Characterization of gene-environment interactions for vitamin D through variance quantitative trait loci: a UK Biobank-based genetic epidemiology study.

Background: Understanding gene-environment interactions associated with 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 interactions are enriched.

Objectives: The study aims to identify vQTLs for serum 25-hydroxy vitamin D (25OHD) concentrations and characterize potential gene-environment interactions 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 = 7800), East Asian (N = 2146), and South Asian (N = 8771) ancestries, respectively. We tested for interactions 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 < 5 × 10) in the European ancestry population. No vQTLs were identified in the non-European ancestry populations, likely because of limited sample sizes. A total of 32 interactions were detected with a false discovery rate <0.05. Although known gene-season of measurement interactions were confirmed, additional interactions were identified involving modifiable risk factors, including time spent outdoors and body mass index. The magnitudes of these interactions were consistent within each locus upon adjusting for the 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 associations may act through sex-biased expression of DHCR7 isoforms in skin tissues because of alternative splicing.

Conclusions: Through the lens of vQTLs, we identified additional gene-environment interactions affecting vitamin D status in addition to the 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.