title: Weighted Protein Interaction Network Analysis of Frontotemporal Dementia.
abstract: The genetic analysis of complex disorders has undoubtedly led to the identification of a wealth of associations between genes and specific traits. However, moving from genetics to biochemistry one gene at a time has, to date, rather proved inefficient and under-powered to comprehensively explain the molecular basis of phenotypes. Here we present a novel approach, weighted protein-protein interaction network analysis (W-PPI-NA), to highlight key functional players within relevant biological processes associated with a given trait. This is exemplified in the current study by applying W-PPI-NA to frontotemporal dementia (FTD): We first built the state of the art FTD protein network (FTD-PN) and then analyzed both its topological and functional features. The FTD-PN resulted from the sum of the individual interactomes built around FTD-spectrum genes, leading to a total of 4198 nodes. Twenty nine of 4198 nodes, called inter-interactome hubs (IIHs), represented those interactors able to bridge over 60% of the individual interactomes. Functional annotation analysis not only reiterated and reinforced previous findings from single genes and gene-coexpression analyses but also indicated a number of novel potential disease related mechanisms, including DNA damage response, gene expression regulation, and cell waste disposal and potential biomarkers or therapeutic targets including EP300. These processes and targets likely represent the functional core impacted in FTD, reflecting the underlying genetic architecture contributing to disease. The approach presented in this study can be applied to other complex traits for which risk-causative genes are known as it provides a promising tool for setting the foundations for collating genomics and wet laboratory data in a bidirectional manner. This is and will be critical to accelerate molecular target prioritization and drug discovery.
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology , Russell Square House, 9-12 Russell Square House, London WC1B 5EH, United Kingdom.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Ferrari
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London , London WC1E 6JF, United Kingdom.
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Lovering
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology , Russell Square House, 9-12 Russell Square House, London WC1B 5EH, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology , Russell Square House, 9-12 Russell Square House, London WC1B 5EH, United Kingdom.|School of Pharmacy, University of Reading , Whiteknights, Reading RG6 6AP, United Kingdom.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Lewis
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology , Russell Square House, 9-12 Russell Square House, London WC1B 5EH, United Kingdom.|School of Pharmacy, University of Reading , Whiteknights, Reading RG6 6AP, United Kingdom.
authors.forename: Claudia
authors.identifier: 0000-0001-5367-4023
authors.initials: C
authors.lastname: Manzoni
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism; D000067780:ELAV-Like Protein 1 / Q000235:genetics / Q000378:metabolism; D057180:Frontotemporal Dementia / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D010641:Phenotype; D025941:Protein Interaction Mapping / Q000379:methods*; D049490:Systems Biology; D000074405:Valosin Containing Protein
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D018797:Cell Cycle Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D000251:Adenosine Triphosphatases; D000074405:Valosin Containing Protein
keywords: complex disorders; frontotemporal dementia; functional enrichment; protein−protein interactions; systems biology; weighted protein network