (ORCID: https://orcid.org/0000-0002-9797-0753)
- Wei Xu (ORCID: https://orcid.org/0009-0008-3338-4545)
- David M. Morris (ORCID: https://orcid.org/0000-0002-9387-1213)
Institutions
- University of Southern Denmark (DK)
- Université de Lille (FR)
- Edinburgh Cancer Research (GB)
- Centre Hospitalier Universitaire de Lille (FR)
- Heriot-Watt University (GB)
- Centre for Global Health Research (CA)
- Athena Research and Innovation Center In Information Communication & Knowledge Technologies (GR)
- Second Affiliated Hospital of Zhejiang University (CN)
- Institute of Genetics and Cancer (GB)
- The Queen's Medical Research Institute (GB)
- Medical Research Council (GB)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-23
- DOI
- https://doi.org/10.1038/s41467-025-63395-1
- Citations
- 3
- Primary Topic
- Bone and Joint Diseases
- Type
- article
- Field-Weighted Citation Impact
- 5.16
Funders
- British Heart Foundation
- Medical Research Council