Contributors: Ferrari, Raffaele; Grassi, Mario; Graziano, Francesca; Palluzzi, Fernando; Archetti, Silvana; Bonomi, Elisa; Bruni, Amalia C.; Maletta, Raffaele G.; Bernardi, Livia; Cupidi, Chiara; Colao, Rosanna; Rainero, Innocenzo; Rubino, Elisa; Pinessi, Lorenzo; Galimberti, Daniela; Scarpini, Elio; Serpente, Maria; Nacmias, Benedetta; Piaceri, Irene; Bagnoli, Silvia; Rossi, Giacomina; Giaccone, Giorgio; Tagliavini, Fabrizio; Benussi, Luisa; Binetti, Giuliano; Ghidoni, Roberta; Singleton, Andrew; Hardy, John; Momeni, Parastoo; Padovani, Alessandro; Borroni, Barbara*
نبذة مختصرة : In frontotemporal dementia (FTD), age at disease onset (AAO) is unpredictable in both early and late-onset cases; AAO variability is found even in autosomal dominant FTD. The present study was aimed at identifying genetic modifiers modulating AAO in a large cohort of Italian FTD patients. We conducted an association analysis on 411 FTD patients, belonging to 7 Italian Centers, and for whom AAO was available. Population structure was evaluated by principal component analysis to infer continuous axes of genetic variation, and single linear regression models were applied. A genetic score (GS) was calculated on the basis of suggestive single nucleotide polymorphisms (SNPs) found by association analyses. GS showed genome-wide significant slope decrease by -3.86 (95% CI: -4.64 to -3.07, p < 2×10-16) per standard deviation of the GS for 6 SNPs mapping to genes involved in neuronal development and signaling, axonal myelinization, and glutamatergic/GABA neurotransmission. An increase of the GS was associated with a decrease of the AAO. Our data indicate that there is indeed a genetic component that underpins and modulates up to 14.5% of variability of AAO in Italian FTD. Future studies on genetic modifiers in FTD are warranted.
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