Polygenic Scores for Type 2 Diabetes Causally Impact Vitamin D Levels Across Diverse Populations

Background: Vitamin D (25(OH)D) deficiency affects over one billion people globally and is associated with type 2 diabetes (T2D) and cardiometabolic diseases. However, causal relationships remain unclear, as vitamin D supplementation have shown limited benefit in reducing T2D risk. Genetic studies have identified variants influencing circulating 25(OH)D levels, but whether genetically determined vitamin D status predicts cardiometabolic outcomes is still uncertain. We therefore used bidirectional Mendelian randomization with genome-wide polygenic scores to evaluate the causal relationship and directionality between vitamin D status and T2D. Methods and Results: We analyzed multi-ethnic populations from the UK Biobank (N = 471,861), and 3,486 participants from the Asian Indian Diabetic Heart Study/Sikh Diabetes Study with serum 25(OH)D measures and genome-wide genotype data. A global polygenic score of vitamin D–raising alleles did not significantly reduce the risk of T2D, coronary artery disease, stroke, or other cardiometabolic risk factors. In contrast, a higher T2D polygenic risk score (PRS) was strongly associated with increased risk for 25(OH)D deficiency (<50 nmol/L). Genetically instrumented analyses showed per SD increase in T2D PRS significantly reduced circulating 25(OH)D levels (β = −8.9 nmol/L; 95% CI: −9.3 to −8.5; p = 3.6 × 10⁻²⁸). Conclusions: Our findings suggest low circulating vitamin D levels are unlikely to causally predict T2D risk but may serve as a marker for secondary prevention in endocrine and cardiovascular health. Instead, genetic susceptibility to T2D appears to contribute to reduced vitamin D levels. Further studies are needed to clarify the mechanisms underlying vitamin D deficiency in diabetes.