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Abstract
Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting the frontal and temporal lobes. Genome-wide association studies (GWAS) on FTD identified only a few risk loci. One of the possible explanations is that FTD is clinically, pathologically, and genetically heterogeneous. An important open question is to what extent epigenetic factors contribute to FTD and whether these factors vary between FTD clinical subgroup. We compared the DNA-methylation levels of FTD cases (n = 128), and of FTD cases with Amyotrophic Lateral Sclerosis (FTD-ALS; n = 7) to those of unaffected controls (n = 193), which resulted in 14 and 224 candidate genes, respectively. Cluster analysis revealed significant class separation of FTD-ALS from controls. We could further specify genes with increased susceptibility for abnormal gene-transcript behavior by jointly analyzing DNA-methylation levels with the presence of mutations in a GWAS FTD-cohort. For FTD-ALS, this resulted in 9 potential candidate genes, whereas for FTD we detected 1 candidate gene (ELP2). Independent validation-sets confirmed the genes DLG1, METTL7A, KIAA1147, IGHMBP2, PCNX, UBTD2, WDR35, and ELP2/SLC39A6 among others. We could furthermore demonstrate that genes harboring mutations and/or displaying differential DNA-methylation, are involved in common pathways, and may therefore be critical for neurodegeneration in both FTD and FTD-ALS.
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Details
Title
Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS
Author
Taskesen, E 1 ; Mishra, A 2 ; van der Sluis, S 2 ; Ferrari, R 3 ; Hernandez, D G 4 ; Nalls, M A 4 ; Rohrer, J D 5 ; Ramasamy, A 6 ; Kwok, J B J 7 ; Dobson-Stone, C 7 ; Schofield, P R 7 ; Halliday, G M 7 ; Hodges, J R 7 ; Piguet, O 7 ; Bartley, L 7 ; Thompson, E 8 ; Haan, E 8 ; Hernández, I 9 ; Ruiz, A 9 ; Boada, M 9 ; Borroni, B 10 ; Padovani, A 10 ; Cruchaga, C 11 ; Cairns, N J 12 ; Benussi, L 13 ; Binetti, G 14 ; Ghidoni, R 13 ; Forloni, G 15 ; Albani, D 15 ; Galimberti, D 16 ; Fenoglio, C 16 ; Serpente, M 16 ; Scarpini, E 16 ; Clarimón, J 17 ; Lleó, A 17 ; Blesa, R 17 ; M Landqvist Waldö 18 ; Nilsson, K 18 ; Nilsson, C 19 ; Mackenzie, I R A 20 ; Hsiung, G-Y R 21 ; Mann, D M A 22 ; Grafman, J 23 ; Morris, C M 24 ; Attems, J 24 ; Griffiths, T D 24 ; McKeith, I G 24 ; Thomas, A J 24 ; Pietrini, P 25 ; Huey, E D 26 ; Wassermann, E M 27 ; Baborie, A 28 ; Jaros, E 24 ; Tierney, M C 27 ; Pastor, P 29 ; Razquin, C 29 ; Ortega-Cubero, S 29 ; Alonso, E 29 ; Perneczky, R 30 ; Diehl-Schmid, J 31 ; Alexopoulos, P 31 ; Kurz, A 31 ; Rainero, I 32 ; Rubino, E 32 ; Pinessi, L 32 ; Rogaeva, E 33 ; P St George-Hyslop 33 ; Rossi, G 34 ; Tagliavini, F 34 ; Giaccone, G 34 ; Rowe, J B 35 ; Schlachetzki, J C M 36 ; Uphill, J 37 ; Collinge, J 37 ; Mead, S 37 ; Danek, A 38 ; Van Deerlin, V M 39 ; Grossman, M 39 ; Trojanowski, J Q 39 ; van der Zee, J 40 ; C Van Broeckhoven 40 ; Cappa, S F 41 ; Leber, I 42 ; Hannequin, D 43 ; Golfier, V 43 ; Vercelletto, M 43 ; Brice, A 42 ; Nacmias, B 44 ; Sorbi, S 44 ; Bagnoli, S 44 ; Piaceri, I 44 ; Nielsen, J E 45 ; Hjermind, L E 45 ; Riemenschneider, M 46 ; Mayhaus, M 46 ; Ibach, B 47 ; Gasparoni, G 46 ; Pichler, S 46 ; W Gu 46 ; Rossor, M N 5 ; Fox, N C 5 ; Warren, J D 5 ; Spillantini, M G 48 ; Morris, H R 3 ; Rizzu, P 49 ; Heutink, P 49 ; Snowden, J S 22 ; Rollinson, S 22 ; Richardson, A 22 ; Gerhard, A 22 ; Bruni, A C 50 ; Maletta, R 50 ; Frangipane, F 50 ; Cupidi, C 50 ; Bernardi, L 50 ; Anfossi, M 50 ; Gallo, M 50 ; Conidi, M E 50 ; Smirne, N 50 ; Rademakers, R 51 ; Baker, M 51 ; Dickson, D W 51 ; Graff-Radford, N R 51 ; Petersen, R C 52 ; Knopman, D 52 ; Josephs, K A 52 ; Boeve, B F 52 ; Parisi, J E 52 ; Seeley, W W 53 ; Miller, B L 54 ; Karydas, A M 54 ; Rosen, H 54 ; van Swieten, J C 55 ; Dopper, E G P 55 ; Seelaar, H 55 ; Scheltens, P 56 ; Logroscino, G 57 ; Capozzo, R 57 ; Novelli, V 58 ; Puca, A A 59 ; Franceschi, M 60 ; Postiglione, A 61 ; Milan, G 61 ; Sorrentino, P 61 ; Kristiansen, M 62 ; H-H Chiang 63 ; Graff, C 63 ; Pasquier, F 64 ; Rollin, A 64 ; Deramecourt, V 64 ; Lebouvier, T 64 ; Kapogiannis, D 65 ; Ferrucci, L 66 ; Pickering-Brown, S 22 ; Singleton, A B 4 ; Hardy, J 3 ; Momeni, P 67 ; Veldink, J H 68 ; van Es, M A 68 ; Smit, A B 69 ; Posthuma, D 1 ; Pijnenburg, Y 70
1 VU University Amsterdam, Center for Neurogenomics and Cognitive Research, Complex Trait Genetics (CTG), Amsterdam Neuroscience, Amsterdam, The Netherlands; VU University Medical Center (VUMC), Alzheimer Center, Amsterdam Neuroscience, Amsterdam, The Netherlands
2 VU University Amsterdam, Center for Neurogenomics and Cognitive Research, Complex Trait Genetics (CTG), Amsterdam Neuroscience, Amsterdam, The Netherlands
3 UCL London, Institute of Neurology, Department of Molecular Neuroscience, London, UK
4 Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35, Bethesda, MD, USA
5 Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK
6 Department of Medical and Molecular Genetics, King’s College London Tower Wing, Guy’s Hospital, London, UK
7 Neuroscience Research Australia, Sydney, Australia
8 South Australian Clinical Genetics Service, SA Pathology at Women’s and Children’s Hospital, North Adelaide, Australia
9 Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
10 Barbara Borroni (Neurology Clinic, University of Brescia, Brescia, Italy), Alessandro Padovani (Neurology Clinic, University of Brescia, Brescia, Italy
11 Department of Psychiatry, Washington University, St. Louis, MO, USA
12 Department of Pathology and Immunology, Washington University, St. Louis, MO, USA
13 Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
14 MAC Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
15 Biology of Neurodegenerative Disorders, IRCCS Istituto di Ricerche Farmacologiche, “Mario Negri”, Milano, Italy
16 University of Milan, Milan, Italy; Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
17 Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
18 Unit of Geriatric Psychiatry, Department of Clinical Sciences, Lund University, Lund, Sweden
19 Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden
20 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
21 Division of Neurology, University of British Columbia, Vancouver, Canada
22 Institute of Brain, Behaviour and Mental Health, University of Manchester, Salford Royal Hospital, Stott Lane, Salford, UK
23 Department of Psychology, Weinberg College of Arts and Sciences, Northwestern University, Chicago, USA
24 Newcastle University, Institute of Neuroscience and Institute for Ageing, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
25 IMT School for Advanced Studies, Lucca, Lucca, Italy
26 Taub Institute, Departments of Psychiatry and Neurology, Columbia University, New York, NY, USA
27 Behavioral Neurology Unit, National Insititute of Neurological Disorders and Stroke, National Insititutes of Health, Bethesda, MD, USA
28 Department of Laboratory Medicine & Pathology, Walter Mackenzie Health Sciences Centre, Alberta, Canada
29 Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain
30 Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology and Medicine, London, UK
31 Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany
32 Neurology I, Department of Neuroscience, University of Torino, Italy, A.O. Città della Salute e della Scienza di Torino, Torino, Italy
33 Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto 60 Leonard Street, Toronto, Ontario, Canada, USA
34 Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
35 Cambridge University Department of Clinical Neurosciences, Cambridge, UK
36 University of California San Diego, Department of Cellular & Molecular Medicine, 9500 Gilman Drive, La Jolla, CA, USA
37 MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square House, Queen Square, London, UK
38 Neurologische Klinik und Poliklinik, Ludwig-Maximilians-Universität, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
39 University of Pennsylvania Perelman School of Medicine, Department of Pathology and Laboratory Medicine, Philadelphia, PA, USA
40 Neurodegenerative Brain Diseases group, VIB-UAntwerp Center of Molecular Neurology, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
41 Neurorehabilitation Unit, Dept. Of Clinical Neuroscience, Vita-Salute University and San Raffaele Scientific Institute, Milan, Italy
42 Inserm, UMR_S975, CRICM; UPMC Univ Paris 06, UMR_S975; CNRS UMR 7225, F-75013, Paris, France; AP-HP, Hôpital de la Salpêtrière, Département de neurologie-centre de références des démences rares, Paris, France
43 Service de Neurologie, Inserm U1079, CNR-MAJ, Rouen University Hospital, Rouen, France
44 Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA) University of Florence, Florence, Italy
45 Danish Dementia Research Centre, Neurogenetics Clinic, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
46 Saarland University, Laboratory for Neurogenetics, Kirrberger Str.1, Bld.90, Homburg/Saar, Germany
47 University Regensburg, Department of Psychiatry, Psychotherapy and Psychosomatics, Universitätsstr. 84, Regensburg, Germany
48 University of Cambridge, Department of Clinical Neurosciences, John Van Geest Brain Repair Centre, Forvie Site, Robinson way, Cambridge, UK
49 German Center for Neurodegenerative Diseases-Tübingen, Tuebingen, Germany
50 Regional Neurogenetic Centre, ASPCZ, Lamezia Terme, Italy
51 Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL, USA
52 Department of Neurology, Mayo Clinic Rochester, Rochester, MN, USA
53 William W Seeley (Department of Neurology, Box 1207, University of California, San Francisco, CA, USA
54 Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA
55 Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands
56 Alzheimer Centre and department of neurology, VU University medical centre, Amsterdam, The Netherlands
57 Department of Basic Medical Sciences, Neurosciences and Sense Organs of the “Aldo Moro” University of Bari, Bari, Italy
58 Medical Genetics Unit, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
59 Cardiovascular Research Unit, IRCCS Multimedica, Milan, Italy
60 Neurology Dept, IRCCS Multimedica, Milan, Italy
61 Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
62 UCL Genomics, Institute of Child Health (ICH), UCL, London, UK
63 Karolinska Institutet, Dept NVS, Alzheimer Research Center, Novum, Stockholm, Sweden
64 Univ Lille, Inserm 1171, DISTALZ, Lille, France
65 National Institute on Aging (NIA/NIH), 3001 S. Hanover St, NM 531, Baltimore, MD, USA
66 Clinical Research Branch, National Institute on Aging, Baltimore, MD, USA
67 Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Science Center, Lubbock, Texas, USA
68 Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
69 VU University Amsterdam, Center for Neurogenomics and Cognitive Research, Department of Molecular and Cellular Neurobiology (MCN), Amsterdam Neuroscience, Amsterdam, The Netherlands
70 VU University Medical Center (VUMC), Alzheimer Center, Amsterdam Neuroscience, Amsterdam, The Netherlands
1 VU University Amsterdam, Center for Neurogenomics and Cognitive Research, Complex Trait Genetics (CTG), Amsterdam Neuroscience, Amsterdam, The Netherlands; VU University Medical Center (VUMC), Alzheimer Center, Amsterdam Neuroscience, Amsterdam, The Netherlands
2 VU University Amsterdam, Center for Neurogenomics and Cognitive Research, Complex Trait Genetics (CTG), Amsterdam Neuroscience, Amsterdam, The Netherlands
3 UCL London, Institute of Neurology, Department of Molecular Neuroscience, London, UK
4 Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35, Bethesda, MD, USA
5 Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK
6 Department of Medical and Molecular Genetics, King’s College London Tower Wing, Guy’s Hospital, London, UK
7 Neuroscience Research Australia, Sydney, Australia
8 South Australian Clinical Genetics Service, SA Pathology at Women’s and Children’s Hospital, North Adelaide, Australia
9 Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
10 Barbara Borroni (Neurology Clinic, University of Brescia, Brescia, Italy), Alessandro Padovani (Neurology Clinic, University of Brescia, Brescia, Italy
11 Department of Psychiatry, Washington University, St. Louis, MO, USA
12 Department of Pathology and Immunology, Washington University, St. Louis, MO, USA
13 Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
14 MAC Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
15 Biology of Neurodegenerative Disorders, IRCCS Istituto di Ricerche Farmacologiche, “Mario Negri”, Milano, Italy
16 University of Milan, Milan, Italy; Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
17 Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
18 Unit of Geriatric Psychiatry, Department of Clinical Sciences, Lund University, Lund, Sweden
19 Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden
20 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
21 Division of Neurology, University of British Columbia, Vancouver, Canada
22 Institute of Brain, Behaviour and Mental Health, University of Manchester, Salford Royal Hospital, Stott Lane, Salford, UK
23 Department of Psychology, Weinberg College of Arts and Sciences, Northwestern University, Chicago, USA
24 Newcastle University, Institute of Neuroscience and Institute for Ageing, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
25 IMT School for Advanced Studies, Lucca, Lucca, Italy
26 Taub Institute, Departments of Psychiatry and Neurology, Columbia University, New York, NY, USA
27 Behavioral Neurology Unit, National Insititute of Neurological Disorders and Stroke, National Insititutes of Health, Bethesda, MD, USA
28 Department of Laboratory Medicine & Pathology, Walter Mackenzie Health Sciences Centre, Alberta, Canada
29 Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain
30 Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology and Medicine, London, UK
31 Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany
32 Neurology I, Department of Neuroscience, University of Torino, Italy, A.O. Città della Salute e della Scienza di Torino, Torino, Italy
33 Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto 60 Leonard Street, Toronto, Ontario, Canada, USA
34 Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
35 Cambridge University Department of Clinical Neurosciences, Cambridge, UK
36 University of California San Diego, Department of Cellular & Molecular Medicine, 9500 Gilman Drive, La Jolla, CA, USA
37 MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square House, Queen Square, London, UK
38 Neurologische Klinik und Poliklinik, Ludwig-Maximilians-Universität, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
39 University of Pennsylvania Perelman School of Medicine, Department of Pathology and Laboratory Medicine, Philadelphia, PA, USA
40 Neurodegenerative Brain Diseases group, VIB-UAntwerp Center of Molecular Neurology, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
41 Neurorehabilitation Unit, Dept. Of Clinical Neuroscience, Vita-Salute University and San Raffaele Scientific Institute, Milan, Italy
42 Inserm, UMR_S975, CRICM; UPMC Univ Paris 06, UMR_S975; CNRS UMR 7225, F-75013, Paris, France; AP-HP, Hôpital de la Salpêtrière, Département de neurologie-centre de références des démences rares, Paris, France
43 Service de Neurologie, Inserm U1079, CNR-MAJ, Rouen University Hospital, Rouen, France
44 Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA) University of Florence, Florence, Italy
45 Danish Dementia Research Centre, Neurogenetics Clinic, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
46 Saarland University, Laboratory for Neurogenetics, Kirrberger Str.1, Bld.90, Homburg/Saar, Germany
47 University Regensburg, Department of Psychiatry, Psychotherapy and Psychosomatics, Universitätsstr. 84, Regensburg, Germany
48 University of Cambridge, Department of Clinical Neurosciences, John Van Geest Brain Repair Centre, Forvie Site, Robinson way, Cambridge, UK
49 German Center for Neurodegenerative Diseases-Tübingen, Tuebingen, Germany
50 Regional Neurogenetic Centre, ASPCZ, Lamezia Terme, Italy
51 Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL, USA
52 Department of Neurology, Mayo Clinic Rochester, Rochester, MN, USA
53 William W Seeley (Department of Neurology, Box 1207, University of California, San Francisco, CA, USA
54 Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA
55 Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands
56 Alzheimer Centre and department of neurology, VU University medical centre, Amsterdam, The Netherlands
57 Department of Basic Medical Sciences, Neurosciences and Sense Organs of the “Aldo Moro” University of Bari, Bari, Italy
58 Medical Genetics Unit, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
59 Cardiovascular Research Unit, IRCCS Multimedica, Milan, Italy
60 Neurology Dept, IRCCS Multimedica, Milan, Italy
61 Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
62 UCL Genomics, Institute of Child Health (ICH), UCL, London, UK
63 Karolinska Institutet, Dept NVS, Alzheimer Research Center, Novum, Stockholm, Sweden
64 Univ Lille, Inserm 1171, DISTALZ, Lille, France
65 National Institute on Aging (NIA/NIH), 3001 S. Hanover St, NM 531, Baltimore, MD, USA
66 Clinical Research Branch, National Institute on Aging, Baltimore, MD, USA
67 Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Science Center, Lubbock, Texas, USA
68 Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
69 VU University Amsterdam, Center for Neurogenomics and Cognitive Research, Department of Molecular and Cellular Neurobiology (MCN), Amsterdam Neuroscience, Amsterdam, The Netherlands
70 VU University Medical Center (VUMC), Alzheimer Center, Amsterdam Neuroscience, Amsterdam, The Netherlands
Pages
1-16
Publication year
2017
Publication date
Aug 2017
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
1957284238
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.