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Lookup NU author(s): Dr Christopher Morris
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2020 Lippincott Williams and Wilkins. All rights reserved. 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. ConclusionsL 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.
Author(s): Costa B, Manzoni C, Bernal-Quiros M, Kia DA, Aguilar M, Alvarez I, Alvarez V, Andreassen OA, Anfossi M, Bagnoli S, Benussi L, Bernardi L, Binetti G, Blackburn DJ, Boada M, Borroni B, Bowns L, Brathen G, Bruni AC, Chiang H-H, Clarimon J, Colville S, Conidi ME, Cope TE, Cruchaga C, Cupidi C, Di Battista ME, Diehl-Schmid J, Diez-Fairen M, Dols-Icardo O, Durante E, Flisar D, Frangipane F, Galimberti D, Gallo M, Gallucci M, Ghidoni R, Graff C, Grafman JH, Grossman M, Hardy J, Hernandez I, Holloway GJT, Huey ED, Illan-Gala I, Karydas A, Khoshnood B, Kramberger MG, Kristiansen M, Lewis PA, Lleo A, Madhan GK, Maletta R, Maver A, Menendez-Gonzalez M, Milan G, Miller BL, Mol MO, Momeni P, Moreno-Grau S, Morris CM, Nacmias B, Nilsson C, Novelli V, Oijerstedt L, Padovani A, Pal S, Panchbhaya Y, Pastor P, Peterlin B, Piaceri I, Pickering-Brown S, Pijnenburg YAL, Puca AA, Rainero I, Rendina A, Richardson AMT, Rogaeva E, Rogelj B, Rollinson S, Rossi G, Rossmeier C, Rowe JB, Rubino E, Ruiz A, Sanchez-Valle R, Sando SB, Santillo AF, Saxon J, Scarpini E, Serpente M, Smirne N, Sorbi S, Suh E, Tagliavini F, Thompson JC, Trojanowski JQ, van Deerlin VM, van der Zee J, van Broeckhoven C, van Rooij JGJ, van Swieten JC, Veronesi A, Vitale E, Waldo ML, Woodward C, Yokoyama JS, Escott-Price V, Polke JM, Ferrari R
Publication type: Article
Publication status: Published
Journal: Neurology
Year: 2020
Volume: 95
Issue: 24
Pages: e3288-e3302
Print publication date: 15/12/2020
Online publication date: 17/09/2020
Acceptance date: 12/08/2020
Date deposited: 26/07/2021
ISSN (print): 0028-3878
ISSN (electronic): 1526-632X
Publisher: Lippincott Williams and Wilkins
URL: https://doi.org/10.1212/WNL.0000000000010914
DOI: 10.1212/WNL.0000000000010914
PubMed id: 32943482
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