Frontotemporal dementia and its subtypes: a genome-wide association study - 17/06/14

Doi : 10.1016/S1474-4422(14)70065-1

Raffaele Ferrari, PhD ^a,^b,^{^{*
Contributed equally}}, Dena G Hernandez, MSc ^b,^c,^{^{*
Contributed equally}}, Michael A Nalls, PhD ^c,^{^{*
Contributed equally}}, Jonathan D Rohrer, PhD ^b,^bw,^{^{*
Contributed equally}}, Adaikalavan Ramasamy, PhD ^b,^cm, John B J Kwok, PhD ^f,^g, Carol Dobson-Stone, PhD ^f,^g, William S Brooks, MBBS ^f,^g, Peter R Schofield, ProfDSc ^f,^g, Glenda M Halliday, ProfPhD ^f,^g, John R Hodges, ProfMD ^f,^g, Olivier Piguet, PhD ^f,^g, Lauren Bartley, MSc ^f, Elizabeth Thompson, MD ^h,ⁱ, Eric Haan, ProfMBBS ^h,ⁱ, Isabel Hernández, MD ^j, Agustín Ruiz, MD ^j, Mercè Boada, MD ^j,^k, Barbara Borroni, MD ^l, Alessandro Padovani, ProfMD ^l, Carlos Cruchaga, PhD ^m,ⁿ, Nigel J Cairns, ProfPhD ^n,^o, Luisa Benussi, PhD ^p, Giuliano Binetti, MD ^p, Roberta Ghidoni, PhD ^q, Gianluigi Forloni, PhD ^r, Daniela Galimberti, PhD ^s,^t, Chiara Fenoglio, PhD ^s,^t, Maria Serpente, PhD ^s,^t, Elio Scarpini, MD ^s,^t, Jordi Clarimón, PhD ^u,^v, Alberto Lleó, MD ^u,^v, Rafael Blesa, MD ^u,^v, Maria Landqvist Waldö, MD ^w, Karin Nilsson, PhD ^w, Christer Nilsson, PhD ^x, Ian R A Mackenzie, ProfMD ^y, Ging-Yuek R Hsiung, MD ^z, David M A Mann, ProfPhD ^aa, Jordan Grafman, ProfPhD ^ab,^ac,^ad, Christopher M Morris, PhD ^ab,^ac,^ae,^af,^ag, Johannes Attems, ProfMD ^ab,^ac,^ae,^af, Timothy D Griffiths, ProfFMedSci ^ab,^ac,^ae,^ag, Ian G McKeith, ProfMD ^ah, Alan J Thomas, ProfPhD ^af, P Pietrini, ProfMD ^ai,^aj, Edward D Huey, MD ^ak, Eric M Wassermann, MD ^al, Atik Baborie, MD ^am, Evelyn Jaros, PhD ^af,^an, Michael C Tierney, MSc ^al, Pau Pastor, MD ^v,^ao,^ap, Cristina Razquin, PhD ^ao, Sara Ortega-Cubero, MD ^v,^ao, Elena Alonso, BSc ^ao, Robert Perneczky, MD ^aq,^ar,^as, Janine Diehl-Schmid, MD ^as, Panagiotis Alexopoulos, MD ^as, Alexander Kurz, MD ^as, Innocenzo Rainero, MD ^at,^au, Elisa Rubino, MD ^at,^au, Lorenzo Pinessi, ProfMD ^at,^au, Ekaterina Rogaeva, PhD ^av, Peter St George-Hyslop, MD ^av,^aw, Giacomina Rossi, PhD ^ax, Fabrizio Tagliavini, MD ^ax, Giorgio Giaccone, MD ^ax, James B Rowe, PhD ^ay,^az,^ba, Johannes C M Schlachetzki, MD ^bb,^bc, James Uphill, BSc ^bd, John Collinge, ProfMD ^bd, Simon Mead, ProfPhD ^bd, Adrian Danek, MD ^be,^bf, Vivianna M Van Deerlin, PhD ^bg, Murray Grossman, ProfMD ^bg, John Q Trojanowski, ProfPhD ^bg, Julie van der Zee, PhD ^bh,^bi, William Deschamps, MSc ^bh,^bi, Tim Van Langenhove, MD ^bh,^bi, Marc Cruts, PhD ^bh,^bi, Christine Van Broeckhoven, ProfPhD ^bh,^bi, Stefano F Cappa, ProfMD ^bj, Isabelle Le Ber, MD ^bk,^bl, Didier Hannequin, ProfMD ^bm, Véronique Golfier, MD ^bn, Martine Vercelletto, MD ^bo, Alexis Brice, MD ^bk,^bl, Benedetta Nacmias, PhD ^bp, Sandro Sorbi, ProfPhD ^bp, Silvia Bagnoli, PhD ^bp, Irene Piaceri, PhD ^bp, Jørgen E Nielsen, MD ^bq,^br, Lena E Hjermind, MD ^bq,^br, Matthias Riemenschneider, ProfMD ^bs,^bt, Manuel Mayhaus, PhD ^bt, Bernd Ibach, PhD ^bu, Gilles Gasparoni, PhD ^bt, Sabrina Pichler, MSc ^bt, Wei Gu, PhD ^bt,^bv, Martin N Rossor, ProfMD ^bw, Nick C Fox, ProfMD ^bw, Jason D Warren, PhD ^bw, Maria Grazia Spillantini, ProfPhD ^bx, Huw R Morris, ProfPhD ^by, Patrizia Rizzu, PhD ^bz, Peter Heutink, ProfPhD ^bz, Julie S Snowden, ProfPhD ^e, Sara Rollinson, PhD ^e, Anna Richardson, MB ^ca, Alexander Gerhard, MD ^cb, Amalia C Bruni, MD ^cc, Raffaele Maletta, MD ^cc, Francesca Frangipane, MD ^cc, Chiara Cupidi, MD ^cc, Livia Bernardi, PhD ^cc, Maria Anfossi, PhD ^cc, Maura Gallo, PhD ^cc, Maria Elena Conidi, PhD ^cc, Nicoletta Smirne, BSc ^cc, Rosa Rademakers, ProfPhD ^cd, Matt Baker, BSc ^cd, Dennis W Dickson, ProfMD ^cd, Neill R Graff-Radford, ProfMD ^ce, Ronald C Petersen, ProfMD ^cf, David Knopman, ProfMD ^cf, Keith A Josephs, ProfMD ^cf, Bradley F Boeve, ProfMD ^cf, Joseph E Parisi, ProfMD ^cg, William W Seeley, MD ^ch, Bruce L Miller, ProfMD ^ch, Anna M Karydas, BA ^ch, Howard Rosen, ProfMD ^ch, John C van Swieten, ProfMD ^ci,^cj, Elise G P Dopper, MD ^ci, Harro Seelaar, PhD ^ci, Yolande A L Pijnenburg, MD ^ck, Philip Scheltens, ProfMD ^ck, Giancarlo Logroscino, MD ^cl, Rosa Capozzo, MD ^cl, Valeria Novelli, PhD ^cn, Annibale A Puca, MD ^co,^cp, Massimo Franceschi, MD ^cq, Alfredo Postiglione, ProfMD ^cr, Graziella Milan, MD ^cs, Paolo Sorrentino, MD ^cs, Mark Kristiansen, PhD ^ct, Huei-Hsin Chiang, PhD ^cu,^cv, Caroline Graff, ProfMD ^cu,^cv, Florence Pasquier, ProfMD ^cw, Adeline Rollin, MD ^cw, Vincent Deramecourt, MD ^cw, Florence Lebert, MD ^cw, Dimitrios Kapogiannis, MD ^cx, Luigi Ferrucci, MD ^d, Stuart Pickering-Brown, ProfPhD ^e, Andrew B Singleton, PhD ^c,^{^{†
Joint last authors}}, John Hardy, ProfPhD ^b,^⁎,^{^{†
Joint last authors}} , Parastoo Momeni, PhD ^a,^{^{†
Joint last authors}}

^a Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Science Center, Lubbock, Texas, USA

^b Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK

^c Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA

^d Clinical Research Branch, National Institute on Aging, Baltimore, MD, USA

^e Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK

^f Neuroscience Research Australia, Sydney, NSW, Australia

^g University of New South Wales, Sydney, NSW, Australia

^h South Australian Clinical Genetics Service, SA Pathology at Women’s and Children’s Hospital, North Adelaide, SA, Australia

ⁱ Department of Paediatrics, University of Adelaide, Adelaide, SA, Australia

^j Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain

^k Hospital Universitari Vall d’Hebron–Institut de Recerca, Universitat Autonoma de Barcelona (VHIR-UAB), Barcelona, Spain

^l Neurology Clinic, University of Brescia, Brescia, Italy

^m Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri, USA

ⁿ Hope Center, Washington University School of Medicine, St Louis, Missouri, USA

^o Department of Pathology and Immunology, Washington University, St Louis, Missouri, USA

^p NeuroBioGen Lab—Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy

^q Proteomics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy

^r Biology of Neurodegenerative Disorders, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy

^s University of Milan, Milan, Italy

^t Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy

^u Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain

^v Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain

^w Unit of Geriatric Psychiatry, Department of Clinical Sciences, Lund University, Sweden

^x Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Sweden

^y Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada

^z Division of Neurology, University of British Columbia, Vancouver, Canada

^aa Institute of Brain, Behaviour and Mental Health, University of Manchester, Salford Royal Hospital, Stott Lane, Salford, UK

^ab Rehabilitation Institute of Chicago, Departments of Physical Medicine and Rehabilitation, Psychiatry, and Cognitive Neurology and Alzheimer’s Disease Center, IL, USA

^ac Feinberg School of Medicine, Northwestern University, IL, USA

^ad Department of Psychology, Weinberg College of Arts and Sciences, Northwestern University, IL, USA

^ae Newcastle Brain Tissue Resource, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK

^af Newcastle University, Institute for Ageing and Health, Campus for Ageing and Vitality, Newcastle upon Tyne, UK

^ag Institute of Neuroscience, Newcastle University Medical School, Newcastle upon Tyne, UK

^ah Biomedical Research Building, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK

^ai Clinical Psychology Branch, Pisa University Hospital, Pisa, Italy

^aj Laboratory of Clinical Biochemistry and Molecular Biology, University of Pisa, Pisa, Italy

^ak Taub Institute, Departments of Psychiatry and Neurology, Columbia University, New York, NY, USA 10032

^al Behavioral Neurology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

^am Neuropathology Department, Walton Centre FT, Liverpool, UK

^an Neuropathology/Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK

^ao Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain

^ap Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain

^aq Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology and Medicine, London, UK

^ar West London Cognitive Disorders Treatment and Research Unit, West London Mental Health Trust, London TW8 8 DS, UK

^as Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany

^at Neurology I, Department of Neuroscience, University of Torino, Italy

^au AO Città della Salute e della Scienza di Torino, Italy

^av Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine, University of Toronto, Toronto, Ontario, Canada

^aw Cambridge Institute for Medical Research and the Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK

^ax Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy

^ay Cambridge University Department of Clinical Neurosciences, Cambridge CB2 0SZ, UK

^az MRC Cognition and Brain Sciences Unit, Cambridge, UK

^ba Behavioural and Clinical Neuroscience Institute, Cambridge, UK

^bb Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, Germany

^bc Department of Molecular Neurology, University Hospital Erlangen, Erlangen, Germany

^bd MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK

^be Neurologische Klinik und Poliklinik, Ludwig-Maximilians-Universität, Munich, Germany

^bf German Center for Neurodegenerative Diseases (DZNE), Munich, Germany

^bg University of Pennsylvania Perelman School of Medicine, Department of Neurology and Penn Frontotemporal Degeneration Center, Philadelphia, PA, USA

^bh Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerp, Belgium

^bi Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium

^bj Neurorehabilitation Unit, Deptartment Of Clinical Neuroscience, Vita-Salute University and San Raffaele Scientific Institute, Milan, Italy

^bk Inserm, UMR_S975, CRICM, F-75013; UPMC Univ Paris 06, UMR_S975, F-75013; and CNRS UMR 7225, F-75013, Paris, France

^bl AP-HP, Hôpital de la Salpêtrière, Département de Neurologie-Centre de Références des Démences Rares, F-75013, Paris, France

^bm Service de Neurologie, Inserm U1079, CNR-MAJ, Rouen University Hospital, France

^bn Service de neurologie, CH Saint Brieuc, France

^bo Service de Neurologie, CHU Nantes, France

^bp Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA) University of Florence, Florence, Italy

^bq Danish Dementia Research Centre, Neurogenetics Clinic, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Denmark

^br Department of Cellular and Molecular Medicine, Section of Neurogenetics, The Panum Institute, University of Copenhagen, Denmark

^bs Saarland University Hospital, Department for Psychiatry and Psychotherapy, Homburg/Saar, Germany

^bt Saarland University, Laboratory for Neurogenetics, Kirrberger, Homburg/Saar, Germany

^bu University Regensburg, Department of Psychiatry, Psychotherapy and Psychosomatics, Universitätsstr 84, Regensburg, Germany

^bv Luxembourg Centre For Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg

^bw Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK

^bx University of Cambridge, Department of Clinical Neurosciences, John Van Geest Brain Repair Centre, Cambridge, UK

^by MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, School of Medicine, Cardiff, UK

^bz German Center of Neurodegenerative Diseases-Tübingen, Tübingen, Germany

^ca Salford Royal Foundation Trust, Faculty of Medical and Human Sciences, University of Manchester, UK

^cb Institute of Brain, Behaviour and Mental Health, The University of Manchester, Withington, Manchester, UK

^cc Regional Neurogenetic Centre, ASPCZ, Lamezia Terme, Italy

^cd Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL, USA

^ce Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, FL, USA

^cf Department of Neurology, Mayo Clinic Rochester, Rochester, MN, USA

^cg Department of Pathology, Mayo Clinic Rochester, Rochester, MN, USA

^ch Department of Neurology, University of California, San Francisco, CA, USA

^ci Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands

^cj Department of Medical Genetics, VU University Medical Centre, Amsterdam, The Netherlands

^ck Alzheimer Centre and Department of Neurology, VU University Medical Centre, Amsterdam, The Netherlands

^cl Department of Basic Medical Sciences, Neurosciences and Sense Organs of the Aldo Moro, University of Bari, Italy

^cm Department of Medical and Molecular Genetics, King’s College London, Guy’s Hospital, London, UK

^cn Department of Molecular Cardiology, IRCCS Fondazione S Maugeri, Pavia, Italy

^co Cardiovascular Research Unit, IRCCS Multimedica, Milan, Italy

^cp Department of Medicine and Surgery, University of Salerno, Baronissi (SA), Italy

^cq Neurology Department, IRCCS Multimedica, Milan, Italy

^cr Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

^cs Geriatric Center Frullone-ASL Napoli 1 Centro, Naples, Italy

^ct UCL Genomics, Institute of Child Health (ICH), UCL, London, UK

^cu Karolinska Institutet, Department NVS, KI-Alzheimer Disease Research Center, Stockholm, Sweden

^cv Department of Geriatric Medicine, Genetics Unit, Karolinska Universtiy Hospital, Stockholm

^cw Université Lille Nord de France, Lille, France

^cx Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA

^* Correspondence to: Prof John Hardy, Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, University College London Institute of Neurology, London WC1N 3BG, UK

Summary

Background

Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes—MAPT, GRN, and C9orf72—have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.

Methods

We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10⁻⁸) single-nucleotide polymorphisms.

Findings

We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10⁻⁸). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10⁻⁸; odds ratio=1·204 [95% CI 1·11–1·30]), rs9268856 (p=5·51 × 10⁻⁹; 0·809 [0·76–0·86]) and rs1980493 (p value=1·57 × 10⁻⁸, 0·775 [0·69–0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10⁻⁷; 0·814 [0·71–0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis.

Interpretation

Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD.

Funding

The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson’s disease, Alzheimer’s Research UK, and Texas Tech University Health Sciences Center.

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Vol 13 - N° 7

P. 686-699 - juillet 2014 Retour au numéro

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Frontotemporal dementia and its subtypes: a genome-wide association study - 17/06/14

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