Genetic architecture of bone marrow fat fraction implies its involvement in osteoporosis risk
Bone marrow adipose tissue, as a distinct adipose subtype, has been implicated in the pathophysiology of skeletal, metabolic, and hematopoietic disorders. To identify its underlying genetic factors, we utilized a deep learning algorithm capable of quantifying bone marrow fat fraction (BMFF) in the vertebrae and proximal femur using magnetic resonance imaging data of over 38,000 UK Biobank participants. Genome-wide association analyses uncovered 373 significant BMFF-associated variants (P-value < 5 × 10<sup>-9</sup>), with enrichment in bone remodeling, metabolism, and hematopoiesis pathway. Furthermore, genetic correlation highlighted a significant association between BMFF and skeletal disease. In about 300,000 individuals, polygenic risk scores derived from three proximal femur BMFF were significantly associated with increased osteoporosis risk. Notably, Mendelian randomization analyses revealed a causal link between proximal femur BMFF and osteoporosis. Here, we show critical insights into the genetic determinants of BMFF and offer perspectives on the biological mechanisms driving osteoporosis development.
Authors
- Zuyou Wu
- Xiaoping Miao (ORCID: https://orcid.org/0000-0002-6818-9722)
- Jianbo Tian (ORCID: https://orcid.org/0000-0001-9493-694X)
- Shuangshuang Tian (ORCID: https://orcid.org/0000-0003-1382-6605)
- Yimin Cai (ORCID: https://orcid.org/0000-0002-2458-1976)
- Caibo Ning (ORCID: https://orcid.org/0000-0002-0049-9492)
- Shuting Xia (ORCID: https://orcid.org/0000-0003-2577-4339)
- Zilong Cao
- Zhen Li (ORCID: https://orcid.org/0000-0001-8037-4245)
- Yang Yang (ORCID: https://orcid.org/0000-0001-7432-4735)
- Jun Chen (ORCID: https://orcid.org/0000-0002-3439-0495)
- Yanmin Li (ORCID: https://orcid.org/0000-0003-1174-3873)
- Qianying Ma
- Jingyi Peng
- Qian Chu (ORCID: https://orcid.org/0000-0001-8192-7630)
- Ying Zhu (ORCID: https://orcid.org/0000-0002-3813-7577)
- Jiali Li
- Chunyi He (ORCID: https://orcid.org/0009-0002-0642-4448)
Institutions
- Bayer (United States) (US)
- Wuhan University (CN)
- Tongji Hospital (CN)
- Huazhong University of Science and Technology (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-12
- DOI
- https://doi.org/10.1038/s41467-025-62826-3
- Citations
- 4
- Primary Topic
- Lipid metabolism and disorders
- Type
- article
- Field-Weighted Citation Impact
- 5.55
Funders
- National Natural Science Foundation of China
- National Science and Technology Major Project
- National Outstanding Youth Science Fund Project of National Natural Science Foundation of China
- Fundamental Research Funds for the Central Universities
- National Science Fund for Distinguished Young Scholars
- Science Fund for Distinguished Young Scholars of Hubei Province