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

• Published in: Neurobiology of aging 2021-03, Vol.99, p.99.e15-99.e22
• Main Authors: Rosas, Irene, Martínez, Carmen, Coto, Eliecer, Clarimón, Jordi, Lleó, Alberto, Illán-Gala, Ignacio, Dols-Icardo, Oriol, Borroni, Barbara, Almeida, Maria Rosário, van der Zee, Julie, Van Broeckhoven, Christine, Bruni, Amalia C., Anfossi, Maria, Bernardi, Livia, Maletta, Raffaele, Serpente, María, Galimberti, Daniela, Scarpini, Elio, Rossi, Giacomina, Caroppo, Paola, Benussi, Luisa, Ghidoni, Roberta, Binetti, Giuliano, Nacmias, Benedetta, Sorbi, Sandro, Piaceri, Irene, Bagnoli, Silvia, Antonell, Anna, Sánchez-Valle, Raquel, De la Casa-Fages, Beatriz, Grandas, Francisco, Diez-Fairen, Mónica, Pastor, Pau, Ferrari, Raffaele, Queimaliños-Perez, Daniel, Pérez-Oliveira, Sergio, Álvarez, Victoria, Menéndez-González, Manuel
• Format: Article
• Language: English
• Subjects: Age at onset; APOE; Frontotemporal dementia; GRN; Survival probability; TP53
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2020.08.018

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. •rs1042522 in TP53 gene is associated with disease onset and survival probability.•rs5848 GRN is associated with a significantly shorter survival probability.•The frequency of ApoƐ4 was significantly increased in the C9orf72 non carriers.•Among the clinical groups, PNFA has a higher frequency of ApoƐ4 carriers.