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Acta Neuropathol. 2016 Aug;132(2):213-24. doi: 10.1007/s00401-016-1566-9. Epub 2016 Mar 30.

A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer's disease.

Author information

1
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, University of Antwerp, CDE Universiteitsplein 1, 2610, Antwerp, Belgium.
2
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
3
Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
4
Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
5
Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
6
Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden.
7
Genetics Unit, Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden.
8
Memory Unit, Department of Neurology, University Hospital Mútua de Terrassa, University of Barcelona School of Medicine, Terrassa, Barcelona, Spain.
9
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
10
Department of Neurology, Complejo Asistencial Universitario de Palencia, Palencia, Spain.
11
Neuroimaging Laboratory, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
12
Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain.
13
Molecular Markers Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy.
14
MAC Memory Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy.
15
Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universidad Autònoma de Barcelona, Barcelona, Spain.
16
Faculty of Medicine and Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal.
17
Neurological Tissue Bank of the Biobanc, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
18
Bioinformatics Unit, Department of Molecular Genetics, VIB, Antwerp, Belgium.
19
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, University of Antwerp, CDE Universiteitsplein 1, 2610, Antwerp, Belgium. christine.vanbroeckhoven@molgen.vib-ua.be.
20
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. christine.vanbroeckhoven@molgen.vib-ua.be.
21
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, University of Antwerp, CDE Universiteitsplein 1, 2610, Antwerp, Belgium. kristel.sleegers@molgen.vib-ua.be.
22
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. kristel.sleegers@molgen.vib-ua.be.

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.

KEYWORDS:

Alzheimer; Early onset; Haploinsufficiency; Loss-of-function; Meta-analysis; Rare variants; SORL1

PMID:
27026413
PMCID:
PMC4947104
DOI:
10.1007/s00401-016-1566-9
[Indexed for MEDLINE]
Free PMC Article

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