Towards Precision Medicine management of vitamin D inadequacy: Development of ancestry- specific polygenic scores and investigation of genetic-environmental interactions affecting vitamin D concentrations
Vitamin D inadequacy affects around 50% of adults in the United States and is associated with numerous adverse health outcomes. Vitamin D blood concentration [25(OH)D] has strong environmental and genetic predictors that may determine how much vitamin D intake is required to reach optimal 25(OH)D. Despite large genome-wide association studies (GWASs), only a small portion of the genetic factors of 25(OH)D has been discovered. The goal of this research is to uncover a fuller set of genetic factors and gene-by-environment interactions, that could be useful for prediction of vitamin D inadequacy, personalized vitamin D supplementation, and prevention of vitamin D associated morbidity and mortality. Using subsets of participants of European (n=9,569) and African ancestry (n=2,761), ancestry-specific polygenic scores (PGSs) were created using PRSice and validated with analyses performed in SAS. Overall SNP heritability and that accounted for by the PGS and published GWAS findings were calculated in GCTA and compared. Finally, interactions between the PGS and environmental predictors of 25(OH)D, available UV radiation and vitamin D intake, were investigated. Findings show that participants with high genetic risk had 25(OH)D that was 1.9- 4.7 ng/ml lower than those with lowest genetic risk (p=0.15 to 3.2x10-13); requiring an additional 317 to 783 IU of vitamin D intake to maintain equivalent 25(OH)D. In European- ancestry participants who reached IOM vitamin D intake guidelines, the proportion of participants achieving adequate 25(OH)D increased as genetic risk decreased (70.4 vs 83.8 in the highest and lowest risk categories, respectively; p=4.1x10-11); providing further evidence that those with high genetic risk require more vitamin D intake to reach adequate 25(OH)D. Where sample size allowed, heritability estimation showed that the PGS explains more heritability than do prior GWAS findings (3.7% vs 1.5%). Additionally, available UV radiation and vitamin D intake were shown to interact with PGS and influence 25(OH)D. Of note, due to limited minority group data, African-ancestry analyses were generally underpowered. PGSs are a powerful predictive tool that, in tandem with assessment of environmental predictors, UV radiation and vitamin D intake, could be leveraged for personalized vitamin D supplementation to prevent the negative downstream effects of vitamin D inadequacy.