Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia

Irene Rosas; Carmen Martínez; Eliecer Coto; Jordi Clarimón; Alberto Lleó; Ignacio Illán-Gala; Oriol Dols-Icardo; Barbara Borroni; Maria Rosário Almeida; Julie van der Zee; Christine Van Broeckhoven; Amalia C Bruni; Maria Anfossi; Livia Bernardi; Raffaele Maletta; María Serpente; Daniela Galimberti; Elio Scarpini; Giacomina Rossi; Paola Caroppo; Luisa Benussi; Roberta Ghidoni; Giuliano Binetti; Benedetta Nacmias; Sandro Sorbi; Irene Piaceri; Silvia Bagnoli; Anna Antonell; Raquel Sánchez-Valle; Beatriz De la Casa-Fages; Francisco Grandas; Mónica Diez-Fairen; Pau Pastor; Raffaele Ferrari; Daniel Queimaliños-Perez; Sergio Pérez-Oliveira; Victoria Álvarez; Manuel Menéndez-González

doi:10.1016/j.neurobiolaging.2020.08.018

Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia

Irene Rosas, Carmen Martínez, Eliecer Coto, Jordi Clarimón, Alberto Lleó, Ignacio Illán-Gala, Oriol Dols-Icardo, Barbara Borroni, Maria Rosário Almeida, Julie van der Zee, Christine Van Broeckhoven, Amalia C Bruni, Maria Anfossi, Livia Bernardi, Raffaele Maletta, María Serpente, Daniela Galimberti, Elio Scarpini, Giacomina Rossi, Paola CaroppoLuisa Benussi, Roberta Ghidoni, Giuliano Binetti, Benedetta Nacmias, Sandro Sorbi, Irene Piaceri, Silvia Bagnoli, Anna Antonell, Raquel Sánchez-Valle, Beatriz De la Casa-Fages, Francisco Grandas, Mónica Diez-Fairen, Pau Pastor, Raffaele Ferrari, Daniel Queimaliños-Perez, Sergio Pérez-Oliveira, Victoria Álvarez, Manuel Menéndez-González

Centro San Giovanni di Dio - Fatebenefratelli

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Journal	Neurobiology of Aging
DOIs	https://doi.org/10.1016/j.neurobiolaging.2020.08.018
Publication status	E-pub ahead of print - Sept 20 2020

Keywords

Frontotemporal dementia
FTD
Apoe
Age at onset
GRN

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10.1016/j.neurobiolaging.2020.08.018

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Rosas, I., Martínez, C., Coto, E., Clarimón, J., Lleó, A., Illán-Gala, I., Dols-Icardo, O., Borroni, B., Almeida, M. R., van der Zee, J., Van Broeckhoven, C., Bruni, A. C., Anfossi, M., Bernardi, L., Maletta, R., Serpente, M., Galimberti, D., Scarpini, E., Rossi, G., ... Menéndez-González, M. (2020). Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia. Neurobiology of Aging. https://doi.org/10.1016/j.neurobiolaging.2020.08.018

Rosas, I, Martínez, C, Coto, E, Clarimón, J, Lleó, A, Illán-Gala, I, Dols-Icardo, O, Borroni, B, Almeida, MR, van der Zee, J, Van Broeckhoven, C, Bruni, AC, Anfossi, M, Bernardi, L, Maletta, R, Serpente, M, Galimberti, D, Scarpini, E, Rossi, G, Caroppo, P, Benussi, L , Ghidoni, R , Binetti, G, Nacmias, B, Sorbi, S, Piaceri, I, Bagnoli, S, Antonell, A, Sánchez-Valle, R, De la Casa-Fages, B, Grandas, F, Diez-Fairen, M, Pastor, P, Ferrari, R, Queimaliños-Perez, D, Pérez-Oliveira, S, Álvarez, V & Menéndez-González, M 2020, 'Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia', Neurobiology of Aging. https://doi.org/10.1016/j.neurobiolaging.2020.08.018

@article{0e4583d0884546c09b40be164b3dc3f5,

title = "Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia",

abstract = "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.",

keywords = "Frontotemporal dementia, FTD, Apoe, Age at onset, GRN",

author = "Irene Rosas and Carmen Mart{\'i}nez and Eliecer Coto and Jordi Clarim{\'o}n and Alberto Lle{\'o} and Ignacio Ill{\'a}n-Gala and Oriol Dols-Icardo and Barbara Borroni and Almeida, {Maria Ros{\'a}rio} and {van der Zee}, Julie and {Van Broeckhoven}, Christine and Bruni, {Amalia C} and Maria Anfossi and Livia Bernardi and Raffaele Maletta and Mar{\'i}a Serpente and Daniela Galimberti and Elio Scarpini and Giacomina Rossi and Paola Caroppo and Luisa Benussi and Roberta Ghidoni and Giuliano Binetti and Benedetta Nacmias and Sandro Sorbi and Irene Piaceri and Silvia Bagnoli and Anna Antonell and Raquel S{\'a}nchez-Valle and {De la Casa-Fages}, Beatriz and Francisco Grandas and M{\'o}nica Diez-Fairen and Pau Pastor and Raffaele Ferrari and Daniel Queimali{\~n}os-Perez and Sergio P{\'e}rez-Oliveira and Victoria {\'A}lvarez and Manuel Men{\'e}ndez-Gonz{\'a}lez",

year = "2020",

month = sep,

day = "20",

doi = "10.1016/j.neurobiolaging.2020.08.018",

language = "English",

journal = "Neurobiology of Aging",

issn = "0197-4580",

publisher = "Elsevier Inc.",

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TY - JOUR

T1 - Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia

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

PY - 2020/9/20

Y1 - 2020/9/20

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 - Frontotemporal dementia

KW - FTD

KW - Apoe

KW - Age at onset

KW - GRN

U2 - 10.1016/j.neurobiolaging.2020.08.018

DO - 10.1016/j.neurobiolaging.2020.08.018

M3 - Article

C2 - 32972771

SN - 0197-4580

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -

Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia

Abstract

Keywords

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