C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts

International FTD-Genetics Consortium, Beatrice Costa, Claudia Manzoni, Manuel Bernal-Quiros, Demis A. Kia, Miquel Aguilar, Ignacio Alvarez, Victoria Alvarez, Ole Andreassen, Maria Anfossi, Silvia Bagnoli, Luisa Benussi, Livia Bernardi, Giuliano Binetti, Daniel Blackburn, Mercè Boada, Barbara Borroni, Lucy Bowns, Geir Bråthen, Amalia C. BruniHuei Hsin Chiang, Jordi Clarimon, Shuna Colville, Maria E. Conidi, Tom E. Cope, Carlos Cruchaga, Chiara Cupidi, Maria Elena Di Battista, Janine Diehl-Schmid, Monica Diez-Fairen, Oriol Dols-Icardo, Elisabetta Durante, Dušan Flisar, Francesca Frangipane, Daniela Galimberti, Maura Gallo, Maurizio Gallucci, Roberta Ghidoni, Caroline Graff, Jordan H. Grafman, Murray Grossman, John Hardy, Isabel Hernández, Guy J.T. Holloway, Valeria Novelli, Annibale A. Puca, Giacomina Rossi, Elio Scarpini, Maria Serpente, Benedetta Nacmias, Sandro Sorbi, Fabrizio Tagliavini

Research output: Contribution to journalArticlepeer-review

Abstract

OBJECTIVE: We sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases. METHODS: We evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD-motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions. RESULTS: We found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 × 10-5; odds ratio (OR) 6.4; confidence interval (CI) 2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 × 10-2; OR 2.5; CI 1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy. CONCLUSIONS: Our results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes.

Original languageEnglish
Pages (from-to)e3288-e3302
JournalNeurology
Volume95
Issue number24
DOIs
Publication statusPublished - Dec 15 2020

ASJC Scopus subject areas

  • Clinical Neurology

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