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.