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 Nacmiass, 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
Neurobiology of Aging,
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 1,066 unaffected control individuals, we identified five patient-only non-synonymous 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 two rare variants located in the predicted binding site for GRN (p=0.001). We extended these observations by analyzing three independent patient/control cohorts sampled in Spain, Italy and Portugal by partners of the EU EOD Consortium, together 1,155 FTD patients and 1,161 control persons. An additional seven patient-only non-synonymous variants were observed in SORT1 in European patients. Meta-analysis of the rare non-synonymous 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.