Web of Science: 51 cites, Scopus: 52 cites, Google Scholar: cites,
A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer's disease
Verheijen, Jan (University of Antwerp. Institute Born-Bunge)
Van den Bossche, Tobi (University Hospital Antwerp (Bèlgica))
van der Zee, Julie (University of Antwerp. Institute Born-Bunge)
Engelborghs, Sebastiaan (University Hospital Antwerp (Bèlgica))
Sánchez Valle, Raquel (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Lladó, Albert (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Graff, Caroline (Karolinska University Hospital and Karolinska Institutet (Suecia))
Thonberg, Håkan (Karolinska University Hospital and Karolinska Institutet (Suecia))
Pastor, Pau (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Ortega-Cubero, Sara (Complejo Asistencial Universitario de Palencia. Departamento de Neurología)
Pastor, Maria A. (Clínica Universidad de Navarra. Departamento de Neurología)
Benussi, Luisa (Istituto Centro San Giovanni di Dio-Fatebenefratelli (Brescia, Itàlia))
Ghidoni, Roberta (Istituto Centro San Giovanni di Dio-Fatebenefratelli (Brescia, Itàlia))
Binetti, Giuliano (Istituto Centro San Giovanni di Dio-Fatebenefratelli (Brescia, Itàlia))
Clarimón, Jordi (Institut d'Investigació Biomèdica Sant Pau)
Lleó Bisa, Alberto (Institut d'Investigació Biomèdica Sant Pau)
Fortea, Juan (Institut d'Investigació Biomèdica Sant Pau)
de Mendonça, Alexandre (University of Lisbon. Faculty of Medicine and Institute of Molecular Medicine)
Martins, Madalena (University of Lisbon. Faculty of Medicine and Institute of Molecular Medicine)
Grau-Rivera, Oriol (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Gelpi, Ellen (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Bettens, Karolien (University of Antwerp. Institute Born-Bunge)
Mateiu, Ligia (University of Antwerp. VIB)
Dillen, Lubina (University of Antwerp. Institute Born-Bunge)
Cras, Patrick (University Hospital Antwerp (Bèlgica))
De Deyn, Peter P. (University Hospital Antwerp (Bèlgica))
Van Broeckhoven, Christine (University of Antwerp. Institute Born-Bunge)
Sleegers, Kristel (University of Antwerp. Institute Born-Bunge)
Universitat Autònoma de Barcelona

Data: 2016
Resum: The sortilin-related receptor 1 (SORL1) gene has been associated with increased risk for Alzheimer's disease (AD). Rare genetic variants in the SORL1 gene have also been implicated in autosomal dominant early-onset AD (EOAD). Here we report a large-scale investigation of the contribution of genetic variability in SORL1 to EOAD in a European EOAD cohort. We performed massive parallel amplicon-based re-sequencing of the full coding region of SORL1 in 1255 EOAD patients and 1938 age- and origin-matched control individuals in the context of the European Early-Onset Dementia (EOD) consortium, originating from Belgium, Spain, Portugal, Italy, Sweden, Germany, and Czech Republic. We identified six frameshift variants and two nonsense variants that were exclusively present in patients. These mutations are predicted to result in haploinsufficiency through nonsense-mediated mRNA decay, which could be confirmed experimentally for SORL1 p. Gly447Argfs*22 observed in a Belgian EOAD patient. We observed a 1. 5-fold enrichment of rare non-synonymous variants in patients (carrier frequency 8. 8 %; SkatOMeta p value 0. 0001). Of the 84 non-synonymous rare variants detected in the full patient/control cohort, 36 were only detected in patients. Our findings underscore a role of rare SORL1 variants in EOAD, but also show a non-negligible frequency of these variants in healthy individuals, necessitating the need for pathogenicity assays. Premature stop codons due to frameshift and nonsense variants, have so far exclusively been found in patients, and their predicted mode of action corresponds with evidence from in vitro functional studies of SORL1 in AD.
Ajuts: European Commission 305299
Instituto de Salud Carlos III PI14/00282
Instituto de Salud Carlos III PI12/01311
Instituto de Salud Carlos III PI13/02434
Nota: Altres ajuts: Research Foundation Flanders/G043211N; Obra Social La Caixa/20131209; PRVOUK P26/1/4/IGA/NT12094-5; SFRH/BPD/29354/2006; Fondazione Cassa di Risparmio di Pistoia e Pescia/2014.0365; Cassa di Risparmio di Firenze/2014.0310; RF-2010-2319722; Swedish Research Council/2015-02926; Sweden Alzheimer Foundation/AF-556561
Drets: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Llengua: Anglès
Document: Article ; recerca ; Versió publicada
Matèria: SORL1 ; Haploinsufficiency ; Loss-of-function ; Rare variants ; Alzheimer ; Early onset ; Meta-analysis
Publicat a: Acta Neuropathologica, Vol. 132 (march 2016) , p. 213-224, ISSN 1432-0533

DOI: 10.1007/s00401-016-1566-9
PMID: 27026413


12 p, 849.5 KB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut d'Investigació Biomèdica Sant Pau
Articles > Articles de recerca
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 Registre creat el 2018-02-07, darrera modificació el 2022-05-25



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