TY - JOUR
T1 - Rare nonsynonymous variants in SORT1 are associated with increased risk for frontotemporal dementia
AU - BELNEU Consortium
AU - EU EOD Consortium
AU - Philtjens, Stéphanie
AU - Van Mossevelde, Sara
AU - van der Zee, Julie
AU - Wauters, Eline
AU - Dillen, Lubina
AU - Vandenbulcke, Mathieu
AU - Vandenberghe, Rik
AU - Ivanoiu, Adrian
AU - Sieben, Anne
AU - Willems, Christiana
AU - Benussi, Luisa
AU - Ghidoni, Roberta
AU - Binetti, Giuliano
AU - Borroni, Barbara
AU - Padovani, Alessandro
AU - Pastor, Pau
AU - Diez-Fairen, Monica
AU - Aguilar, Miquel
AU - de Mendonça, Alexandre
AU - Miltenberger-Miltényi, Gabriel
AU - Hernández, Isabel
AU - Boada, Merce
AU - Ruiz, Agustín
AU - Nacmias, Benedetta
AU - Sorbi, Sandro
AU - Almeida, Maria Rosário
AU - Santana, Isabel
AU - Clarimón, Jordi
AU - Lleó, Alberto
AU - Frisoni, Giovanni B.
AU - Sanchez-Valle, Raquel
AU - Lladó, Albert
AU - Gómez-Tortosa, Estrella
AU - Gelpi, Ellen
AU - Van den Broeck, Marleen
AU - Peeters, Karin
AU - Cras, Patrick
AU - De Deyn, Peter P.
AU - Engelborghs, Sebastiaan
AU - Cruts, Marc
AU - Van Broeckhoven, Christine
N1 - Publisher Copyright:
© 2018 The Authors
PY - 2018/6
Y1 - 2018/6
N2 - 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.
AB - 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.
KW - Frontotemporal dementia
KW - Genetic association
KW - Granulin
KW - Rare variants
KW - Sortilin
UR - https://www.scopus.com/pages/publications/85044008028
UR - https://www.scopus.com/pages/publications/85044008028#tab=citedBy
U2 - 10.1016/j.neurobiolaging.2018.02.011
DO - 10.1016/j.neurobiolaging.2018.02.011
M3 - Article
C2 - 29555433
AN - SCOPUS:85044008028
SN - 0197-4580
VL - 66
SP - 181.e3-181.e10
JO - Neurobiology of Aging
JF - Neurobiology of Aging
ER -