Protein localization as a principal feature of the etiology and comorbidity of genetic diseases

Proteins targeting the same subcellular localization tend to participate in mutual protein–protein interactions (PPIs) and are often functionally associated. Here, we investigated the relationship between disease‐associated proteins and their subcellular localizations, based on the assumption that protein pairs associated with phenotypically similar diseases are more likely to be connected via subcellular localization. The spatial constraints from subcellular localization significantly strengthened the disease associations of the proteins connected by subcellular localizations. In particular, certain disease types were more prevalent in specific subcellular localizations. We analyzed the enrichment of disease phenotypes within subcellular localizations, and found that there exists a significant correlation between disease classes and subcellular localizations. Furthermore, we found that two diseases displayed high comorbidity when disease‐associated proteins were connected via subcellular localization. We newly explained 7584 disease pairs by using the context of protein subcellular localization, which had not been identified using shared genes or PPIs only. Our result establishes a direct correlation between protein subcellular localization and disease association, and helps to understand the mechanism of human disease progression. Synopsis It was shown that the emergence of phenotypically similar diseases are triggered as a result of molecular connections between disease‐causing genes (Oti and Brunner, 2007 ; Zaghloul and Katsanis, 2010 ). From a genetics, perspective diseases are associated with certain genes (Goh et al , 2007 ; Feldman et al , 2008 ), whereas from a proteomics perspective phenotypically similar diseases are connected via biological modules such as protein–protein interactions (PPIs) or molecular pathways (Lage et al , 2007 ; Jiang et al , 2008 ; Wu et al , 2008 ; Linghu et al , 2009 ; Suthram et al , 2010 ). These molecular connections between diseases were observed on the population level as well: diseases connected through molecular connections such as shared genes, PPIs, and metabolic pathways tend to show elevated comorbidity (Rzhetsky et al , 2007 ; Lee et al , 2008 ; Zhernakova et al , 2009 ; Park et al , 2009a , 2009b ). While these findings constitute a step toward improving our understanding of the mechanism of disease progression, there are still many more molecule‐level connections between disease pairs that need to be explo