Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study

作者：Cyril Pottier, Xiaolai Zhou, Ralph B. Perkerson, Matt Baker, Gregory D. Jenkins, Daniel Serie, Roberta Ghidoni, Luisa Benussi, Giuliano Binetti, Adolfo López de Munain, Miren Zulaica, Fermín Moreno, Isabelle Le Ber, Florence Pasquier, Didier Hannequin, Raquel Sánchez‐Valle, Anna Antonell, Albert Lladó, Tammee M. Parsons, NiCole A. Finch, Elizabeth Finger, Carol F. Lippa, Edward D. Huey, Manuela Neumann, Peter Heutink, Matthis Synofzik, Carlo Wilke, Robert A. Rissman, Jarosław Sławek, Emilia J. Sitek, Peter Johannsen, Jørgen E. Nielsen, Yingxue Ren, Marka van Blitterswijk, Mariely DeJesus‐Hernandez, Elizabeth Christopher, Melissa E. Murray, Kevin F. Bieniek, Bret M. Evers, Camilla Ferrari, Sara Rollinson, Anna Richardson, Elio Scarpini, Giorgio Fumagalli, Alessandro Padovani, John Hardy, Parastoo Momeni, Raffaele Ferrari, Francesca Frangipane, Raffaele Maletta, Maria Anfossi, Maura Gallo, Leonard Petrucelli, EunRan Suh, Oscar L Lopez, Tsz Hang Wong, Jeroen van Rooij, Harro Seelaar, Simon Mead, Richard J. Caselli, Eric M. Reiman, Marwan N. Sabbagh, Mads Kjølby, Anders Nykjær, Anna M. Karydas, Adam L. Boxer, Lea T. Grinberg, Jordan Grafman, Salvatore Spina, Adrian L. Oblak, M-Marsel Mesulam, Sandra Weıntraub, Changiz Geula, John R. Hodges, Olivier Piguet, William S. Brooks, David J. Irwin, John Q. Trojanowski, Edward B. Lee, Keith A. Josephs, Joseph E. Parisi, Nilüfer Ertekin‐Taner, David S. Knopman, Benedetta Nacmias, Irene Piaceri, Silvia Bagnoli, Sandro Sorbi, Marla Gearing, Jonathan D. Glass, Thomas G. Beach, Sandra E. Black, Mario Masellis, Ekaterina Rogaeva, Jean‐Paul Vonsattel, Lawrence S. Honig, Julia Kofler, Amalia C. Bruni, Julie S. Snowden, David Mann, Stuart Pickering‐Brown, Janine Diehl‐Schmid, Juliane Winkelmann, Daniela Galimberti, Caroline Graff, Linn Öijerstedt, Claire Troakes, Safa Al‐Sarraj, Carlos Cruchaga, Nigel J. Cairns, Jonathan D. Rohrer, Glenda M. Halliday, John B. Kwok, John C. van Swieten, Charles L. White, Bernardino Ghetti, Jill R. Murell, Ian R. Mackenzie, Ging‐Yuek Robin Hsiung, Barbara Borroni, Giacomina Rossi, Fabrizio Tagliavini, Zbigniew K. Wszołek, Ronald C. Petersen, Eileen H. Bigio, Murray Grossman, Vivianna M. Van Deerlin, William W. Seeley, Bruce L. Miller, Neill R. Graff‐Radford, Bradley F. Boeve, Dennis W. Dickson, Joanna M. Biernacka, Rosa Rademakers · 发表于：The Lancet Neurology · 年份：2018 · DOI：10.1016/s1474-4422(18)30126-1 · 被引用次数：135 · 研究领域：Amyotrophic Lateral Sclerosis Research、Genetic Neurodegenerative Diseases、Parkinson's Disease Mechanisms and Treatments

Background Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers. Methods The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p<1 × 10 −5 ) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin. Findings Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5...