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

Costa, Beatrice, Manzoni, Claudia, Bernal-Quiros, Manuel, Kia, Demis A., Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Andreassen, Ole, Anfossi, Maria, Bagnoli, Silvia, Benussi, Luisa, Bernardi, Livia, Binetti, Giuliano, Blackburn, Daniel, Boada, Mercè, Borroni, Barbara, Bowns, Lucy, Bråthen, Geir, Bruni, Amalia C., Chiang, Huei-Hsin, Clarimon, Jordi, Colville, Shuna, Conidi, Maria E., Cope, Tom E., Cruchaga, Carlos, Cupidi, Chiara, Di Battista, Maria Elena, Diehl-Schmid, Janine, Diez-Fairen, Monica, Dols-Icardo, Oriol, Durante, Elisabetta, Flisar, Dusan, Frangipane, Francesca, Galimberti, Daniela, Gallo, Maura, Gallucci, Maurizio, Ghidoni, Roberta, Graff, Caroline, Grafman, Jordan H., Grossman, Murray, Hardy, John, Hernández, Isabel, Holloway, Guy JT, Huey, Edward D., Illán-Gala, Ignacio, Karydas, Anna, Khoshnood, Behzad, Kramberger, Milica G., Kristiansen, Mark, Lewis, Patrick A., Lleó, Alberto, Madhan, Gaganjit K., Maletta, Raffaele, Maver, Ales, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce, Mol, Merel O., Momeni, Parastoo, Moreno-Grau, Sonia, Morris, Chris M., Nacmias, Benedetta, Nilsson, Christer, Novelli, Valeria, Öijerstedt, Linn, Padovani, Alessandro, Pal, Suvankar, Panchbhaya, Yasmin, Pastor, Pau, Peterlin, Borut, Piaceri, Irene, Pickering-Brown, Stuart, Pijnenburg, Yolande A.L., Puca, Annibale A., Rainero, Innocenzo, Rendina, Antonella, Richardson, Anna MT, Rogaeva, Ekaterina, Rogelj, Boris, Rollinson, Sara, Rossi, Giacomina, Rossmeier, Carola, Rowe, James B., Rubino, Elisa, Ruiz, Agustín, Sanchez-Valle, Raquel, Sando, Sigrid B, Santillo, Alexander F., Saxon, Jennifer, Scarpini, Elio, Serpente, Maria, Smirne, Nicoletta, Sorbi, Sandro, Suh, EunRan, Tagliavini, Fabrizio, Thompson, Jennifer C., Trojanowski, John Q., Van Deerlin, Vivianna M., Van der Zee, Julie, Van Broeckhoven, Christine, van Rooij, Jeroen, Van Swieten, John C, Veronesi, Arianna, Vitale, Emilia, Waldö, Maria L, Woodward, Cathy, Yokoyama, Jennifer, Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483, Polke, James M. and Ferrari, Raffaele 2020. C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts. Neurology 95 (24) , e3288-e3302. 10.1212/WNL.0000000000010914

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine
Additional Information:	This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Publisher:	American Academy of Neurology
ISSN:	0028-3878
Date of First Compliant Deposit:	26 October 2020
Date of Acceptance:	12 August 2020
Last Modified:	25 Jul 2024 16:14
URI:	https://orca.cardiff.ac.uk/id/eprint/135950

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