Abstract
Vitamin D deficiency has been linked to numerous comorbid diseases. Despite this recognition, the effectiveness of vitamin D supplementation in improving clinical outcomes remains uncertain. To shed light on the underlying cause-effect relationships and molecular mechanisms involved, we analyzed effects of over 4000 diseases on information transfers between biological processes in human tissues. Spectral clustering of the data generated identified relationships between disease phenotypes and perturbations of protein network-network interactions mediating information transfers in tissues. Examination of these relationships discovered an integrated regulatory scheme involving interactions between 188 proteins responsive to vitamin D (vitamin D interactome). Functional analysis established a central role of fifteen proteins (core vitamin D interactome) in vitamin D pharmacology and their involvement in multiple reciprocal feedback loops. Identification of functions affected by this core regulatory framework provides new insights into relationships between vitamin D deficiency-associated comorbidities, epigenetic regulation of vitamin D pharmacology, and impact of mutations on disease. Recognition of these functional relationships suggests that vitamin D associated comorbidities may not be fully treatable by vitamin D supplementation alone. Further examination of consequences of perturbations of protein interactions within the core vitamin D interactome identified 590 morbidities exhibiting physical changes co-expressed in vitamin D deficiency. Further analysis revealed that these comorbidities can be differentiated based on cause-effect relationships defined by characteristic patterns of physical abnormalities and effects on protein network interactions. These findings demonstrate the utility of systems biology-based cause-effect analyses to unravel complex relationships involving multiple diseases and multiple biological processes; thereby providing a more comprehensive understanding of comorbidities and the impact of vitamin D deficiency on health.