Functional and topological modularity of disease genes explain comorbidity of human genetic diseases.

MasterMolecular connection is primary mechanism for comorbidity of distinct diseases in population. However, molecular connection allows only partial explanation of disease comorbidity, for two main reasons. First, disease is consequence of perturbation in group of genes rather than in single gene. Secondly, single gene may contribute to multiple cellular functions whose perturbations lead to unrelated diseases. While the role of various molecular connections in disease comorbidity is well studied, the contribution of modularity of disease genes has remained unclear. Here, we report that the modularity of disease causing genes impacts comorbidity of associated disease pairs. Modularity is the cause of low comorbidity among molecular connected disease pairs and high comorbidity among molecular disconnected disease pairs. Modularity of genes successfully increases the coverage of comorbid disease pairs explained. Furthermore, it improves prediction performance for significant comorbidity of human genetic diseases. Our study highlights the role of modularity of disease genes in understanding the manifestation of related diseases in human population and its implication toward bridging the gap in molecular and phenotypic connections