Weighted Protein Interaction Network Analysis of Frontotemporal Dementia
Raffaele Ferrari,Ruth C. Lovering,John Hardy,Patrick A. Lewis,Patrick A. Lewis,Claudia Manzoni,Claudia Manzoni +6 more
TLDR
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 and will be critical to accelerate molecular target prioritization and drug discovery.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 in...read more
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The central role of DNA damage and repair in CAG repeat diseases.
Thomas Massey,Lesley Jones +1 more
TL;DR: How DNA damage and repair could trigger, and also result from, CAG repeat expansion to drive neurodegeneration is considered.
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Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets
Demis A. Kia,David Zhang,Sebastian Guelfi,Claudia Manzoni,Leon Hubbard,Regina H. Reynolds,Juan A. Botía,Mina Ryten,Raffaele Ferrari,Patrick A. Lewis,Patrick A. Lewis,Nigel Williams,Daniah Trabzuni,John Hardy,Nicholas W. Wood,Alastair J. Noyce,Rauan Kaiyrzhanov,Ben Middlehurst,Manuela Tan,Henry Houlden,Huw R. Morris,Helene Plun-Favreau,Peter Holmans,Jose Bras,John P. Quinn,Kin Y. Mok,Kerri J. Kinghorn,Kimberley Billingsley,Patrick Lewis,Sebastian R Schreglmann,Rita Guerreiro,Ruth C. Lovering,Lea R'Bibo,Mie Rizig,Valentina Escott-Price,Viorica Chelban,Thomas Foltynie,Alexis Brice,Fabrice Danjou,Suzanne Lesage,Jean-Christophe Corvol,Maria Martinez,Claudia Schulte,Kathrin Brockmann,Javier Simón-Sánchez,Peter Heutink,Patrizia Rizzu,Manu Sharma,Thomas Gasser,Aude Nicolas,Mark R. Cookson,Sara Bandres-Ciga,Cornelis Blauwendraat,David Craig,Faraz Faghri,J. Raphael Gibbs,Dena G. Hernandez,Kendall Van Keuren-Jensen,Joshua M. Shulman,Hampton L. Leonard,Mike A. Nalls,Laurie Robak,Steven J. Lubbe,Steven Finkbeiner,Niccolo E. Mencacci,Codrin Lungu,Andrew B. Singleton,Sonja W. Scholz,Xylena Reed,Roy N. Alcalay,Ziv Gan-Or,Guy A. Rouleau,Lynne Krohn,Jacobus J. van Hilten,Johan Marinus,Astrid Adarmes-Gómez,Miquel Aguilar,Ignacio Alvarez,Victoria Alvarez,Francisco J. Barrero,Jesús Alberto Bergareche Yarza,Inmaculada Bernal-Bernal,Marta Blazquez,Marta Bonilla-Toribio,Juan A. Botía,María Teresa Boungiorno,Dolores Buiza-Rueda,Ana Cámara,Fátima Carrillo,Mario Carrión-Claro,Debora Cerdan,Jordi Clarimón,Yaroslau Compta,Monica Diez-Fairen,Oriol Dols-Icardo,Jacinto Duarte,Raquel Duran,Francisco Escamilla-Sevilla,Mario Ezquerra,Cici Feliz,Manel Fernández,Rubén Fernández-Santiago,Ciara Garcia,Pedro J. Garcia-Ruiz,Pilar Gómez-Garre,Maria Jose Gomez Heredia,Isabel González-Aramburu,Ana Gorostidi Pagola,Janet Hoenicka,Jon Infante,Adriano Jimenez-Escrig,Jaime Kulisevsky,Miguel A. Labrador-Espinosa,Jose Lopez-Sendon,Adolfo López de Munain Arregui,Daniel Macias,Irene Martínez Torres,Juan Marín,María José Martí,Juan Carlos Martínez-Castrillo,Carlota Méndez-del-Barrio,Manuel Menéndez González,Marina Mata Adolfo Mínguez,Pablo Mir,Elisabet Mondragon Rezola,Esteban Muñoz,Javier Pagonabarraga,Pau Pastor,Francisco Perez Errazquin,Teresa Periñán-Tocino,Javier Ruiz-Martínez,Clara Ruz,Antonio Sanchez Rodriguez,María Sierra,Esther Suarez-Sanmartin,Cesar Tabernero,Juan Pablo Tartari,Cristina Tejera-Parrado,Eduard Tolosa,Francesc Valldeoriola,Laura Vargas-González,Lydia Vela,Francisco Vives,Alexander Zimprich,Lasse Pihlstrøm,Mathias Toft,Sulev Kõks,Pille Taba,Sharon Hassin-Baer,Michael E. Weale,Adaikalavan Ramasamy,Colin Smith,Manuel Sebastian Guelfi,Karishma D’Sa,Paola Forabosco +154 more
TL;DR: In this paper, the authors used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals.
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CSF sAPPβ, YKL-40, and NfL along the ALS-FTD spectrum.
Ignacio Illán-Gala,Daniel Alcolea,Victor Montal,Oriol Dols-Icardo,Laia Muñoz,Noemi de Luna,Janina Turon-Sans,Elena Cortés-Vicente,Ma Belén Sánchez-Saudinós,Andrea Subirana,Isabel Sala,Rafael Blesa,Jordi Clarimón,Juan Fortea,Ricard Rojas-García,Alberto Lleó +15 more
TL;DR: This study provides Class III evidence that CSF levels of sAPPβ, YKL-40, and NfL are useful to assess frontotemporal neurodegeneration and the progression rate in the ALS-FTD continuum.
Journal ArticleDOI
Genetics and molecular mechanisms of frontotemporal lobar degeneration: an update and future avenues
TL;DR: The state-of-the-art genetics of familial FTLD are surveyed and the current understanding of the genetic architecture of sporadic FTLD is recapitulate by summarizing results of genome-wide association studies performed in FTLD to date.
Journal ArticleDOI
A novel network analysis approach reveals DNA damage, oxidative stress and calcium/cAMP homeostasis-associated biomarkers in frontotemporal dementia.
Fernando Palluzzi,Raffaele Ferrari,Francesca Graziano,Valeria Novelli,Giacomina Rossi,Daniela Galimberti,Innocenzo Rainero,Luisa Benussi,Benedetta Nacmias,Amalia C. Bruni,Daniele Cusi,Daniele Cusi,Erika Salvi,Barbara Borroni,Mario Grassi +14 more
TL;DR: A broad FTD genetic interaction map of the Italian population is designed, through a novel network-based approach modelled on the concepts of disease-relevance and interaction perturbation, combining Steiner tree search and Structural Equation Model (SEM) analysis, showing a strong connection between Calcium/cAMP metabolism, oxidative stress-induced Serine/Threonine kinases activation, and postsynaptic membrane potentiation.
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