Comorbidities in the diseasome are more apparent than real: What Bayesian filtering reveals about the comorbidities of depression

Comorbidity patterns have become a major source of information to explore shared mechanisms of pathogenesis between disorders. In hypothesis-free exploration of comorbid conditions, disease-disease networks are usually identified by pairwise methods. However, interpretation of the results is hindered by several confounders. In particular a very large number of pairwise associations can arise indirectly through other comorbidity associations and they increase exponentially with the increasing breadth of the investigated diseases. To investigate and filter this effect, we computed and compared pairwise approaches with a systems-based method, which constructs a sparse Bayesian direct multimorbidity map (BDMM) by systematically eliminating disease-mediated comorbidity relations. Additionally, focusing on depression-related parts of the BDMM, we evaluated correspondence with results from logistic regression, text-mining and molecular-level measures for comorbidities such as genetic overlap and the interactome-based association score. We used a subset of the UK Biobank Resource, a cross-sectional dataset including 247 diseases and 117,392 participants who filled out a detailed questionnaire about mental health. The sparse comorbidity map confirmed that depressed patients frequently suffer from both psychiatric and somatic comorbid disorders. Notably, anxiety and obesity show strong and direct relationships with depression. The BDMM identified further directly co-morbid somatic disorders, e.g. irritable bowel syndrome, fibromyalgia, or migraine. Using the subnetwork of depression and metabolic disorders for functional analysis, the interactome-based system-level score showed the best agreement with the sparse disease network. This indicates that these epidemiologically strong disease-disease relations have improved correspondence with expected molecular-level mechanisms. The substantially fewer number of comorbidity relations in the BDMM compared to pairwise methods implies that biologically meaningful comorbid relations may be less frequent than earlier pairwise methods suggested. The computed interactive comprehensive multimorbidity views over the diseasome are available on the web at Co=MorNet: bioinformatics.mit.bme.hu/UKBNetworks

The interplay between evolution, regulation and tissue specificity in the Human Hereditary Diseasome

Background: Human disease genes can be distinguished from essential (embryonically lethal) and non-disease genes using gene attributes. Such attributes include gene age, tissue specificity of expression, regulatory capacity, sequence length, rate of sequence variation and capacity for interaction. The resulting information has been used to inform data mining approaches seeking to identify novel disease genes. Given the dynamic nature of this field and the rapid rise in relevant information, we have chosen to perform a single integrated mining approach to explore relationships among gene attributes and thereby characterise evolutionary trends associated with disease genes.Results: All against all cross comparison of 2,522 disease gene attributes revealed significant relationships existed between the age, disease-association and expression pattern of genes and the tissues within which they are expressed. We found that the over-representation of disease genes among old genes holds for tissue-specific genes, but the correlation between age and disease association vanished when conditioning on tissue-specificity. Of the 32 tissues studied, the genes expressed in pancreas are on average older than the genes expressed in any other tissue, while the testis expressed the lowest proportion of old genes. Following a focussed analysis on the impact of regulatory apparatus on evolution of disease genes, we show that regulators, comprising transcription factors and post-translation modified proteins, are over-represented among ancient disease genes. In addition, we show that the proportion of regulator genes is affected by gene age among disease genes and by tissue-specificity among non-disease genes. Finally, using 55,606 true positive gene interaction data, we find that old disease genes interacts with other old disease genes and interacting new genes interacts with genes originating from higher phylostrata.Conclusion: This study supports the non-random nature of the human diseasome. We have identified a variety of distinct features and correlations to other molecular attributes that can be used to distinguish the set of disease causing genes. This was achieved by harnessing the power of mining large scale datasets from OMIM and other databases. Ultimately such knowledge may contribute to the identification of novel human disease genes and an enhanced understanding of human biology

Exploring the cellular basis of human disease through a large-scale mapping of deleterious genes to cell types

Table S5. Disease–cell-type association P values computed using the GSC method. (XLS 686 kb

A Network of Genes, Genetic Disorders, and Brain Areas

The network-based approach has been used to describe the relationship among genes and various phenotypes, producing a network describing complex biological relationships. Such networks can be constructed by aggregating previously reported associations in the literature from various databases. In this work, we applied the network-based approach to investigate how different brain areas are associated to genetic disorders and genes. In particular, a tripartite network with genes, genetic diseases, and brain areas was constructed based on the associations among them reported in the literature through text mining. In the resulting network, a disproportionately large number of gene-disease and disease-brain associations were attributed to a small subset of genes, diseases, and brain areas. Furthermore, a small number of brain areas were found to be associated with a large number of the same genes and diseases. These core brain regions encompassed the areas identified by the previous genome-wide association studies, and suggest potential areas of focus in the future imaging genetics research. The approach outlined in this work demonstrates the utility of the network-based approach in studying genetic effects on the brain