Investigation of the role of rare TREM2 variants in frontotemporal dementia subtypes

Autor: Manuel Seijo-Martínez, Lutz Frölich, Wolfgang Maier, Eckart Rüther, M. Lennarz, Frank Jessen, Axel Wetter, Cristina Razquin, Mercè Boada, Anja Slotosch, Fermin Moreno, Lluís Tárraga, Alberto Lleó, Elena Lorenzo, Dmitriy Drichel, Maria A. Pastor, Jordi Gascon, Jaume Campdelacreu, Tanja Duenkel, Juan Fortea, Michael Hüll, Marinella Damian, Steffen Wolfsgruber, Isabel Hernández, Stefanie Heilmann, Alfredo Ramirez, Sara Ortega-Cubero, Hojjat Ahmadzadehfar, Begoña Indakoetxea, Jordi Clarimón, Michael T. Heneka, Jens Wiltfang, Ramón Reñé, Holger Jahn, Adolfo López de Munain, Michael Wagner, Pau Pastor, Christian Luckhaus, Klaus Fliessbach, Ana Gorostidi, Raquel Sánchez-Valle, Oliver Peters, Tim Becker, Agustín Ruiz, Mario Riverol, Johannes Kornhuber, Mathias Thelen, Albert Lladó
Rok vydání: 2014
Předmět:
Male
Aging
Linkage disequilibrium
Medizin
genetics [Alzheimer Disease]
Linkage Disequilibrium
0302 clinical medicine
genetics [Membrane Glycoproteins]
genetics [Receptors
Immunologic]
Receptors
Immunologic
genetics [Frontotemporal Dementia]
Genetics
Aged
80 and over
0303 health sciences
Membrane Glycoproteins
General Neuroscience
Alzheimer's disease
Middle Aged
genetics [Genetic Variation]
3. Good health
Phenotype
Frontotemporal Dementia
Female
Frontotemporal dementia
Single-nucleotide polymorphism
Case-control studies
classification [Frontotemporal Dementia]
Biology
03 medical and health sciences
Alzheimer Disease
mental disorders
medicine
Dementia
Humans
ddc:610
Genetic Association Studies
030304 developmental biology
Genetic association
Aged
TREM2 protein
human
Genetic heterogeneity
TREM2
nutritional and metabolic diseases
Genetic Variation
Sequence Analysis
DNA
medicine.disease
nervous system diseases
Minor allele frequency
Neurology (clinical)
Geriatrics and Gerontology
030217 neurology & neurosurgery
Developmental Biology
Zdroj: Neurobiology of aging 35(11), 2657.e13-2657.e19 (2014). doi:10.1016/j.neurobiolaging.2014.06.018
NEUROBIOLOGY OF AGING
r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname
ISSN: 1558-1497
0197-4580
DOI: 10.1016/j.neurobiolaging.2014.06.018
Popis: 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. (C) 2014 Elsevier Inc. All rights reserved.
Databáze: OpenAIRE
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