Integrative Analysis of Vitamin D-Associated Genetic Variants Reveals Cis-Regulatory Architecture and Multigenic Mechanisms Underlying Chronic Disease-Relevant Pathways.

Vitamin D is a pleiotropic regulator of immune, metabolic, and endocrine homeostasis and has been implicated in a broad spectrum of chronic diseases. Although genome-wide association studies (GWAS) have identified numerous genetic variants associated with vitamin D-related traits, most signals reside in noncoding regions, limiting biological interpretation and disease-oriented translation. Here, we present an integrative analytical framework to interpret vitamin D-associated genetic variation by linking variant-level associations to cis-regulatory architecture, gene-level aggregation, and functional organization. Vitamin D-related traits were curated from the GWAS Catalog using ontology-guided criteria. Genome-wide significant variants were functionally annotated and mapped to nearby genes using a standardized ± 50-kb cis-regulatory window. Independent variants were aggregated at the gene level to prioritize robust candidate genes for downstream analysis. We found that vitamin D-associated variants were widely distributed across the genome and were predominantly enriched in noncoding regulatory regions. Cis-regulatory mapping revealed extensive SNP-gene multiplicity, reflecting complex local regulatory architectures. Gene-level aggregation identified a prioritized set of genes supported by multiple independent variants, which converged on pathways central to chronic disease biology, including immune regulation, metabolic processes, endocrine signaling, and intracellular signal transduction. Network-based integration further revealed modular regulatory structures characterized by coordinated pathway convergence. Together, these results indicate that vitamin D-associated genetic variation contributes to chronic disease susceptibility through coordinated cis-regulatory and multigenic mechanisms rather than isolated gene effects.