title: A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer's disease.
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.
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, University of Antwerp, CDE Universiteitsplein 1, 2610, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Verheijen
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, University of Antwerp, CDE Universiteitsplein 1, 2610, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Department of Neurology, Antwerp University Hospital, Edegem, Belgium.|Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
authors.forename: Tobi
authors.initials: T
authors.lastname: Van den Bossche
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, University of Antwerp, CDE Universiteitsplein 1, 2610, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: van der Zee
authors.affiliation: Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.affiliation: Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Sanchez-Valle
authors.affiliation: Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Lladó
authors.affiliation: Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden.|Genetics Unit, Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Graff
authors.affiliation: Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden.|Genetics Unit, Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Thonberg
authors.affiliation: Memory Unit, Department of Neurology, University Hospital Mútua de Terrassa, University of Barcelona School of Medicine, Terrassa, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Pau
authors.initials: P
authors.lastname: Pastor
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.|Department of Neurology, Complejo Asistencial Universitario de Palencia, Palencia, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Ortega-Cubero
authors.affiliation: Department of Neurology, Complejo Asistencial Universitario de Palencia, Palencia, Spain.|Neuroimaging Laboratory, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.|Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Pastor
authors.affiliation: Molecular Markers Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Benussi
authors.affiliation: Molecular Markers Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ghidoni
authors.affiliation: Molecular Markers Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy.|MAC Memory Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Binetti
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.|Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universidad Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Clarimon
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.|Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universidad Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Lleó
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.|Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universidad Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Fortea
authors.affiliation: Faculty of Medicine and Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: Alexandre
authors.initials: A
authors.lastname: de Mendonça
authors.affiliation: Faculty of Medicine and Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: Madalena
authors.initials: M
authors.lastname: Martins
authors.affiliation: Neurological Tissue Bank of the Biobanc, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Oriol
authors.initials: O
authors.lastname: Grau-Rivera
authors.affiliation: Neurological Tissue Bank of the Biobanc, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Ellen
authors.initials: E
authors.lastname: Gelpi
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, University of Antwerp, CDE Universiteitsplein 1, 2610, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Karolien
authors.initials: K
authors.lastname: Bettens
authors.affiliation: Bioinformatics Unit, Department of Molecular Genetics, VIB, Antwerp, Belgium.
authors.forename: Ligia
authors.initials: L
authors.lastname: Mateiu
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, University of Antwerp, CDE Universiteitsplein 1, 2610, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Lubina
authors.initials: L
authors.lastname: Dillen
authors.affiliation: Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Cras
authors.affiliation: Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, University of Antwerp, CDE Universiteitsplein 1, 2610, Antwerp, Belgium. christine.vanbroeckhoven@molgen.vib-ua.be.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. christine.vanbroeckhoven@molgen.vib-ua.be.
authors.forename: Christine
authors.identifier: http://orcid.org/0000-0003-0183-7665
authors.initials: C
authors.lastname: Van Broeckhoven
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, University of Antwerp, CDE Universiteitsplein 1, 2610, Antwerp, Belgium. kristel.sleegers@molgen.vib-ua.be.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. kristel.sleegers@molgen.vib-ua.be.
authors.forename: Kristel
authors.initials: K
authors.lastname: Sleegers
mesh_terms: D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012306:Risk; D044465:White People
chemical_list: D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; C102582:SORL1 protein, human
keywords: Alzheimer; Early onset; Haploinsufficiency; Loss-of-function; Meta-analysis; Rare variants; SORL1