Genome-wide gene-environment interaction study uncovers 162 vitamin D status variants using a precise ambient UVB measure
Vitamin D status is influenced by genetic and environmental factors-primarily sun exposure. Using satellite weather data, we estimated an ambient UVB dose for each participant based on residential address and date of sampling. We conducted genome-wide tests in 338,977 UK Biobank White British participants, adjusted for age, sex, supplements, UVB dose, and 10 principal components to account for population structure. We applied three models to test for genetic effects: marginal only, main and interaction, and joint effects. We identified 307 variants associated with standardised log-transformed 25-hydroxyvitamin D (25OHD) concentration, 162 of which were not previously identified in GWAS. We identify an increase in SNP-heritability by increasing ambient UVB exposure quintiles (h<sup>2</sup><sub>Q1</sub> = 8.48% vs. h<sup>2</sup><sub>Q5</sub> = 15.56%). Downstream annotation implicated genes in the 25OHD pathway, including the circadian regulator, BMAL1. This and further findings suggest that vitamin D status and circadian rhythm may be entangled and that vitamin D metabolites may have a role as mediators of seasonal physiological fluctuations, including metabolism, and in turn explain the established associations with lipid metabolism pathways.
Authors
- Michiel van Weele (ORCID: https://orcid.org/0000-0002-3191-5604)
- Malcolm G. Dunlop (ORCID: https://orcid.org/0000-0002-3033-5851)
- Rasha Shraim (ORCID: https://orcid.org/0000-0002-3351-1179)
- Cathy Wyse (ORCID: https://orcid.org/0000-0003-1673-647X)
- Stefan Pilz (ORCID: https://orcid.org/0000-0002-7959-1311)
- Ross McManus (ORCID: https://orcid.org/0000-0002-0529-9617)
- Román Romero‐Ortuño (ORCID: https://orcid.org/0000-0002-3882-7447)
- Benjamin S. Fletcher (ORCID: https://orcid.org/0009-0000-9986-5677)
- Evropi Τheodoratou (ORCID: https://orcid.org/0000-0001-5887-9132)
- James F. Wilson (ORCID: https://orcid.org/0000-0001-5751-9178)
- Marcus E. Kleber (ORCID: https://orcid.org/0000-0003-0663-7275)
- Lina Zgaga (ORCID: https://orcid.org/0000-0003-4089-9703)
- Lorna M. Lopez (ORCID: https://orcid.org/0000-0002-0241-9783)
- Maria Timofeeva (ORCID: https://orcid.org/0000-0002-2503-4253)
- Jos van Geffen (ORCID: https://orcid.org/0000-0003-2121-4553)
- Winfried März
Institutions
- Synlab Czech (Czechia) (CZ)
- Royal Netherlands Meteorological Institute (NL)
- National University of Ireland, Maynooth (IE)
- University of Southern Denmark (DK)
- Ollscoil na Gaillimhe – University of Galway (IE)
- Medical University of Graz (AT)
- Trinity College Dublin (IE)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- Edinburgh Cancer Research (GB)
- Synlab (Germany) (DE)
- St. James's Hospital (IE)
- Institute of Genetics and Cancer (GB)
- Medical Research Council (GB)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-28
- DOI
- https://doi.org/10.1038/s41467-025-65820-x
- Citations
- 2
- Primary Topic
- Vitamin D Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 2.94
Funders
- Scottish Government
- Gujarat Council on Science and Technology
- Cancer Research UK
- European Commission
- Gillings School of Public Health
- Horizon 2020 Framework Programme
- Medical Research Council