Maksim Kitsak1,2, Amitabh Sharma1,2,3, Jörg Menche1,2,4,5, Emre Guney1,2,6, Susan Dina Ghiassian1,2,7, Joseph Loscalzo8 & Albert-László Barabási1,2,4,7,8,9
Genes carrying mutations associated with genetic diseases are present in all human cells; yet, clinical manifestations of genetic diseases are usually highly tissue-specific. Although some disease genes are expressed only in selected tissues, the expression patterns of disease genes alone cannot explain the observed tissue specificity of human diseases. Here we hypothesize that for a disease to manifest itself in a particular tissue, a whole functional subnetwork of genes (disease module) needs to be expressed in that tissue. Driven by this hypothesis, we conducted a systematic study of the expression patterns of disease genes within the human interactome. We find that genes expressed in a specific tissue tend to be localized in the same neighborhood of the interactome. By contrast, genes expressed in different tissues are segregated in distinct network neighborhoods. Most important, we show that it is the integrity and the completeness of the expression of the disease module that determines disease manifestation in selected tissues. This approach allows us to construct a disease-tissue network that confirms known and predicts unexpected disease-tissue associations.