TY - JOUR
T1 - Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia
AU - the EU EOD Consortium
AU - IFGC
AU - Rosas, Irene
AU - Martínez, Carmen
AU - Coto, Eliecer
AU - Clarimón, Jordi
AU - Lleó, Alberto
AU - Illán-Gala, Ignacio
AU - Dols-Icardo, Oriol
AU - Borroni, Barbara
AU - Almeida, Maria Rosário
AU - van der Zee, Julie
AU - Van Broeckhoven, Christine
AU - Bruni, Amalia C.
AU - Anfossi, Maria
AU - Bernardi, Livia
AU - Maletta, Raffaele
AU - Serpente, María
AU - Galimberti, Daniela
AU - Scarpini, Elio
AU - Rossi, Giacomina
AU - Caroppo, Paola
AU - Benussi, Luisa
AU - Ghidoni, Roberta
AU - Binetti, Giuliano
AU - Nacmias, Benedetta
AU - Sorbi, Sandro
AU - Piaceri, Irene
AU - Bagnoli, Silvia
AU - Antonell, Anna
AU - Sánchez-Valle, Raquel
AU - De la Casa-Fages, Beatriz
AU - Grandas, Francisco
AU - Diez-Fairen, Mónica
AU - Pastor, Pau
AU - Ferrari, Raffaele
AU - Queimaliños-Perez, Daniel
AU - Pérez-Oliveira, Sergio
AU - Álvarez, Victoria
AU - Menéndez-González, Manuel
N1 - Funding Information:
The authors are indebted to all the patients and their families for their participation. The authors wish to thank Fundación Parkinson Asturias-Obra Social Cajastur for their support. The authors also thank the IFGC (https://ifgcsite.wordpress.com/), the EUEOD, and DEGESCO for facilitating this study. The authors thank Valeria Rolle Sóñora, Plataforma de Bioestadística y Epidemiología del ISPA. I.R. is supported by a grant from Fundación Jose Luis Castaño-SEQC. This study is supported by grant PI 15/00878 (Fondos Feder) to V.A. O.D.-I. is funded by the Association for Frontotemporal Degeneration (Clinical Research Postdoctoral Fellowship, AFTD 2019–2021). I.I.-G. is supported by the Rio Hortega grant (CM17/00074) from “Acción Estratégica en Salud 2013-2016” and the Global Brain Health Institute (Atlantic Fellow for Equity in Brain Health). J.C. and V.A. research's groups are members of Dementia Genetics Spanish Consortium (DEGESCO). C.V.B. and J.v.d.Z. were in part funded by the Flemish Government initiated ImpulseProgram on Networks for Dementia Research (VIND) and the Methusalem Excellence Program, the Research Foundation Flanders (FWO), and the University of Antwerp ResearchFund. L.B. G.B. and R.G. are supported by the Italian Ministry of Health (L.B. G.B. and R.G.: Ricerca Corrente; R.G. and G.B.: grant no. RF-2016–02361492). A.A. is funded by Departament de Salut de la Generalitat de Catalunya, Pla Estrategic de recerca i innovació en salut (PERIS) 2016–2020 (SLT002/16/00329). R.S.V. received funding from the Marató de TV3 (grant no. 20143810). P.P. is supported by the Spanish Ministry of Science and Innovation (SAF2013-47939-R [2013–2018]). R.F. is supported by the Alzheimer's Society (grant number 284).
Funding Information:
I.R. is supported by a grant from Fundación Jose Luis Castaño-SEQC. This study is supported by grant PI 15/00878 (Fondos Feder) to V.A. O.D.-I. is funded by the Association for Frontotemporal Degeneration (Clinical Research Postdoctoral Fellowship, AFTD 2019–2021). I.I.-G. is supported by the Rio Hortega grant (CM17/00074) from “Acción Estratégica en Salud 2013-2016” and the Global Brain Health Institute (Atlantic Fellow for Equity in Brain Health). J.C. and V.A. research's groups are members of Dementia Genetics Spanish Consortium (DEGESCO). C.V.B. and J.v.d.Z. were in part funded by the Flemish Government initiated ImpulseProgram on Networks for Dementia Research (VIND) and the Methusalem Excellence Program, the Research Foundation Flanders (FWO), and the University of Antwerp ResearchFund. L.B., G.B., and R.G. are supported by the Italian Ministry of Health (L.B., G.B., and R.G.: Ricerca Corrente; R.G. and G.B.: grant no. RF-2016–02361492). A.A. is funded by Departament de Salut de la Generalitat de Catalunya, Pla Estrategic de recerca i innovació en salut (PERIS) 2016–2020 (SLT002/16/00329). R.S.V. received funding from the Marató de TV3 (grant no. 20143810). P.P. is supported by the Spanish Ministry of Science and Innovation (SAF2013-47939-R [2013–2018]). R.F. is supported by the Alzheimer's Society (grant number 284).
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/3
Y1 - 2021/3
N2 - Frontotemporal dementia (FTD) is a clinical, genetic, and pathologic heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APOƐ4, rs5848 in GRN, and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 FTD patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p < 0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (hazard ratio [HR] = 4.12), and the progressive nonfluent aphasia group showed the highest onset age (p = 0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p = 0.02) and survival (HR = 1.73) and rs5848 GRN with a significantly shorter survival in CC homozygous patients (HR = 1.98). The frequency of APOƐ4 carriers was significantly increased in the C9orf72 noncarriers (p = 0.022). Although validation of our findings is necessary, our results suggest that TP53, GRN, and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials.
AB - Frontotemporal dementia (FTD) is a clinical, genetic, and pathologic heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APOƐ4, rs5848 in GRN, and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 FTD patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p < 0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (hazard ratio [HR] = 4.12), and the progressive nonfluent aphasia group showed the highest onset age (p = 0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p = 0.02) and survival (HR = 1.73) and rs5848 GRN with a significantly shorter survival in CC homozygous patients (HR = 1.98). The frequency of APOƐ4 carriers was significantly increased in the C9orf72 noncarriers (p = 0.022). Although validation of our findings is necessary, our results suggest that TP53, GRN, and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials.
KW - Age at onset
KW - APOE
KW - Frontotemporal dementia
KW - GRN
KW - Survival probability
KW - TP53
UR - http://www.scopus.com/inward/record.url?scp=85091493931&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2020.08.018
DO - 10.1016/j.neurobiolaging.2020.08.018
M3 - Article
C2 - 32972771
AN - SCOPUS:85091493931
SN - 0197-4580
VL - 99
SP - 99.e15-99.e22
JO - Neurobiology of Aging
JF - Neurobiology of Aging
ER -