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Neurobiol Aging. 2018 Jun;66:181.e3-181.e10. doi: 10.1016/j.neurobiolaging.2018.02.011. Epub 2018 Feb 17.

Rare nonsynonymous variants in SORT1 are associated with increased risk for frontotemporal dementia.

Author information

1
Neurodegenerative Brain Diseases Group, Center for Molecular Neurology VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
2
Neurodegenerative Brain Diseases Group, Center for Molecular Neurology VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA), Middelheim and Hoge Beuken, Antwerp, Belgium; Department of Neurology, Antwerp University Hospital (UZA), Edegem, Belgium.
3
Department of Neurosciences, Faculty of Medicine, KU Leuven, Leuven, Belgium; Department of Old Age Psychiatry and Memory Clinic, University Hospitals Leuven, Leuven, Belgium.
4
Department of Neurosciences, Faculty of Medicine, KU Leuven, Leuven, Belgium; Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
5
Department of Neurology, Saint-Luc University Hospital and Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium.
6
Department of Neurology, University Hospital Ghent and University of Ghent, Ghent, Belgium.
7
Department of Neurology, Jessa Hospital, Hasselt, Belgium.
8
Molecular Markers Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy.
9
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.
10
Neurology Unit, University of Brescia, Brescia, Italy.
11
Memory Unit, Department of Neurology, University Hospital Mutua de Terrassa, University of Barcelona, Terrassa, Barcelona, Spain. Centro de Investigación Biomédica en Red Enfermedades Neurdegenerativas (CIBERNED), Madrid, Spain; Fundacio de Docencia i Recerca Mutua de Terrassa, Terrassa, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.
12
Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
13
Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
14
Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.
15
Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy; IRCCS Don Gnocchi, Firenze, Italy.
16
Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
17
Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
18
Hôpitaux Universitaires de Genève et Université de Genève, Geneva, Switzerland; IRCCS Fatebenefratelli, Brescia, Italy.
19
Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
20
Department of Neurology, Fundación Jiménez Díaz, Madrid, Spain.
21
Neurological Tissue Bank of the Biobanc - Hospital Clinic-Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
22
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Department of Neurology, Antwerp University Hospital (UZA), Edegem, Belgium.
23
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA), Middelheim and Hoge Beuken, Antwerp, Belgium.
24
Neurodegenerative Brain Diseases Group, Center for Molecular Neurology VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Electronic address: christine.vanbroeckhoven@molgen.vib-ua.be.
25
Neurodegenerative Brain Diseases Group, Center for Molecular Neurology VIB, Antwerp, Belgium.

Abstract

We investigated the genetic role of sortilin (SORT1) in frontotemporal dementia (FTD). SORT1 is the neuronal receptor for granulin, encoded by the progranulin gene (GRN), a major causal gene for inherited FTD. In Belgian cohorts of 636 FTD patients and 1066 unaffected control individuals, we identified 5 patient-only nonsynonymous rare variants in SORT1. Rare variant burden analysis showed a significant increase in rare coding variants in patients compared to control individuals (p = 0.04), particularly in the β-propeller domain (p = 0.04), with 2 rare variants located in the predicted binding site for GRN (p = 0.001). We extended these observations by analyzing 3 independent patient/control cohorts sampled in Spain, Italy, and Portugal by partners of the European Early-Onset Dementia Consortium, together with 1155 FTD patients and 1161 control persons. An additional 7 patient-only nonsynonymous variants were observed in SORT1 in European patients. Meta-analysis of the rare nonsynonymous variants in the Belgian and European patient/control cohorts revealed a significant enrichment in FTD patients (p = 0.006), establishing SORT1 as a genetic risk factor for FTD.

KEYWORDS:

Frontotemporal dementia; Genetic association; Granulin; Rare variants; Sortilin

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