Vitamin D deficiency poses a major public health burden, increasing the risk of osteoporosis, fractures, multiple sclerosis, and all-cause mortality. Genetic variants involved in vitamin D synthesis and metabolism have undergone positive selection in Western Eurasians, especially among Northern Europeans over the past 5000 years. UVB exposure is the main environmental determinant of vitamin D levels, yet paradoxically, Western Eurasians residing in northern latitudes have higher levels than those in southern regions, with the Eastern Mediterranean and the Middle East recognised as deficiency hotspots. The extent to which these disparities are due to genetic or environmental differences remains unclear. The UK Biobank (UKB) offers a unique opportunity to explore determinants of vitamin D deficiency across diverse populations, given its large multi-ethnic sample residing in a relatively uniform environment, yet the majority of genetic association studies focus on individuals of European descent.
Leveraging UKB’s sample diversity, we aim to apply advanced population genomics tools to whole genome sequence data to genetically define two previously uncharacterised UKB groups, Mediterraneans and Middle Easterners, and investigate ancestry-specific pathways related to vitamin D deficiency, by answering the following research questions:
1) Are there differences in measured and genetically determined vitamin D levels between Mediterranean and Middle Eastern populations as compared to Northern Europeans residing in the UK?
2) To what extent does genetic, phenotypic and environmental variation explain differences in vitamin D levels between Mediterranean/Middle Eastern and Northern European populations?
3) Do gene-environment interactions contribute to lower vitamin D levels among Mediterranean and Middle Eastern populations?
