Metadata and PubMed databases to demonstrate that symptom variability for a particular disease correlates with the density of protein-protein interactions linked to the pathobiology of that disease 16. For example, they observed that overlap for 78 symptoms between the inflammatory bowel disorders ulcerative colitis and Crohn’s disease was also common to a number of infectious diseases linked to the development of intestinal inflammation and colonic mucosal effacement that define these diseases pathologically. Specifically, symptom linkage paralleled a pattern of gene network connectivity between ulcerative colitis and Crohn’s disease and various intestinal viral, bacterial, and parasitic infections whose incidence is, in turn, implicated in the clinical expression of bowel inflammation in patients 60, 61. These findings are conceptually similar to evidence by others indicating that the probability among patients diagnosed with a single disease developing another specific condition is not random. Analyses of the Phenotypic Disease Network, which links disease groups within the human disease interactome according to common phenotype modules, suggest connected co-morbidities follow along the lines of proteomic connectivity and may be relevant to inform disease prognosis (Figure 4) 62. order Enzastaurin Furthermore, network analyses haveWiley Interdiscip Rev Syst Biol Med. Author manuscript; available in PMC 2016 July 01.Wang et al.Pageexposed disease similarities based on genetic connectivity not identified by classical population genomics alone. In a proof-of-concept analysis of 1.5 million data records, Rzhetsky and colleagues reported polymorphism overlap between bipolar disorder and schizophrenia, and between bipolar disorder and autism by up to 60 and 75 , respectively 59. Despite the incompleteness of the human interactome, Menche and colleagues studied disease-disease relationships using network topological analysis and provided evidence that interactome network-based location of each disease module reflects its pathobiological relationship to other diseases 63. This approach has illuminated unexpected gene overlap between diseases that are, by convention, regarded as unrelated clinical entities. For example, SMARCA4 is a protein associated with myocardial infarction, which in their interactome is linked with the proteins ALK, MYC, and NFKB2 that are implicated in the pathogenesis of lymphoma. Associations such as these may account for heretofore incompletely explained JC-1MedChemExpress JC-1 epidemiological associations between diseases that are seemingly unrelated biologically, including in this instance large cell lymphoma and myocardial infarction, which share a comorbidity rate that is higher than anticipated based on current understanding of their respective pathobiologies. Furthermore, a number of diseases occupying overlapping modules within the interactome, but for which known pathobiological relationships are lacking, were also reported, including glomerulonephritis and biliary cirrhosis, glioma and myocardial infarction, hepatic cirrhosis and spondylitis, albuminuria and respiratory disease, among other pairs. Forthcoming empiric efforts are required to crystalize the mechanisms by which to account for disease interrelatedness among these phenotypes. The extent to which these early observations may redefine the epidemiology of complex syndromes remains to be determined. Nevertheless, these contributions illuminate overlap in the biological substrate underlying.Metadata and PubMed databases to demonstrate that symptom variability for a particular disease correlates with the density of protein-protein interactions linked to the pathobiology of that disease 16. For example, they observed that overlap for 78 symptoms between the inflammatory bowel disorders ulcerative colitis and Crohn’s disease was also common to a number of infectious diseases linked to the development of intestinal inflammation and colonic mucosal effacement that define these diseases pathologically. Specifically, symptom linkage paralleled a pattern of gene network connectivity between ulcerative colitis and Crohn’s disease and various intestinal viral, bacterial, and parasitic infections whose incidence is, in turn, implicated in the clinical expression of bowel inflammation in patients 60, 61. These findings are conceptually similar to evidence by others indicating that the probability among patients diagnosed with a single disease developing another specific condition is not random. Analyses of the Phenotypic Disease Network, which links disease groups within the human disease interactome according to common phenotype modules, suggest connected co-morbidities follow along the lines of proteomic connectivity and may be relevant to inform disease prognosis (Figure 4) 62. Furthermore, network analyses haveWiley Interdiscip Rev Syst Biol Med. Author manuscript; available in PMC 2016 July 01.Wang et al.Pageexposed disease similarities based on genetic connectivity not identified by classical population genomics alone. In a proof-of-concept analysis of 1.5 million data records, Rzhetsky and colleagues reported polymorphism overlap between bipolar disorder and schizophrenia, and between bipolar disorder and autism by up to 60 and 75 , respectively 59. Despite the incompleteness of the human interactome, Menche and colleagues studied disease-disease relationships using network topological analysis and provided evidence that interactome network-based location of each disease module reflects its pathobiological relationship to other diseases 63. This approach has illuminated unexpected gene overlap between diseases that are, by convention, regarded as unrelated clinical entities. For example, SMARCA4 is a protein associated with myocardial infarction, which in their interactome is linked with the proteins ALK, MYC, and NFKB2 that are implicated in the pathogenesis of lymphoma. Associations such as these may account for heretofore incompletely explained epidemiological associations between diseases that are seemingly unrelated biologically, including in this instance large cell lymphoma and myocardial infarction, which share a comorbidity rate that is higher than anticipated based on current understanding of their respective pathobiologies. Furthermore, a number of diseases occupying overlapping modules within the interactome, but for which known pathobiological relationships are lacking, were also reported, including glomerulonephritis and biliary cirrhosis, glioma and myocardial infarction, hepatic cirrhosis and spondylitis, albuminuria and respiratory disease, among other pairs. Forthcoming empiric efforts are required to crystalize the mechanisms by which to account for disease interrelatedness among these phenotypes. The extent to which these early observations may redefine the epidemiology of complex syndromes remains to be determined. Nevertheless, these contributions illuminate overlap in the biological substrate underlying.