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

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  • Cyril Pottier, Mayo Clinic in Jacksonville, Florida
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  • Xiaolai Zhou, Mayo Clinic in Jacksonville, Florida
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  • Ralph B. Perkerson, Mayo Clinic in Jacksonville, Florida
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  • Matt Baker, Mayo Clinic in Jacksonville, Florida
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  • Gregory D. Jenkins, Mayo Clinic
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  • Daniel J. Serie, Mayo Clinic in Jacksonville, Florida
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  • Roberta Ghidoni, IRCCS Istituto Centro San Giovanni di Dio-Fatebenefratelli
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  • Luisa Benussi, IRCCS Istituto Centro San Giovanni di Dio-Fatebenefratelli
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  • Giuliano Binetti, IRCCS Istituto Centro San Giovanni di Dio-Fatebenefratelli
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  • Adolfo López de Munain, University of the Basque Country, Centro para Investigación en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid
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  • Miren Zulaica, University of the Basque Country, Centro para Investigación en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid
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  • Fermin Moreno, University of the Basque Country, Centro para Investigación en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid
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  • Isabelle Le Ber, Pitie-Salpetriere Hospital, LOCEAN Laboratory
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  • Florence Pasquier, University of Lille
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  • Didier Hannequin, Centre Hospitalier Universitaire de Rouen
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  • Raquel Sánchez-Valle, Clinical and Provincial Hospital of Barcelona
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  • Anna Antonell, Clinical and Provincial Hospital of Barcelona
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  • Albert Lladó, Clinical and Provincial Hospital of Barcelona
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  • Tammee M. Parsons, Mayo Clinic in Jacksonville, Florida
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  • Ni Cole A. Finch, Mayo Clinic in Jacksonville, Florida
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  • Elizabeth C. Finger, University of Western Australia
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  • Carol F. Lippa, Thomas Jefferson University Hospital
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  • Edward D. Huey, Columbia University Medical Center
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  • Manuela Neumann, Molecular Neuropathology of Neurodegenerative Diseases, University Tübingen
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  • Peter Heutink, Hertie-Institute for Clinical Brain Research and Center for Neurology, Molecular Neuropathology of Neurodegenerative Diseases
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  • Matthis Synofzik, Hertie-Institute for Clinical Brain Research and Center for Neurology, Molecular Neuropathology of Neurodegenerative Diseases
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  • Carlo Wilke, Hertie-Institute for Clinical Brain Research and Center for Neurology, Molecular Neuropathology of Neurodegenerative Diseases
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  • Robert A. Rissman, VA Boston Healthcare System, University of California, San Diego
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  • Jaroslaw Slawek, Medical University of Gdansk
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  • Emilia Sitek, Medical University of Gdansk
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  • Peter Johannsen, University of Copenhagen
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  • Jørgen E. Nielsen
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  • Yingxue Ren, Mayo Clinic in Jacksonville, Florida
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  • Marka van Blitterswijk, Mayo Clinic in Jacksonville, Florida
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  • Mariely DeJesus-Hernandez, Mayo Clinic in Jacksonville, Florida
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  • Elizabeth Christopher, Mayo Clinic in Jacksonville, Florida
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  • Melissa E. Murray, Mayo Clinic in Jacksonville, Florida
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  • Kevin F. Bieniek, Mayo Clinic in Jacksonville, Florida
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  • Bret M. Evers, University of Texas Southwestern Medical Center
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  • Camilla Ferrari, IRCCS Don Gnocchi
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  • Sara Rollinson, University of Manchester School of Medicine
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  • Anna Richardson, Salford Royal Hospital
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  • Elio Scarpini, Universita degli Studi di Milano
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  • Giorgio G. Fumagalli, Universita degli Studi di Milano, Università Degli Studi di Firenze
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  • Alessandro Padovani, University of Brescia
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  • John Hardy, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London
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  • Parastoo Momeni, Rona Holdings
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  • Raffaele Ferrari, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London
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  • Francesca Frangipane, ASP Catanzaro
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  • Raffaele Maletta, ASP Catanzaro
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  • Maria Anfossi, ASP Catanzaro
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  • Maura Gallo, ASP Catanzaro
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  • Leonard Petrucelli, Mayo Clinic in Jacksonville, Florida
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  • Eun Ran Suh, The Pennsylvania State University
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  • Oscar L. Lopez, University of Pittsburgh
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  • Tsz H. Wong, Erasmus University Medical Center
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  • Jeroen G.J. van Rooij, Erasmus University Medical Center
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  • Harro Seelaar, Erasmus University Medical Center
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  • Simon Mead, UCL
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  • Richard J. Caselli, Mayo Clinic Scottsdale-Phoenix, Arizona
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  • Eric M. Reiman, Banner Alzheimer's Institute
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  • Marwan Noel Sabbagh, University of Arizona College of Medicine Phoenix
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  • Mads Kjolby
  • Anders Nykjaer
  • Anna M. Karydas, University of California, San Francisco
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  • Adam L. Boxer, University of California, San Francisco
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  • Lea T. Grinberg, University of California, San Francisco
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  • Jordan Grafman, Northwestern University
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  • Salvatore Spina, University of California, San Francisco, Indiana University School of Medicine Indianapolis
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  • Adrian Oblak, Indiana University School of Medicine Indianapolis
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  • M. Marsel Mesulam, Northwestern University
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  • Sandra Weintraub, Northwestern University
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  • Changiz Geula, Northwestern University
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  • John R. Hodges, Sydney University, Sydney, University of Sydney Faculty of Medicine
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  • Olivier Piguet, Sydney University, Sydney
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  • William S. Brooks, Sydney University, Sydney, University of New South Wales (UNSW) Australia
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  • David J. Irwin, The Pennsylvania State University
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  • John Q. Trojanowski, The Pennsylvania State University
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  • Edward B. Lee, The Pennsylvania State University
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  • Keith A. Josephs, Mayo Clinic
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  • Joseph E. Parisi, Mayo Clinic
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  • Nilüfer Ertekin-Taner, Mayo Clinic in Jacksonville, Florida
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  • David S. Knopman, Mayo Clinic
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  • Benedetta Nacmias, Università Degli Studi di Firenze
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  • Irene Piaceri, Università Degli Studi di Firenze
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  • Silvia Bagnoli, Università Degli Studi di Firenze
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  • Sandro Sorbi, IRCCS Don Gnocchi, Università Degli Studi di Firenze
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  • Marla Gearing, Emory University
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  • Jonathan Glass, Emory University
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  • Thomas G. Beach, Banner Sun Health Research Institute
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  • Sandra E. Black, University of Toronto and Sunnybrook Health Sciences Centre
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  • Mario Masellis, University of Toronto and Sunnybrook Health Sciences Centre
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  • Ekaterina Rogaeva, University of Toronto
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  • Jean Paul Vonsattel, Columbia University Medical Center
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  • Lawrence S. Honig, Columbia University Medical Center
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  • Julia Kofler, University of Pittsburgh
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  • Amalia C. Bruni, ASP Catanzaro
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  • Julie Snowden, Salford Royal Hospital
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  • David Mann, Manchester University
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  • Stuart Pickering-Brown, University of Manchester School of Medicine
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  • Janine Diehl-Schmid, Technische Universitat Munchen
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  • Juliane Winkelmann, Technische Universität München
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  • Daniela Galimberti, Universita degli Studi di Milano
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  • Caroline Graff, Karolinska Institutet, Karolinska University Hospital
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  • Linn Öijerstedt, Karolinska Institutet, Karolinska University Hospital
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  • Claire Troakes, King's College London
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  • Safa Al-Sarraj, King's College London, The National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care West (NIHR CLAHRC West) at University Hospitals Bristol NHS Foundation Trust
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  • Carlos Cruchaga, Internal Medicine, Washington University in St. Louis, School of Medicine
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  • Nigel J. Cairns, Internal Medicine, Washington University in St. Louis, School of Medicine
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  • Jonathan D. Rohrer, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London
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  • Glenda M. Halliday, Sydney University, Sydney, University of Sydney Faculty of Medicine
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  • John B. Kwok, Sydney University, Sydney
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  • John C. van Swieten, Erasmus University Medical Center, VU University Medical Center
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  • Charles L. White, University of Texas Southwestern Medical Center
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  • Bernardino Ghetti, Indiana University School of Medicine Indianapolis
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  • Jill R. Murell, Indiana University School of Medicine Indianapolis
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  • Ian R.A. Mackenzie, The University of British Columbia
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  • Ging Yuek R. Hsiung, The University of British Columbia
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  • Barbara Borroni, University of Brescia
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  • Giacomina Rossi, Foundation IRCCS Neurological Institute Carlo Besta
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  • Fabrizio Tagliavini, Foundation IRCCS Neurological Institute Carlo Besta
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  • Zbigniew K. Wszolek, Mayo Clinic in Jacksonville, Florida
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  • Ronald C. Petersen, Mayo Clinic
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  • Eileen H. Bigio, Northwestern University
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  • Murray Grossman, The Pennsylvania State University
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  • Vivianna M. Van Deerlin, The Pennsylvania State University
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  • William W. Seeley, University of California, San Francisco
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  • Bruce L. Miller, University of California, San Francisco
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  • Neill R. Graff-Radford, Mayo Clinic in Jacksonville, Florida
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  • Bradley F. Boeve, Mayo Clinic
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  • Dennis W. Dickson, Mayo Clinic in Jacksonville, Florida
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  • Joanna M. Biernacka, Mayo Clinic
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  • Rosa Rademakers, Mayo Clinic in Jacksonville, Florida

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, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited from 26 sites, 20 of which overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery or replication stages, or in the meta-analysis. However, in the case-control analysis, we replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio [OR] 0·54, 95% CI 0·46–0·63; p=3·54 × 10−16), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (rs36196656 meta-analysis OR 1·49, 95% CI 1·30–1·71; p=1·58 × 10−8). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in cerebellar tissue (p=0·04). No effect of rs36196656 on plasma and CSF progranulin concentrations was detected by ELISA; however, co-immunoprecipitation experiments in HEK293T cells did suggest a direct binding of progranulin and GFRA2. Interpretation: TMEM106B-related and GFRA2-related pathways might be future targets for treatments for FTLD, but the biological interaction between progranulin and these potential disease modifiers requires further study. TMEM106B and GFRA2 might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling, especially for asymptomatic individuals. Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Canadian Institutes of Health Research, Italian Ministry of Health, UK National Institute for Health Research, National Health and Medical Research Council of Australia, and the French National Research Agency.

Original languageEnglish
JournalThe Lancet Neurology
Volume17
Issue6
Pages (from-to)548-558
Number of pages11
ISSN1474-4422
DOIs
Publication statusPublished - 1 Jun 2018

Bibliographical note

Copyright © 2018 Elsevier Ltd. All rights reserved.

    Research areas

  • Age of Onset, Aged, Case-Control Studies, Cerebellum/metabolism, Female, Frontotemporal Lobar Degeneration/genetics, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study, Glial Cell Line-Derived Neurotrophic Factor Receptors/genetics, Humans, Male, Middle Aged, Mutation/genetics, Progranulins/genetics, RNA, Messenger/metabolism

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