Genome-wide gene-environment interaction study uncovers 162 vitamin D status variants using a precise ambient UVB measure

Rasha Shraim, Maria Timofeeva, Cathy Wyse, Jos van Geffen, Michiel van Weele, Roman Romero-Ortuno, Lorna M. Lopez, Marcus E. Kleber, Stefan Pilz, Winfried März, Benjamin S. Fletcher, James F. Wilson, Evropi Theodoratou, Malcolm G. Dunlop, Ross McManus and Lina Zgaga ()
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Rasha Shraim: Trinity College Dublin, Department of Public Health and Primary Care, Institute of Population Health
Maria Timofeeva: University of Edinburgh, Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine
Cathy Wyse: Maynooth University, Department of Biology
Jos van Geffen: Royal Netherlands Meteorological Institute
Michiel van Weele: Royal Netherlands Meteorological Institute
Roman Romero-Ortuno: Trinity College Dublin, Discipline of Medical Gerontology, School of Medicine
Lorna M. Lopez: Maynooth University, Department of Biology
Marcus E. Kleber: SYNLAB MVZ für Humangenetik
Stefan Pilz: Medical University of Graz, Department of Internal Medicine, Division of Endocrinology and Diabetology
Winfried März: SYNLAB MVZ für Humangenetik
Benjamin S. Fletcher: University of Edinburgh, Centre for Global Health Research, Usher Institute
James F. Wilson: University of Edinburgh, Centre for Global Health Research, Usher Institute
Evropi Theodoratou: University of Edinburgh, Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer
Malcolm G. Dunlop: University of Edinburgh, Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine
Ross McManus: Trinity College Dublin, Department of Clinical Medicine, Trinity Translational Medicine Institute
Lina Zgaga: Trinity College Dublin, Department of Public Health and Primary Care, Institute of Population Health

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract 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 (h2Q1 = 8.48% vs. h2Q5 = 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.

Date: 2025
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DOI: 10.1038/s41467-025-65820-x

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