Common and rare TBK1 variants in early-onset Alzheimer disease in a European cohort
Verheijen, Jan (University of Antwerp)
van der Zee, Julie (University of Antwerp)
Gijselinck, Ilse (University of Antwerp)
Van den Bossche, Tobi (University Hospital Antwerp (Bèlgica))
Dillen, Lubina (University of Antwerp)
Heeman, Bavo (University of Antwerp)
Gómez-Tortosa, Estrella (Hospital Universitario Fundación Jiménez Díaz)
Lladó, Albert (Hospital Clínic i Provincial de Barcelona)
Sanchez-Valle, Raquel (Hospital Clínic i Provincial de Barcelona)
Graff, Caroline (Karolinska University Hospital and Karolinska Institutet (Suecia))
Pastor, Pau (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Pastor, Maria A. (Clínica Universidad de Navarra)
Benussi, Luisa (Istituto Centro San Giovanni di Dio-Fatebenefratelli)
Ghidoni, Roberta (Istituto Centro San Giovanni di Dio-Fatebenefratelli)
Binetti, Giuliano (Istituto Centro San Giovanni di Dio-Fatebenefratelli)
Clarimón, Jordi (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
de Mendonça, Alexandre (University of Lisbon)
Gelpi, Ellen (Hospital Clínic i Provincial de Barcelona)
Tsolaki, Magda (Aristotle University of Thessaloniki)
Diehl-Schmid, Janine (Technische Universität München)
Nacmias, Benedetta (University of Florence)
Almeida, Maria Rosário (University of Coimbra)
Borroni, Barbara (University of Brescia)
Matej, Radoslav (Thomayer Hospital in Prague)
Ruiz, Agustín (Fundació ACE)
Engelborghs, Sebastiaan (University Hospital Antwerp (Bèlgica))
Vandenberghe, Rik (University Hospitals Leuven (Bèlgica))
De Deyn, Peter P. (University Hospital Antwerp (Bèlgica))
Cruts, Marc (University of Antwerp)
Van Broeckhoven, Christine (University of Antwerp)
Sleegers, Kristel (University of Antwerp)
Goeman, Johan
Nuytten, Dirk
Vandenbulcke, Mathieu
Santens, Patrick 700 1_
Sieben, Anne
Dermaut, Bart
Versijpt, Jan
Michotte, Alex
Deryck, Olivier
Bergmans, Bruno
Willems, Christiana
Ivanoiu, Adrian
Salmon, Eric
Alexopoulos, Panagiotis (Technische Universität München)
Sorbi, Sandro
Bessi, Valentina
Bagnoli, Silvia
Santana, Isabel
Simões do Couto, Frederico
Martins, Madalena
Thonberg, Häkan
Fratiglioni, Laura
Padovani, Alessandro
Rohan, Zdenek
Razquin, Cristina
Lorenzo, Elena
Iglesias, Elena
Seijo-Martínez, Manuel
Rene, Ramon
Gascon, Jordi
Campdelacreu, Jaume
Koutroumani, Maria
Lleó, Alberto (Institut d'Investigació Biomèdica Sant Pau)
Fortea, Juan (Institut d'Investigació Biomèdica Sant Pau)
Blesa, Rafael (Institut d'Investigació Biomèdica Sant Pau)
Universitat Autònoma de Barcelona

Date:	2018
Abstract:	TANK-binding kinase 1 (TBK1) loss-of-function (LoF) mutations are known to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), often combined with memory deficits early in the disease course. We performed targeted resequencing of TBK1 in 1253 early onset Alzheimer's disease (EOAD) patients from 8 European countries to investigate whether pathogenic TBK1 mutations are enriched among patients with clinical diagnosis of EOAD. Variant frequencies were compared against 2117 origin-matched controls. We identified only 1 LoF mutation (p. Thr79del) in a patient clinically diagnosed with Alzheimer's disease and a positive family history of ALS. We did not observe enrichment of rare variants in EOAD patients compared to controls, nor of rare variants affecting NFκB induction. Of 3 common coding variants, rs7486100 showed evidence of association (OR 1. 46 [95% CI 1. 13-1. 9]; p-value 0. 01). Homozygous carriers of the risk allele showed reduced expression of TBK1 (p-value 0. 03). Our findings are not indicative of a significant role for TBK1 mutations in EOAD. The association between common variants in TBK1, disease risk and reduced TBK1 expression warrants follow-up in FTD/ALS cohorts.
Grants:	Ministerio de Ciencia e Innovación SAF2010-18277 Ministerio de Economía y Competitividad PI14/00099 Ministerio de Economía y Competitividad PI14/00282
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Early onset Alzheimer's disease ; Frontotemporal dementia ; Loss-of-function ; RNA sequencing ; TBK1
Published in:	Neurobiology of Aging, Vol. 62 (february 2018) , p. 245.e1-245.e7, ISSN 1558-1497

DOI: 10.1016/j.neurobiolaging.2017.10.012
PMID: 29146049

7 p, 663.7 KB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
Articles > Published articles