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This Item Is the Archived Peer-Reviewed Author-Version Of This item is the archived peer-reviewed author-version of: Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases Reference: Ferrari Rafaelle, Wang Yungpeng, Vandrovcova Jana, Van Broeckhoven Christine [medewerker], et. al.- Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases Journal of neurology, neurosurgery and psychiatry - ISSN 0022-3050 - 88:2(2017), p. 152-164 Full text (Publisher's DOI): http://dx.doi.org/doi:10.1136/JNNP-2016-314411 Institutional repository IRUA Methods We performed a 2-stage genome wide association study (GWAS) on clinical FTD analyzing a total of 3,526 FTD cases and 9,402 controls with European ancestry. We conducted separate association analyses for each FTD subtype (behavioural variant FTD [bvFTD], semantic dementia [SD], progressive non-fluent aphasia [PNFA], and FTD overlapping with motor neuron disease [FTD-MND]) and then meta-analyzed the entire dataset in discovery phase (2,154 cases vs. 4,308 controls). We carried forward replication of the novel suggestive loci in an independent sample series (1,372 cases vs. 5,094 controls) and then performed joint phase and brain e/mQTL (expression/methylation quantitative trait loci) analyses for the associated and suggestive SNPs. Findings We identified novel associations exceeding the genome wide significance threshold (p-value<5x10-8) that encompassed the HLA locus at 6p21·3 in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC for the bvFTD subtype. Analysis of expression and methylation quantitative trait loci (e/mQTL) data suggested that these loci might affect expression and methylation in-cis. Interpretation This study points to immune system processes (link to 6p21·3) and possibly to lysosomal and autophagy pathways (link to 11q14) as potentially involved in FTD. The new loci will need to be replicated in future studies to better define their association with disease and possibly shed light on the pathomechanisms contributing to FTD. Funding Intramural funding from the National Institute of Neurological Disorders and Stroke (NINDS) and National Institute on Aging (NIA), the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK (ARUK), and Texas Tech University Health Sciences Center (TTUHSC) office of the Dean. Manuscript Frontotemporal dementia and its subtypes: a genome wide association study Raffaele Ferrari1,2’MSc, Dena G Hernandez2,3’MSc, Michael A Nalls3’PhD, Jonathan D Rohrer2,72’PhD, Adaikalavan Ramasamy2,89PhD, John BJ Kwok6,7PhD, Carol Dobson-Stone6,7PhD, William S Brooks6,7MBBS, Peter R Schofield6,7DSc, Glenda M Halliday6,7PhD, John R Hodges6,7MD, Olivier Piguet6,7PhD, Lauren Bartley6MSc, Elizabeth Thompson8,9MD, Eric Haan8,9MBBS, Isabel Hernández10MD, Agustín Ruiz10 MD, Mercè Boada10,11 MD, Barbara Borroni12MD, Alessandro Padovani12MD, Carlos Cruchaga13,14PhD, Nigel J Cairns14,15PhD, Luisa Benussi16PhD, Giuliano Binetti16MD, Roberta Ghidoni17PhD, Gianluigi Forloni18PhD, Daniela Galimberti19,20PhD, Chiara Fenoglio19,20PhD, Maria Serpente19,20PhD, Elio Scarpini19,20MD, Jordi Clarimón21,22PhD, Alberto Lleó21,22MD, Rafael Blesa21,22MD, Maria Landqvist Waldö23MD, Karin Nilsson23PhD, Christer Nilsson24PhD, Ian RA Mackenzie25MD, Ging-Yuek R Hsiung26MD, David MA Mann27PhD, Jordan Grafman28,29PhD, Christopher M Morris30,31,32PhD, Johannes Attems31MD, Timothy D Griffiths32 FMedSci, Ian G McKeith33MD, Alan J Thomas31PhD, Pietro Pietrini34MD, Edward D Huey35MD, Eric M Wassermann36MD, Atik Baborie37MD, Evelyn Jaros31,38PhD, Michael C Tierney36MSc, Pau Pastor39,40,22MD, Cristina Razquin39PhD, Sara Ortega-Cubero39,22MD, Elena Alonso39 BSc, Robert Perneczky41,42,43MD, Janine Diehl-Schmid43MD, Panagiotis Alexopoulos43MD, Alexander Kurz43MD, Innocenzo Rainero44MD, Elisa Rubino44MD, Lorenzo Pinessi44MD, Ekaterina Rogaeva45PhD, Peter St George-Hyslop45,46MD, Giacomina Rossi47PhD, Fabrizio Tagliavini47MD, Giorgio Giaccone47MD, James B Rowe48,49,50PhD, Johannes CM Schlachetzki51,52MD, James Uphill53 BSc, John Collinge53MD, Simon Mead53PhD, Adrian Danek54,55MD, Vivianna M Van Deerlin56PhD, Murray Grossman56MD, John Q Trojanowski56PhD, Julie van der Zee57,58PhD, William Deschamps57,58MSc, Tim Van Langenhove57,58MD, Marc Cruts57,58PhD, Christine Van Broeckhoven57,58PhD, The Belgian Neurology Consortium and the European Early-Onset Dementia consortium, Stefano F Cappa59MD, Isabelle Le Ber60,61MD, Didier Hannequin62MD, Véronique Golfier63MD, Martine Vercelletto64MD, Alexis Brice60,61MD, The French research network on FTLD/FTLD-ALS, Benedetta Nacmias65PhD, Sandro Sorbi65PhD, Silvia Bagnoli65PhD, Irene Piaceri65PhD, Jørgen E Nielsen66,67MD, Lena E Hjermind66,67MD, Matthias Riemenschneider68,69MD, Manuel Mayhaus69PhD, Bernd Ibach70PhD, Gilles Gasparoni69PhD, Sabrina Pichler69MSc, Wei Gu69,71PhD, Martin N Rossor72MD, Nick C Fox72MD, Jason D Warren72PhD, Maria Grazia Spillantini73PhD, Huw R Morris74PhD, Patrizia Rizzu75PhD, Peter Heutink75PhD, Julie S Snowden5PhD, Sara Rollinson5PhD, Anna Richardson76MB, Alexander Gerhard77MD, Amalia C Bruni78MD, Raffaele Maletta78MD, Francesca Frangipane78MD, Chiara Cupidi78MD, Livia Bernardi78PhD, Maria Anfossi78PhD, Maura Gallo78PhD, Maria Elena Conidi78PhD, Nicoletta Smirne78BSc, Rosa Rademakers79PhD, Matt Baker79BSc, Dennis W Dickson79MD, Neill R Graff-Radford80MD, Ronald C Petersen81MD, David Knopman81MD, Keith A Josephs81MD, Bradley F Boeve81MD, Joseph E Parisi82MD, William W Seeley83MD, Bruce L Miller84MD, Anna M Karydas84BA, Howard Rosen84MD, John C van Swieten85,86MD, Elise GP Dopper85MD, Harro 1 Seelaar85PhD, Yolande AL Pijnenburg87MD, Philip Scheltens87MD, Giancarlo Logroscino88MD, Rosa Capozzo88MD, Valeria Novelli90PhD, Annibale A Puca91,92MD, Massimo Franceschi93MD, Alfredo Postiglione94MD, Graziella Milan95MD, Paolo Sorrentino95MD, Mark Kristiansen96PhD, Huei-Hsin Chiang97,98PhD, Caroline Graff97,98MD, Florence Pasquier99MD, Adeline Rollin99MD, Vincent Deramecourt99MD, Florence Lebert99MD, Dimitrios Kapogiannis100MD, UK Brain Expression Consortium, North American Brain Expression Consortium, Luigi Ferrucci4MD, Stuart Pickering-Brown5PhD, Andrew B Singleton3*PhD, John Hardy2°*PhD and Parastoo Momeni1*PhD. Affiliations 1. Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Science Center, Lubbock, Texas, USA 2. Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK 3. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA 4. Clinical Research Branch, National Institute on Aging, Baltimore, MD, USA 5. Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK 6. Neuroscience Research Australia, Sydney, NSW 2031, Australia 7. University of New South Wales, Sydney, NSW 2052, Australia 8. South Australian Clinical Genetics Service, SA Pathology (at Women's and Children's Hospital), North Adelaide, SA 5006, Australia 9. Department of Paediatrics, University of Adelaide, Adelaide, SA 5000, Australia 10. Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain 11. Hospital Universitari Vall d’Hebron–Institut de Recerca, Universitat Autonoma de Barcelona (VHIR-UAB), Barcelona, Spain 12. Neurology Clinic, University of Brescia, Brescia, Italy 13. Department of Psychiatry, Washington University, St. Louis, MO, USA 14. Hope Center, Washington University School of Medicine, St. Louis, Missouri, USA 15. Department of Pathology and Immunology, Washington University, St. Louis, Missouri, USA 16. NeuroBioGen Lab-Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy 17. Proteomics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia Italy 18. Biology of Neurodegenerative Disorders, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy 19. University of Milan, Milan, Italy 20. Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, via F. Sforza 35, 20122, Milan 21. Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain 22. Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain 23. Unit of Geriatric Psychiatry, Department of Clinical Sciences, Lund University, Sweden 2 24. Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Sweden 25. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada 26. Division of Neurology, University of British Columbia, Vancouver, Canada 27. Institute of Brain, Behaviour and Mental Health, University of Manchester, Salford Royal Hospital, Stott Lane, Salford, M6 8HD, UK 28. Rehabilitation Institute of Chicago, Departments of Physical Medicine and Rehabilitation, Psychiatry, and Cognitive Neurology & Alzheimer's Disease Center; Feinberg School of Medicine, Northwestern University 29. Department of Psychology, Weinberg College of Arts and Sciences, Northwestern University 30. Newcastle Brain Tissue Resource, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK 31. Newcastle University, Institute for Ageing and Health, Campus for Ageing and Vitality, NE4 5PL, Newcastle upon Tyne, UK 32. Institute of Neuroscience, Newcastle University Medical
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