Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia

Raffaele Ferrari, Mario Grassi, Francesca Graziano, Fernando Palluzzi, Silvana Archetti, Elisa Bonomi, Amalia C. Bruni, Raffaele G. Maletta, Livia Bernardi, Chiara Cupidi, Rosanna Colao, Innocenzo Rainero, Elisa Rubino, Lorenzo Pinessi, Daniela Galimberti, Elio Scarpini, Maria Serpente, Benedetta Nacmias, Irene Piaceri, Silvia BagnoliGiacomina Rossi, Giorgio Giaccone, Fabrizio Tagliavini, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Andrew Singleton, John Hardy, Parastoo Momeni, Alessandro Padovani, Barbara Borroni

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1271-1278
Number of pages8
JournalJournal of Alzheimer's Disease
Volume56
Issue number4
DOIs
Publication statusPublished - 2017

Keywords

  • Age at onset
  • Frontotemporal dementia
  • GWAS
  • Polymorphism

ASJC Scopus subject areas

  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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    Ferrari, R., Grassi, M., Graziano, F., Palluzzi, F., Archetti, S., Bonomi, E., Bruni, A. C., Maletta, R. G., Bernardi, L., Cupidi, C., Colao, R., Rainero, I., Rubino, E., Pinessi, L., Galimberti, D., Scarpini, E., Serpente, M., Nacmias, B., Piaceri, I., ... Borroni, B. (2017). Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia. Journal of Alzheimer's Disease, 56(4), 1271-1278. https://doi.org/10.3233/JAD-160949