Background Understanding gene-environment interaction effects influencing vitamin D status may refine nutrition and public health strategies for vitamin D deficiency. Recent methodological advances have enabled the identification of variance quantitative trait loci (vQTLs) where gene-environment interaction effects are enriched. Objectives To identify vQTLs for serum 25-hydroxy vitamin D (25OHD) concentration and characterize potential gene-environment interaction effects of vQTLs. Methods We conducted vQTL discovery for 25OHD using a newly developed quantile integral linear model in the UK Biobank individuals of European (N = 313,514), African (N = 7,800), East Asian (N = 2,146), and South Asian (N = 8,771) ancestries, respectively. We tested for interaction effects between the identified vQTL lead variants and 18 environmental, biological, or lifestyle factors, followed by multiple sensitivity analyses. Results We identified 19 independent vQTL lead variants (p-value <5x10-8) in the European ancestry population. No vQTLs were identified in the non-European ancestry populations, likely due to limited sample sizes. A total of 32 interaction effects were detected with a false discovery rate <0.05. While known gene-season of measurement interaction effects were confirmed, additional interaction effects were identified involving modifiable risk factors, including time spent outdoors and body mass index. The magnitudes of these interaction effects were consistent within each locus upon adjusting for season of measurement and other covariates. We also identified a gene-sex interaction at a vQTL that implicates DHCR7. Integrating transcript- and protein-level evidence, we found that the sex-differentiated genetic effects may act through sex-biased expression of DHCR7 isoforms in skin tissues due to alternative splicing. Conclusions Through the lens of vQTLs, we identified additional gene-environment interaction effects affecting vitamin D status apart from season of measurement. These findings may provide new insights into the etiology of vitamin D deficiency and encourage personalized prevention and management of associated diseases for at-risk individuals.

T.L. and W.Z. have been consulting for Five Prime Sciences Inc. for research programs unrelated to this study. The other authors declare no conflict of interest.

T.L. has been supported by start-up funding from the Office of the Vice Chancellor for Research and Graduate Education, School of Medicine and Public Health, and Department of Population Health Sciences at the University of Wisconsin-Madison, and a Schmidt AI in Science Postdoctoral Fellowship. W.Z. has been supported by an Institut de Valorisation des Donnees Postdoctoral Fellowship. L.S. and A.D.P. have been supported by the Canadian Institutes of Health Research (PJT-180460).

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This research has been conducted using the UK Biobank Resource under Application Number 64875. UK Biobank has approval from the North West Multi-centre Research Ethics Committee (MREC) as a Research Tissue Bank (RTB) approval. This approval means that researchers do not require separate ethical clearance and can operate under the RTB approval.

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Full summary statistics for both vQTL and QTL analyses are available at https://figshare.com/s/a6c1d92d9cc765e0d58b. All other data produced in the present work are contained in the manuscript.

https://figshare.com/s/82f05d4c830dc4af50ac