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

Alberto Lleó, Beatrice Costa, Claudia Manzoni, Manuel Bernal-Quiros, Demis A. Kia, Miquel Aguilar Barberà, Ignacio Alvarez, Victoria Alvarez, Ole A. Andreassen, Maria Anfossi, Silvia Bagnoli, Luisa Benussi, Livia Bernardi, Giuliano Binetti, Daniel Blackburn, Mercè Boada, Barbara Borroni, Lucy Bowns, Geir Bråthen, Amalia BruniHuei-Hsin Chiang, Jordi Clarimón, 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, Edward D. Huey, Ignacio Illán-Gala, Anna Karydas, Behzad Khoshnood, Milica G. Kramberger, Mark Kristiansen, Patrick A. Lewis, Gaganjit K. Madhan, Raffaele Maletta, Aleš Maver, Manuel Menendez-Gonzalez, Graziella Milan, Bruce Miller, Merel O. Mol, Parastoo Momeni, Sonia Moreno-Grau, Chris M. Morris, Benedetta Nacmias, Christer Nilsson, Valeria Novelli, Linn Öijerstedt, Alessandro Padovani, Suvankar Pal, Yasmin Panchbhaya, Pau Pastor, Borut Peterlin, Irene Piaceri, Stuart Pickering-Brown, Yolande A. L. Pijnenburg, Annibale A. Puca, Innocenzo Rainero, Antonella Rendina, Anna M. T. Richardson, Ekaterina Rogaeva, Boris Rogelj, Sara Rollinson, Giacomina Rossi, Carola Rossmeier, James B. Rowe, Elisa Rubino, Agustín Ruiz, Raquel Sanchez-Valle, Sigrid B. Sando, Alexander F. Santillo, Jennifer Saxon, Elio Scarpini, Maria Serpente, Nicoletta Smirne, Sandro Sorbi, EunRan Suh, Fabrizio Tagliavini, Jennifer C. Thompson, John Q. Trojanowski, Vivianna M. Van Deerlin, Julie Van der Zee, Christine Van Broeckhoven, Jeroen van Rooij, John C. Van Swieten, Arianna Veronesi, Emilia Vitale, Maria L. Waldö, Cathy Woodward, Jennifer Yokoyama, Valentina Escott-Price, James M. Polke, Raffaele Ferrari

Producció científica: Contribució a una revistaArticleRecercaAvaluat per experts

5 Cites (Scopus)

Resum

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. 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. 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. 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.
Idioma originalEnglish
Pàgines (de-a)#e3288-e3302
RevistaNeurology
Volum95
DOIs
Estat de la publicacióPublicada - 2020

Fingerprint

Navegar pels temes de recerca de 'C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts'. Junts formen un fingerprint únic.

Com citar-ho