A disease module in the interactome explains disease heterogeneity, drug response and captures novel pathways and genes in asthma.

Recent advances in genetics have spurred rapid progress towards the systematic identification of genes involved in complex diseases. Still, the detailed understanding of the molecular and physiological mechanisms through which these genes affect disease phenotypes remains a major challenge. Here, we identify the asthma disease module, i.e. the local neighborhood of the interactome whose perturbation is associated with asthma, and validate it for functional and pathophysiological relevance, using both computational and experimental approaches. We find that the asthma disease module is enriched with modest GWAS P-values against the background of random variation, and with differentially expressed genes from normal and asthmatic fibroblast cells treated with an asthma-specific drug. The asthma module also contains immune response mechanisms that are shared with other immune-related disease modules. Further, using diverse omics (genomics, gene-expression, drug response) data, we identify the GAB1 signaling pathway as an important novel modulator in asthma. The wiring diagram of the uncovered asthma module suggests a relatively close link between GAB1 and glucocorticoids (GCs), which we experimentally validate, observing an increase in the level of GAB1 after GC treatment in BEAS-2B bronchial epithelial cells. The siRNA knockdown of GAB1 in the BEAS-2B cell line resulted in a decrease in the NFkB level, suggesting a novel regulatory path of the pro-inflammatory factor NFkB by GAB1 in asthma.

[1]  N. Datson,et al.  A genome-wide signature of glucocorticoid receptor binding in neuronal PC12 cells , 2012, BMC Neuroscience.

[2]  M. Daly,et al.  Proteins Encoded in Genomic Regions Associated with Immune-Mediated Disease Physically Interact and Suggest Underlying Biology , 2011, PLoS genetics.

[3]  B. Celli,et al.  Addressing the complexity of chronic obstructive pulmonary disease: from phenotypes and biomarkers to scale-free networks, systems biology, and P4 medicine. , 2011, American journal of respiratory and critical care medicine.

[4]  T. Beaty,et al.  Gene expression analysis uncovers novel hedgehog interacting protein (HHIP) effects in human bronchial epithelial cells. , 2013, Genomics.

[5]  Rappold,et al.  Human Molecular Genetics , 1996, Nature Medicine.

[6]  T. Nurmagambetov,et al.  Costs of asthma in the United States: 2002-2007. , 2011, The Journal of allergy and clinical immunology.

[7]  A. Sandford,et al.  INVITED REVIEW SERIES: CUTTING EDGE TECHNOLOGIES , 2011 .

[8]  B. Lambrecht,et al.  Treatment of experimental asthma by decoy-mediated local inhibition of activator protein-1. , 2005, American journal of respiratory and critical care medicine.

[9]  A. Barabasi,et al.  Interactome Networks and Human Disease , 2011, Cell.

[10]  Søren Brunak,et al.  MetaRanker 2.0: a web server for prioritization of genetic variation data , 2013, Nucleic Acids Res..

[11]  Jean-Loup Guillaume,et al.  Fast unfolding of communities in large networks , 2008, 0803.0476.

[12]  P. Robinson,et al.  Walking the interactome for prioritization of candidate disease genes. , 2008, American journal of human genetics.

[13]  M E J Newman,et al.  Community structure in social and biological networks , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[14]  A. Zhernakova,et al.  Detecting shared pathogenesis from the shared genetics of immune-related diseases , 2009, Nature Reviews Genetics.

[15]  G. Sármay,et al.  The multiple function of Grb2 associated binder (Gab) adaptor/scaffolding protein in immune cell signaling. , 2006, Immunology letters.

[16]  Michael Q. Zhang,et al.  Network-based global inference of human disease genes , 2008, Molecular systems biology.

[17]  K. Münger,et al.  Clld7, a candidate tumor suppressor on chromosome 13q14, regulates pathways of DNA damage/repair and apoptosis. , 2010, Cancer research.

[18]  Kevin D Bunting,et al.  Grb2-associated binding (Gab) proteins in hematopoietic and immune cell biology. , 2011, American journal of blood research.

[19]  N. Frossard,et al.  The nerve growth factor and its receptors in airway inflammatory diseases. , 2008, Pharmacology & therapeutics.

[20]  Yongjin Li,et al.  Discovering disease-genes by topological features in human protein-protein interaction network , 2006, Bioinform..

[21]  Howard L McLeod,et al.  CANDID: a flexible method for prioritizing candidate genes for complex human traits , 2008, Genetic epidemiology.

[22]  P. Matthews,et al.  Pathway and network-based analysis of genome-wide association studies in multiple sclerosis , 2009, Human molecular genetics.

[23]  Inge Jonassen,et al.  Linkage-disequilibrium-based binning affects the interpretation of GWASs. , 2012, American journal of human genetics.

[24]  M. Vidal,et al.  Protein interaction maps for model organisms , 2001, Nature Reviews Molecular Cell Biology.

[25]  A. Barabasi,et al.  The human disease network , 2007, Proceedings of the National Academy of Sciences.

[26]  Xuetao Cao,et al.  Scaffolding Adaptor Protein Gab1 Is Required for TLR3/4- and RIG-I–Mediated Production of Proinflammatory Cytokines and Type I IFN in Macrophages , 2010, The Journal of Immunology.

[27]  Mehmet Koyutürk,et al.  DADA: Degree-Aware Algorithms for Network-Based Disease Gene Prioritization , 2011, BioData Mining.

[28]  Nir Friedman,et al.  A functional and regulatory map of asthma. , 2008, American journal of respiratory cell and molecular biology.

[29]  Hawoong Jeong,et al.  A protein interaction network associated with asthma. , 2008, Journal of theoretical biology.

[30]  Albert-László Barabási,et al.  A Dynamic Network Approach for the Study of Human Phenotypes , 2009, PLoS Comput. Biol..

[31]  L. Bladh,et al.  Identification of a functional glucocorticoid response element in the promoter of the cyclin-dependent kinase inhibitor p57Kip2. , 2003, Journal of molecular endocrinology.

[32]  A. Barabasi,et al.  Network medicine : a network-based approach to human disease , 2010 .

[33]  Y. Moreau,et al.  Computational tools for prioritizing candidate genes: boosting disease gene discovery , 2012, Nature Reviews Genetics.

[34]  Yudong D. He,et al.  Systems analysis of eleven rodent disease models reveals an inflammatome signature and key drivers , 2012, Molecular systems biology.

[35]  E. Schadt,et al.  Unifying immunology with informatics and multiscale biology , 2014, Nature Immunology.

[36]  R. Sharan,et al.  Protein networks in disease. , 2008, Genome research.

[37]  P. Finn,et al.  Hubs in biological interaction networks exhibit low changes in expression in experimental asthma , 2007, Molecular systems biology.

[38]  Florence Demenais,et al.  A large-scale, consortium-based genomewide association study of asthma. , 2010, The New England journal of medicine.

[39]  D. Davies,et al.  Effects Of IL-13 And IL-17 On Fibroblasts Derived From The Proximal And Distal Airways , 2011, ATS 2011.

[40]  A. Barabasi,et al.  Hierarchical Organization of Modularity in Metabolic Networks , 2002, Science.

[41]  B. Séraphin,et al.  A generic protein purification method for protein complex characterization and proteome exploration , 1999, Nature Biotechnology.

[42]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[43]  E. Schadt,et al.  Integrating siRNA and protein-protein interaction data to identify an expanded insulin signaling network. , 2009, Genome research.

[44]  Roded Sharan,et al.  Associating Genes and Protein Complexes with Disease via Network Propagation , 2010, PLoS Comput. Biol..

[45]  B. Snel,et al.  Predicting disease genes using protein–protein interactions , 2006, Journal of Medical Genetics.

[46]  Albert-László Barabási,et al.  A DIseAse MOdule Detection (DIAMOnD) Algorithm Derived from a Systematic Analysis of Connectivity Patterns of Disease Proteins in the Human Interactome , 2015, PLoS Comput. Biol..

[47]  M. DePamphilis,et al.  HUMAN DISEASE , 1957, The Ulster Medical Journal.

[48]  Arun K. Ramani,et al.  How complete are current yeast and human protein-interaction networks? , 2006, Genome Biology.

[49]  Sune Lehmann,et al.  Link communities reveal multiscale complexity in networks , 2009, Nature.

[50]  Ryan D. Hernandez,et al.  Meta-analysis of Genome-wide Association Studies of Asthma In Ethnically Diverse North American Populations , 2011, Nature Genetics.

[51]  Anton J. Enright,et al.  An efficient algorithm for large-scale detection of protein families. , 2002, Nucleic acids research.

[52]  David C. Wilson,et al.  Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease , 2012, Nature.

[53]  Lee, Jk,et al.  Lebrikizumab treatment in adults with asthma. , 2011 .

[54]  Deok-Sun Lee,et al.  Viral Perturbations of Host Networks Reflect Disease Etiology , 2012, PLoS Comput. Biol..

[55]  Sapna Kumari,et al.  Evaluation of Gene Association Methods for Coexpression Network Construction and Biological Knowledge Discovery , 2012, PloS one.

[56]  S. Horvath,et al.  Variations in DNA elucidate molecular networks that cause disease , 2008, Nature.

[57]  J. Stockman,et al.  A Large-Scale, Consortium-Based Genomewide Association Study of Asthma , 2012 .

[58]  A. Barabasi,et al.  An empirical framework for binary interactome mapping , 2008, Nature Methods.

[59]  Yusuke Nakamura,et al.  Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population , 2011, Nature Genetics.

[60]  B. Chipps Genomewide Association Between GLCCI1 and Response to Glucocorticoid Therapy in Asthma , 2012, Pediatrics.

[61]  K. N. Chandrika,et al.  Analysis of the human protein interactome and comparison with yeast, worm and fly interaction datasets , 2006, Nature Genetics.

[62]  Bassem A. Hassan,et al.  Gene prioritization through genomic data fusion , 2006, Nature Biotechnology.

[63]  Helga Thorvaldsdóttir,et al.  Molecular signatures database (MSigDB) 3.0 , 2011, Bioinform..

[64]  M. Ashburner,et al.  The Gene Ontology Consortium , 2000 .