Rare-Variant Genome-Wide Association and Polygenic Score Assessment of Vitamin D Status in a Middle Eastern Population

Vitamin D deficiency is highly prevalent in the Middle East despite abundant sunlight; however, most genetic studies have focused on common variants in Europeans only. We analyzed whole-genome sequences from 13,808 Qatar Biobank participants, evaluating rare variants (minor allele frequency 0.01–0.0001) for associations with serum 25-hydroxyvitamin D (25(OH)D) levels and deficiency risk (≤20 ng/mL) in independent discovery (n = 5885) and replication (n = 7767) cohorts, followed by meta-analyses. In quantitative analyses, the discovery cohort identified 41 genome-wide significant signals, including CD36 rs192198195 (p = 2.48 × 10⁻⁸), and replication found 46, including SLC16A7 rs889439631 (p = 2.19 × 10⁻⁸), implicating lipid metabolism pathways. In binary analyses, replication revealed POTEB3 rs2605913 (p = 2.8 × 10⁻⁸), while meta-analysis (n = 13,652) uncovered SLC25A37 rs952825245 (p = 5.15 × 10⁻¹²), a locus associated with cancer and vitamin D signaling. Rare-variant polygenic scores derived from discovery significantly predicted continuous (R² = 0.146, p = 9.08 × 10⁻¹²) and binary traits (AUC = 0.548, OR = 0.99, p = 9.22 × 10⁻⁶) in replication. This first rare-variant GWAS of vitamin D in Middle Easterners identifies novel loci and pathways, underscores the contribution of ancestry-specific rare alleles, and supports integrating rare and common variants to guide precision management in high-burden populations.