Author(s):
Philtjens, Stéphanie ; Van Mossevelde, Sara ; van der Zee, Julie ; Wauters, Eline ; Dillen, Lubina ; Vandenbulcke, Mathieu ; Vandenberghe, Rik ; Ivanoiu, Adrian ; Sieben, Anne ; Willems, Christiana ; Benussi, Luisa ; Ghidoni, Roberta ; Binetti, Giuliano ; Borroni, Barbara ; Padovani, Alessandro ; Pastor, Pau ; Diez-Fairen, Monica ; Aguilar, Miquel ; De Mendonça, Alexandre ; Miltenberger-Miltenyi, Gabriel ; Hernández, Isabel ; Boada, Merce ; Ruiz, Agustín ; Nacmias, Benedetta ; Sorbi, Sandro ; Almeida, Maria Rosário ; Santana, Isabel ; Clarimón, Jordi ; Lleó, Alberto ; Frisoni, Giovanni B. ; Sanchez-Valle, Raquel ; Lladó, Albert ; Gómez-Tortosa, Estrella ; Gelpi, Ellen ; Van den Broeck, Marleen ; Peeters, Karin ; Cras, Patrick ; De Deyn, Peter P. ; Engelborghs, Sebastiaan ; Cruts, Marc ; Van Broeckhoven, Christine
Date: 2018
Persistent ID: http://hdl.handle.net/10451/50450
Origin: Repositório da Universidade de Lisboa
Subject(s): Frontotemporal dementia; Genetic association; Granulin; Rare variants; Sortilin
Description
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.
