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Protein network analysis reveals selectively vulnerable regions and biological processes in FTD

2018; Wolters Kluwer; Volume: 4; Issue: 5 Linguagem: Inglês

10.1212/nxg.0000000000000266

2376-7839

Luke W. Bonham, Natasha Z. R. Steele, Celeste M. Karch, Claudia Manzoni, Ethan G. Geier, Natalie Wen, Aaron Ofori-Kuragu, Parastoo Momeni, John Hardy, Zachary Miller, Christopher P. Hess, Patrick A. Lewis, Bruce L. Miller, William W. Seeley, Sergio E. Baranzini, Rahul S. Desikan, Raffaele Ferrari, Jennifer S. Yokoyama, Raffaele Ferrari, Dena Hernandez, Mike A. Nalls, Jonathan D. Rohrer, Adaikalavan Ramasamy, John B. Kwok, Carol Dobson‐Stone, Peter R. Schofield, Glenda M. Halliday, J. R. Hodges, Olivier Piguet, Laura Bartley, E. Aubrey Thompson, Iván Hernández Ramírez, Agustı́n Ruiz, Merçé Boada, Barbara Borroni, Alessandro Padovani, Carlos Cruchaga, N.J. Cairns, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Gianluigi Forloni, Diego Albani, Daniela Galimberti, Chiara Fenoglio, María Serpente, Elio Scarpini, Jordi Clarimón, Alberto Lleó, Rafael Blesa, María Landqvist Waldö, Kristina Nilsson, Christer Nilsson, Ian R. Mackenzie, Ging‐Yuek Robin Hsiung, David M. A. Mann, Jordan Grafman, Christopher M. Morris, Johannes Attems, Timothy D. Griffiths, Ian G. McKeith, Alan Thomas, Pietro Pietrini, Edward D. Huey, Eric M. Wassermann, Atik Baborie, Evelyn Jaros, Michael Tierney, Pau Pástor, Cristina Razquín, Sara Ortega‐Cubero, Elena Alonso, Robert Perneczky, Janine Diehl‐Schmid, Panagiotis Alexopoulos, Alexander Kurz, Innocenzo Rainero, Elisa Rubino, Lorenzo Pinessi, E. Rogaeva, Peter St George‐Hyslop, Giacomina Rossi, Fabrizio Tagliavini, Giorgio Giaccone, Diego Albani, James B. Rowe, Johannes C. M. Schlachetzki, James Uphill, John Collinge, Simon Mead, Adrian Danek, V.M. Van Deerlin, Murray Grossman, J Q Trojanowski, Julie van der Zee, Christine Van Broeckhoven, Stefano F. Cappa, Isabelle Leber, Didier Hannequin, Véronique Golfier, Martine Vercelletto, Alexis Brice, Benedetta Nacmias, Sandro Sorbi, Silvia Bagnoli, Irene Piaceri, Jørgen E. Nielsen, L. E. Hjermind, Markus J. Riemenschneider, Manuel Mayhaus, Bernd Ibach, Gilles Gasparoni, Sabrina Pichler, Wei Gu, Martin N. Rossor, Nick C. Fox, Jason D. Warren, Maria Grazia Spillantini, Huw R. Morris, Patrizia Rizzu, Peter Heutink, Julie S. Snowden, Sara Rollinson, Anna Richardson, Alexander Gerhard, Amalia C. Bruni, Raffaele Maletta, Francesca Frangipane, Chiara Cupidi, Livia Bernardi, Maria Anfossi, Maura Gallo, Maria Elena Conidi, Nicoletta Smirne, Rosa Rademakers, Matt Baker, Dennis W. Dickson, Neill R. Graff‐Radford, Ronald Petersen, David S. Knopman, K. Josephs, B. F. Boeve, J. E. Parisi, William W. Seeley, Bruce L. Miller, Anna M. Karydas, Howard J. Rosen, John C. van Swieten, Elise G.P. Dopper, Harro Seelaar, Yolande A.L. Pijnenburg, Philip Scheltens, Giancarlo Logroscino, Rosa Capozzo, Valeria Novelli, Annibale Alessandro Puca, M. Franceschi, A. Postiglione, Graziella Milan, Paolo Sorrentino, Mark Kristiansen, H-H Chiang, Caroline Graff, Florence Pasquier, Adeline Rollin, Vincent Deramecourt, Thibaud Lebouvier, Dimitrios Kapogiannis, Luigi Ferrucci, Stuart Pickering‐Brown, Andrew Singleton, John Hardy, Parastoo Momeni,

Neurological diseases and metabolism

The neuroanatomical profile of behavioral variant frontotemporal dementia (bvFTD) suggests a common biological etiology of disease despite disparate pathologic causes; we investigated the genetic underpinnings of this selective regional vulnerability to identify new risk factors for bvFTD.We used recently developed analytical techniques designed to address the limitations of genome-wide association studies to generate a protein interaction network of 63 bvFTD risk genes. We characterized this network using gene expression data from healthy and diseased human brain tissue, evaluating regional network expression patterns across the lifespan as well as the cell types and biological processes most affected in bvFTD.We found that bvFTD network genes show enriched expression across the human lifespan in vulnerable neuronal populations, are implicated in cell signaling, cell cycle, immune function, and development, and are differentially expressed in pathologically confirmed frontotemporal lobar degeneration cases. Five of the genes highlighted by our differential expression analyses, BAIAP2, ERBB3, POU2F2, SMARCA2, and CDC37, appear to be novel bvFTD risk loci.Our findings suggest that the cumulative burden of common genetic variation in an interacting protein network expressed in specific brain regions across the lifespan may influence susceptibility to bvFTD.