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

Stéphanie Philtjens; Sara Van Mossevelde; Julie van der Zee; Eline Wauters; Lubina Dillen; Mathieu Vandenbulcke; Rik Vandenberghe; Adrian Ivanoiu; Anne Sieben; Christiana Willems; Luisa Benussi; Roberta Ghidoni; Giuliano Binetti; Barbara Borroni; Alessandro Padovani; Pau Pastor; Monica Diez-Fairen; Miquel Aguilar; Alexandre de Mendonça; Gabriel Miltenberger-Miltényi; Isabel Hernández; Merce Boada; Agustín Ruiz; Benedetta Nacmias; Sandro Sorbi; Maria Rosário Almeida; Isabel Santana; Jordi Clarimón; Alberto Lleó; Giovanni B Frisoni; Raquel Sanchez-Valle; Albert Lladó; Estrella Gómez-Tortosa; Ellen Gelpi; Marleen Van den Broeck; Karin Peeters; Patrick Cras; Peter P De Deyn; Sebastiaan Engelborghs; Marc Cruts; Christine Van Broeckhoven; BELNEU Consortium; EU EOD Consortium

doi:10.1016/j.neurobiolaging.2018.02.011

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

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

Authors

Stéphanie Philtjens¹, Sara Van Mossevelde², Julie van der Zee¹, Eline Wauters¹, Lubina Dillen¹, Mathieu Vandenbulcke³, Rik Vandenberghe⁴, Adrian Ivanoiu⁵, Anne Sieben⁶, Christiana Willems⁷, Luisa Benussi⁸, Roberta Ghidoni⁸, Giuliano Binetti⁹, Barbara Borroni¹⁰, Alessandro Padovani¹⁰, Pau Pastor¹¹, Monica Diez-Fairen¹¹, Miquel Aguilar¹¹, Alexandre de Mendonça¹², Gabriel Miltenberger-Miltényi¹², Isabel Hernández¹³, Merce Boada¹³, Agustín Ruiz¹³, Benedetta Nacmias¹⁴, Sandro Sorbi¹⁵, Maria Rosário Almeida¹⁶, Isabel Santana¹⁶, Jordi Clarimón¹⁷, Alberto Lleó¹⁷, Giovanni B Frisoni¹⁸, Raquel Sanchez-Valle¹⁹, Albert Lladó¹⁹, Estrella Gómez-Tortosa²⁰, Ellen Gelpi²¹, Marleen Van den Broeck¹, Karin Peeters¹, Patrick Cras²², Peter P De Deyn²³, Sebastiaan Engelborghs²³, Marc Cruts¹, Christine Van Broeckhoven²⁴; BELNEU Consortium²⁵; EU EOD Consortium²⁵

Affiliations

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: [email protected].
²⁵ Neurodegenerative Brain Diseases Group, Center for Molecular Neurology VIB, Antwerp, Belgium.

PMID: 29555433
DOI: 10.1016/j.neurobiolaging.2018.02.011

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Vesicular Transport / chemistry
Adaptor Proteins, Vesicular Transport / genetics*
Aged
Belgien
Binding Sites
Cohort Studies
Europa
Female
Genetic Association Studies*
Genetic Variation / genetics*
Humans
Intercellular Signaling Peptides and Proteins
Male
Middle Aged
Progranulins
Protein Binding
Protein Domains
Risk

Substances

Adaptor Proteins, Vesicular Transport
GRN protein, human
Intercellular Signaling Peptides and Proteins
Progranulins
sortilin