Rare-Variant Genome-Wide Association and Polygenic Score Assessment of Vitamin D Status in the Qatari Population

Vitamin D deficiency is highly common in the Middle East despite abundant sunlight; however, most genetic studies have concentrated on common variants in Europeans. We analyzed whole-genome sequences from 13,808 Qatar Biobank participants, testing rare variants (minor allele frequency 0.01–0.0001) for quantitative 25-hydroxyvitamin D (25(OH)D) levels and deficiency risk (<20 ng/mL) in independent discovery (n=5,885) and replication (n=7,767) cohorts, followed by meta-analyses. Discovery analysis identified 41 genome-wide significant rare variants, including CD36 rs192198195 (P = 2.48 × 10⁻8), and replication found 46, including SLC16A7 rs889439631 (P = 2.19 × 10⁻⁸), implicating lipid metabolism pathways. Binary analysis revealed RAP1GAP rs577185477 (P = 4.5 × 10⁻⁸), linked to endothelial and immune regulation, while the meta-analysis uncovered SLC25A37 rs952825245 (P = 5.15 × 10⁻¹²), associated with vitamin D signaling. Rare-variant polygenic scores derived from discovery cohort significantly predicted both 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 cohort. This is the 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 for precision prevention in high-burden populations.