Web of Science: 25 citations, Scopus: 26 citations, Google Scholar: citations,
A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer's disease
Verheijen, Jan (Institute Born-Bunge, University of Antwerp, Antwerp, Belgium)
Van den Bossche, Tobi (Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium)
van der Zee, Julie (Institute Born-Bunge, University of Antwerp, Antwerp, Belgium)
Engelborghs, Sebastiaan (Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium)
Sánchez Valle, Raquel (Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain)
Lladó, Albert (Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain)
Graff, Caroline (Genetics Unit, Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden)
Thonberg, Håkan (Genetics Unit, Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden)
Pastor, Pau (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain)
Ortega-Cubero, Sara (Department of Neurology, Complejo Asistencial Universitario de Palencia, Palencia, Spain)
Pastor, Maria A. (Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain)
Benussi, Luisa (Molecular Markers Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy)
Ghidoni, Roberta (Molecular Markers Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy)
Binetti, Giuliano (MAC Memory Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy)
Clarimon, Jordi (Institut d'Investigació Biomèdica Sant Pau)
Lleó Bisa, Alberto (Institut d'Investigació Biomèdica Sant Pau)
Fortea Ormaechea, Juan (Institut d'Investigació Biomèdica Sant Pau)
de Mendonça, Alexandre (Faculty of Medicine and Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal)
Martins, Madalena (Faculty of Medicine and Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal)
Grau-Rivera, Oriol (Neurological Tissue Bank of the Biobanc, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain)
Gelpi, Ellen (Neurological Tissue Bank of the Biobanc, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain)
Bettens, Karolien (Institute Born-Bunge, University of Antwerp, Antwerp, Belgium)
Mateiu, Ligia (Bioinformatics Unit, Department of Molecular Genetics, VIB, Antwerp, Belgium)
Dillen, Lubina (Institute Born-Bunge, University of Antwerp, Antwerp, Belgium)
Cras, Patrick (Department of Neurology, Antwerp University Hospital, Edegem, Belgium)
De Deyn, Peter P. (Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium)
Van Broeckhoven, Christine (Institute Born-Bunge, University of Antwerp, Antwerp, Belgium)
Sleegers, Kristel (Institute Born-Bunge, University of Antwerp, Antwerp, Belgium)

Date: 2016
Abstract: 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.
Note: 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
Note: Número d'acord de subvenció EU/FP7/305299
Note: Número d'acord de subvenció ISCIII/PI14/00282
Note: Número d'acord de subvenció ISCIII/PI12/01311
Note: Número d'acord de subvenció ISCIII/PI13/02434
Rights: 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
Language: Anglès.
Document: article ; recerca ; publishedVersion
Subject: SORL1 ; Haploinsufficiency ; Loss-of-function ; Rare variants ; Alzheimer ; Early onset ; Meta-analysis
Published in: Acta Neuropathologica, Vol. 132 (march 2016) , p. 213-224, ISSN 1432-0533

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


12 p, 849.5 KB

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Research literature > UAB research groups literature > Research Centres and Groups (scientific output) > Health sciences and biosciences > Institut d'Investigació Biomèdica Sant Pau
Articles > Research articles
Articles > Published articles

 Record created 2018-02-07, last modified 2019-09-10



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