title: Investigation of the role of rare TREM2 variants in frontotemporal dementia subtypes.
abstract: 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.
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Thelen
authors.affiliation: 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.
authors.forename: Cristina
authors.initials: C
authors.lastname: Razquin
authors.affiliation: Memory Clinic of Fundaciò ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Hernández
authors.affiliation: 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.
authors.forename: Ana
authors.initials: A
authors.lastname: Gorostidi
authors.affiliation: Alzheimer's Disease and Other Cognitive Disorders Unit, Department of Neurology, Hospital Clinic, IDIBAPS, Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Sánchez-Valle
authors.affiliation: 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.
authors.forename: Sara
authors.initials: S
authors.lastname: Ortega-Cubero
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Wolfsgruber
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Drichel
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Fliessbach
authors.affiliation: Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Duenkel
authors.affiliation: Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Marinella
authors.initials: M
authors.lastname: Damian
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Heilmann
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Slotosch
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Lennarz
authors.affiliation: Department of Neurology, Hospital do Salnés, Pontevedra, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Seijo-Martínez
authors.affiliation: Department of Neurology, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Rene
authors.affiliation: Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kornhuber
authors.affiliation: Department of Psychiatry, Charité, Berlin, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Peters
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Luckhaus
authors.affiliation: Department of Psychiatry, University of Hamburg, Hamburg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Jahn
authors.affiliation: Centre for Geriatric Medicine and Section of Gerontopsychiatry and Neuropsychology, Medical School, University of Freiburg, Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hüll
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany.
authors.forename: Eckart
authors.initials: E
authors.lastname: Rüther
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Wiltfang
authors.affiliation: 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.
authors.forename: Elena
authors.initials: E
authors.lastname: Lorenzo
authors.affiliation: Department of Neurology, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Gascon
authors.affiliation: 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.
authors.forename: Alberto
authors.initials: A
authors.lastname: Lleó
authors.affiliation: Alzheimer's Disease and Other Cognitive Disorders Unit, Department of Neurology, Hospital Clinic, IDIBAPS, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Lladó
authors.affiliation: Department of Neurology, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Campdelacreu
authors.affiliation: 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.
authors.forename: Fermin
authors.initials: F
authors.lastname: Moreno
authors.affiliation: Department of Nuclear Medicine, University of Bonn, Bonn, Germany.
authors.forename: Hojjat
authors.initials: H
authors.lastname: Ahmadzadehfar
authors.affiliation: 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.
authors.forename: Juan
authors.initials: J
authors.lastname: Fortea
authors.affiliation: 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.
authors.forename: Begoña
authors.initials: B
authors.lastname: Indakoetxea
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Bonn, Germany.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Heneka
authors.affiliation: Department of Radiology, University of Essen, Essen, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Wetter
authors.affiliation: 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.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Pastor
authors.affiliation: Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Riverol
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Becker
authors.affiliation: Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Frölich
authors.affiliation: Memory Clinic of Fundaciò ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: Lluís
authors.initials: L
authors.lastname: Tárraga
authors.affiliation: Memory Clinic of Fundaciò ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: Mercè
authors.initials: M
authors.lastname: Boada
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wagner
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Jessen
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.affiliation: 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.
authors.forename: Jordi
authors.initials: J
authors.lastname: Clarimón
authors.affiliation: 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.
authors.forename: Adolfo
authors.initials: A
authors.lastname: López de Munain
authors.affiliation: Memory Clinic of Fundaciò ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: Agustín
authors.initials: A
authors.lastname: Ruiz
authors.affiliation: 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.
authors.forename: Pau
authors.initials: P
authors.lastname: Pastor
authors.affiliation: 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.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ramirez
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics; D005260:Female; D057180:Frontotemporal Dementia / Q000145:classification / Q000235:genetics*; D056726:Genetic Association Studies; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D011971:Receptors, Immunologic / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human
keywords: Alzheimer's disease; Case-control studies; Frontotemporal dementia; Genetic association studies