Global Genetic Variation in Circulating 25-Hydroxyvitamin D: A Systematic Review of GWAS Evidence Across Different...

Vitamin D deficiency is a global health concern, yet circulating 25-hydroxyvitamin D (25OHD) concentrations vary substantially across geographical regions and ancestral groups. Genetic predisposition may contribute to these differences. This systematic review aimed to synthesize evidence from genome-wide association studies (GWAS) on genetic variation associated with circulating 25OHD across populations from different ancestral backgrounds and to evaluate linkage disequilibrium (LD) between reported variants.

A systematic review was conducted according to PRISMA 2020 guidelines. PubMed and the GWAS Catalog were searched to identify genome-wide association studies (GWAS) on circulating 25-hydroxyvitamin D (25OHD) concentrations. Studies were screened against predefined eligibility criteria, and data were extracted using a standardized framework. Methodological quality was assessed using a standardized tool, and study power adequacy was assessed formally. Genome-wide significant SNPs were extracted, and unique variants between studies were grouped by ancestry. Among these, dbSNP-indexed variants were grouped into genomic cluster windows and evaluated for LD structure.

Fifteen GWAS were included. Across these studies, 349 genome-wide significant SNP associations were identified, corresponding to 294 unique variants, of which 283 were indexed in dbSNP and retained for genomic and LD analyses. Variant discovery was dominated by large-scale European-ancestry studies, although African, Middle Eastern, East Asian, Hispanic/Latino, South Asian, and trans-ethnic studies also contributed signals. Some evidence of ancestry-specific variation was apparent, yet not conclusive due to lower study power in non-European cohorts. Variant aggregation was strongest at biologically relevant vitamin D loci, including GC, CYP2R1, DHCR7/NADSYN1, and FLG. Fifteen variants were replicated in at least two independent cohorts. LD-based clustering identified several high LD groups comprising variants identified across studies, with the strongest LD appearing between variants within established vitamin D-related loci, particularly GC, CYP2R1, DHCR7/NADSYN1, and FLG.

Circulating 25OHD appears to be influenced by shared core loci involved in vitamin D metabolism, across ancestries. Although some evidence of ancestry-specific variation was identified, findings should be interpreted with caution, in light of the predominance of European-ancestry GWAS and scarcity of sufficiently powered GWAS for other ancestral populations. Larger GWAS in non-European populations are essential for improving ancestry-specific variant discovery and interpretation.