title: Frontotemporal dementia: insights into the biological underpinnings of disease through gene co-expression network analysis.
abstract: BACKGROUND
  In frontotemporal dementia (FTD) there is a critical lack in the understanding of biological and molecular mechanisms involved in disease pathogenesis. The heterogeneous genetic features associated with FTD suggest that multiple disease-mechanisms are likely to contribute to the development of this neurodegenerative condition. We here present a systems biology approach with the scope of i) shedding light on the biological processes potentially implicated in the pathogenesis of FTD and ii) identifying novel potential risk factors for FTD. We performed a gene co-expression network analysis of microarray expression data from 101 individuals without neurodegenerative diseases to explore regional-specific co-expression patterns in the frontal and temporal cortices for 12 genes (MAPT, GRN, CHMP2B, CTSC, HLA-DRA, TMEM106B, C9orf72, VCP, UBQLN2, OPTN, TARDBP and FUS) associated with FTD and we then carried out gene set enrichment and pathway analyses, and investigated known protein-protein interactors (PPIs) of FTD-genes products.
  
  
  RESULTS
  Gene co-expression networks revealed that several FTD-genes (such as MAPT and GRN, CTSC and HLA-DRA, TMEM106B, and C9orf72, VCP, UBQLN2 and OPTN) were clustering in modules of relevance in the frontal and temporal cortices. Functional annotation and pathway analyses of such modules indicated enrichment for: i) DNA metabolism, i.e. transcription regulation, DNA protection and chromatin remodelling (MAPT and GRN modules); ii) immune and lysosomal processes (CTSC and HLA-DRA modules), and; iii) protein meta/catabolism (C9orf72, VCP, UBQLN2 and OPTN, and TMEM106B modules). PPI analysis supported the results of the functional annotation and pathway analyses.
  
  
  CONCLUSIONS
  This work further characterizes known FTD-genes and elaborates on their biological relevance to disease: not only do we indicate likely impacted regional-specific biological processes driven by FTD-genes containing modules, but also do we suggest novel potential risk factors among the FTD-genes interactors as targets for further mechanistic characterization in hypothesis driven cell biology work.
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, Russell Square House, 9-12 Russell Square House, London, WC1N 3BG, UK. r.ferrari@ucl.ac.uk.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Ferrari
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Cittadella Universitaria di Cagliari, 09042, Monserrato, Sardinia, Italy. paola.forabosco@cnr.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Forabosco
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, Russell Square House, 9-12 Russell Square House, London, WC1N 3BG, UK. jana.vandrovcova@csc.mrc.ac.uk.|King's College London, Department of Medical & Molecular Genetics, Guy's Hospital, London, SE1 9RT, UK. jana.vandrovcova@csc.mrc.ac.uk.
authors.forename: Jana
authors.initials: J
authors.lastname: Vandrovcova
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, Russell Square House, 9-12 Russell Square House, London, WC1N 3BG, UK. j.botia@ucl.ac.uk.|King's College London, Department of Medical & Molecular Genetics, Guy's Hospital, London, SE1 9RT, UK. j.botia@ucl.ac.uk.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Botía
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, Russell Square House, 9-12 Russell Square House, London, WC1N 3BG, UK. m.guelfi@ucl.ac.uk.|King's College London, Department of Medical & Molecular Genetics, Guy's Hospital, London, SE1 9RT, UK. m.guelfi@ucl.ac.uk.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Guelfi
authors.affiliation: Dementia Research Centre, UCL Institute of Neurology, University College London, London, WC1N 3BG, UK. jason.warren@ucl.ac.uk.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Warren
authors.affiliation: Omixy, 107 Cheapside, EC2V 6DN, London, UK. parastoo@omixy.com.
authors.forename: Parastoo
authors.initials: P
authors.lastname: Momeni
authors.affiliation: King's College London, Department of Medical & Molecular Genetics, Guy's Hospital, London, SE1 9RT, UK. michael.weale@kcl.ac.uk.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Weale
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, Russell Square House, 9-12 Russell Square House, London, WC1N 3BG, UK. mina.ryten@ucl.ac.uk.|King's College London, Department of Medical & Molecular Genetics, Guy's Hospital, London, SE1 9RT, UK. mina.ryten@ucl.ac.uk.
authors.forename: Mina
authors.initials: M
authors.lastname: Ryten
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, Russell Square House, 9-12 Russell Square House, London, WC1N 3BG, UK. j.hardy@ucl.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
mesh_terms: D000375:Aging; D000818:Animals; D001931:Brain Mapping; D057180:Frontotemporal Dementia / Q000235:genetics*; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D012307:Risk Factors; D016875:tau Proteins / Q000235:genetics
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D016875:tau Proteins