Genetic Determinants of Vitamin D Deficiency in the Middle Eastern Qatari Population by a Genome-Wide Association Study

Abstract

Abstract Epidemiological studies have revealed that Middle Eastern countries have the highest incidence of Vitamin D deficiency with severe complications. However, the impact of Vitamin D polymorphisms and the performance of polygenic models have been studied primarily in European with little knowledge of the Middle Eastern. Here, we conducted the first genome-wide association study to identify genetic determinants of Vitamin D levels in Middle Eastern populations using a whole genome sequencing approach in 6,047 discovery subjects. We discovered a novel variant, rs2298850 (P-value = 1.71 × 10-08, effect size (Beta) = -0.1285), in a region of a known locus for the group-specific component gene (GC). We also confirmed the association of Vitamin D to several variants, including rs11723621 (P-value = 1.93 × 10-08, Beta = -0.12574) and rs4588 (P-value = 8.06 × 10-08, Beta = -0.1188) in the GC. A GWAS meta-analysis combining results from our Qatari cohort and previous European data identified novel variants in known loci, including rs67609747 and rs1945603 on chromosome 11. We found a moderately low heritability of Vitamin D (estimated at 18%) compared to Europeans. Finally, a low predictive performance of European ancestry-derived polygenic scores was observed when applied to the Qatari individuals. These results emphasize the diversity in the genetic architecture and its impact on preventive and precision medicine across different populations. Our findings offer novel perspectives on the physiological mechanisms and genetic factors contributing to the variation of Vitamin D levels in the Qatari population.