[en] Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. Rare TREM2 variants have been recently identified in families affected by FTD-like phenotype. However, genetic studies of the role of rare TREM2 variants in FTD have generated conflicting results possibly because of difficulties on diagnostic accuracy. The aim of the present study was to investigate associations between rare TREM2 variants and specific FTD subtypes (FTD-S). The entire coding sequence of TREM2 was sequenced in FTD-S patients of Spanish (n = 539) and German (n = 63) origin. Genetic association was calculated using Fisher exact test. The minor allele frequency for controls was derived from in-house genotyping data and publicly available databases. Seven previously reported rare coding variants (p.A28V, p.W44X, p.R47H, p.R62H, p.T66M, p.T96K, and p.L211P) and 1 novel missense variant (p.A105T) were identified. The p.R47H variant was found in 4 patients with FTD-S. Two of these patients showed cerebrospinal fluid pattern of amyloid beta, tau, and phosphorylated-tau suggesting underlying Alzheimer's disease (AD) pathology. No association was found between p.R47H and FTD-S. A genetic association was found between p.T96K and FTD-S (p = 0.013, odds ratio = 4.23, 95% Confidence Interval [1.17-14.77]). All 6 p.T96K patients also carried the TREM2 variant p.L211P, suggesting linkage disequilibrium. The remaining TREM2 variants were found in 1 patient, respectively, and were absent in controls. The present findings provide evidence that p.T96K is associated with FTD-S and that p.L211P may contribute to its pathogenic effect. The data also suggest that p.R47H is associated with an FTD phenotype that is characterized by the presence of underlying AD pathology.
Disciplines :
Neurology
Author, co-author :
Thelen, Mathias; Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany
Razquin, Cristina; Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra School of Medicine, Pamplona, Spain, Center for Network Biomedical Research into Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
Hernández, Isabel; Memory Clinic of Fundaciò ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
Gorostidi, Ana; Center for Network Biomedical Research into Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain, Neuroscience Area, BioDonostia Health Research Institute, San Sebastian, Spain
Sánchez-Valle, Raquel; Alzheimer's Disease and Other Cognitive Disorders Unit, Department of Neurology, Hospital Clinic, IDIBAPS, Barcelona, Spain
Ortega-Cubero, Sara; Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra School of Medicine, Pamplona, Spain, Center for Network Biomedical Research into Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
Wolfsgruber, Steffen; Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Drichel, Dmitriy; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Fliessbach, Klaus; Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Duenkel, Tanja; Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany
Damian, Marinella; Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany
Heilmann, Stefanie; Institute of Human Genetics, University of Bonn, Bonn, Germany
Slotosch, Anja; Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany
Lennarz, Martina; Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany
Seijo-Martínez, Manuel; Department of Neurology, Hospital do Salnés, Pontevedra, Spain
Rene, Ramón; Department of Neurology, Hospital Universitari de Bellvitge, Barcelona, Spain
Kornhuber, Johannes; Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany
Peters, Oliver; Department of Psychiatry, Charité, Berlin, Germany
Luckhaus, Christian; Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany
Jahn, Holger; Department of Psychiatry, University of Hamburg, Hamburg, Germany
Hüll, Michael; Centre for Geriatric Medicine and Section of Gerontopsychiatry and Neuropsychology, Medical School, University of Freiburg, Freiburg, Germany
Rüther, Eckart; Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany
Wiltfang, Jens; Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany
Lorenzo, Elena; Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra School of Medicine, Pamplona, Spain, Center for Network Biomedical Research into Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
Gascon, Jordi; Department of Neurology, Hospital Universitari de Bellvitge, Barcelona, Spain
Lleó, Alberto; Center for Network Biomedical Research into Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain, Department of Neurology, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Lladó, Albert; Alzheimer's Disease and Other Cognitive Disorders Unit, Department of Neurology, Hospital Clinic, IDIBAPS, Barcelona, Spain
Campdelacreu, Jaume; Department of Neurology, Hospital Universitari de Bellvitge, Barcelona, Spain
Moreno, Fermin; Center for Network Biomedical Research into Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain, Neuroscience Area, BioDonostia Health Research Institute, San Sebastian, Spain, Department of Neurology, Donostia University Hospital, San Sebastian, Spain
Ahmadzadehfar, Hojjat; Department of Nuclear Medicine, University of Bonn, Bonn, Germany
Dementia Genetics Spanish Consortium (DEGESCO)
Fortea, Juan; Center for Network Biomedical Research into Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain, Department of Neurology, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Indakoetxea, Begoña; Center for Network Biomedical Research into Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain, Neuroscience Area, BioDonostia Health Research Institute, San Sebastian, Spain, Department of Neurology, Donostia University Hospital, San Sebastian, Spain
HENEKA, Michael ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany, Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Bonn, Germany
Wetter, Axel; Department of Radiology, University of Essen, Essen, Germany
Pastor, Maria A; Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain, Neuroimaging Laboratory, Division of Neuroscience, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Riverol, Mario; Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain
Becker, Tim; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany, Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany
Frölich, Lutz; Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany
Tárraga, Lluís; Memory Clinic of Fundaciò ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
Boada, Mercè; Memory Clinic of Fundaciò ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
Wagner, Michael; Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Jessen, Frank; Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Maier, Wolfgang; Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Clarimón, Jordi; Center for Network Biomedical Research into Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain, Department of Neurology, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
López de Munain, Adolfo; Center for Network Biomedical Research into Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain, Neuroscience Area, BioDonostia Health Research Institute, San Sebastian, Spain, Department of Neurology, Donostia University Hospital, San Sebastian, Spain, Department of Neurosciences, University of Basque Country, San Sebastian, Spain
Ruiz, Agustín; Memory Clinic of Fundaciò ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
Pastor, Pau ; Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra School of Medicine, Pamplona, Spain, Center for Network Biomedical Research into Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain, Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain
Ramirez, Alfredo; Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany, Institute of Human Genetics, University of Bonn, Bonn, Germany. Electronic address: alfredo.ramirez@ukb.uni-bonn.de
German Federal Ministry of Education and Research Department of Health of the Government of Navarra, Spain Instituto de Salud Carlos III, Ministerio de Economía y Competitividad Instituto de Salud Carlos III
Funding text :
We thank all participants for their contribution to this project. We are indebted to Mrs Trinitat Port-Carbó and her family for their support to the Fundació ACE research programs. The work described in the present publication was performed within the context of the German Research Network on Dementia (KND) and the German Research Network on Degenerative Dementia (KNDD), which are funded by the German Federal Ministry of Education and Research (grants KND: 01GI0102 , 01GI0420 , 01GI0422 , 01GI0423 , 01GI0429 , 01GI0431 , 01GI0433 , 01GI0434 ; grants KNDD: 01GI1007A , 01GI0710 , 01GI0711 , 01GI0712 , 01GI0713 , 01GI0714 , 01GI0715 , 01GI0716 , 01ET1006B ). This work was supported by grants from the Department of Health of the Government of Navarra, Spain to PP (references 13085 and 3/2008 ). AR is supported by grant PI13/02434 ( Instituto de Salud Carlos III, Ministerio de Economía y Competitividad , Spain). This study was supported in part by the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III cofunded by FEDER (Fondo Europeo de Desarrollo Regional) (PI11/00234). This study was partially supported by grants from Instituto de Salud Carlos III ( PI12/01311 ).
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