A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease
Year: 2016
Type: article
Study design: Observational Study
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.
Source: Acta Neuropathologica
Authors: Jan Verheijen, Tobi Van den Bossche, Julie van der Zee, Sebastiaan Engelborghs, Raquel Sanchez-Valle, Albert Lladó, Caroline Graff, Håkan Thonberg, Pau Pastor, Sara Ortega-Cubero, Maria A. Pastor, Luisa Benussi, Roberta Ghidoni, Giuliano Binetti, Jordi Clarimon, Alberto Lleó, Juan Fortea, Alexandre de Mendonça, Madalena Martins, Oriol Grau-Rivera, Ellen Gelpi, Karolien Bettens, Ligia Mateiu, Lubina Dillen, Patrick Cras, Peter P. De Deyn, Christine Van Broeckhoven, Kristel Sleegers
Institutions: University of Antwerp, Institute Born-Bunge, Antwerp University Hospital, ZNA Middelheim Hospital, Hospital Clínic de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Karolinska University Hospital, Karolinska Institutet, Instituto de Salud Carlos III, Biomedical Research Networking Center on Neurodegenerative Diseases, University Hospital Mútua de Terrassa, Centro de Investigación Biomédica en Red, Universitat de Barcelona, Complejo Asistencial Universitario de Palencia, Clinica Universidad de Navarra, Centro de Investigación Médica Aplicada, Universidad de Navarra, Centro San Giovanni di Dio Fatebenefratelli, Universitat Autònoma de Barcelona, Hospital de Sant Pau, University of Lisbon
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,990
Funders: Fondazione Cassa di Risparmio di Pistoia e Pescia, Univerzita Karlova v Praze, European Commission, Fonds Wetenschappelijk Onderzoek, Ministero della Salute, Ministerio de Economía y Competitividad, Karolinska Institutet, Vetenskapsrådet, Koning Boudewijnstichting, Swedish Brain Power, Stockholms Universitet, Demensfonden, Fondation pour la Recherche sur Alzheimer, Fundação para a Ciência e a Tecnologia, Instituto de Salud Carlos III, European Regional Development Fund
Awards: G1385847799, Utilidad clínica de 23 loci vinculados a la Enfermedad de Alzheimer en sujetos en riesgo de conversión a demencia, G2058225858, SYSTEMS BIOLOGY OF PATHWAYS INVOLVING BRAIN AGEING, G2377181310, Fenotipos clínicos y nuevos biomarcadores fisiopatológicos, diagnósticos y pronósticos en la enfermedad de Alzheimer de inicio precoz y variante conductual de la demencia frontotemporal, G3015794865, G3115756612, G3559709381, G5893827543, G6631046788, G7529559963, Human genetic studies of Alzheimer disease and other dementias, Molecular genetics of early-onset Alzheimer's disease., G8131093742, IDENTIFICATION OF GENETIC RISK FACTORS FOR PARKINSON'SDISEASE USING MICRORNOMICS AND PROTEOMICS
OpenAlex ID: W2325841306