TY - JOUR
T1 - C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts
AU - International FTD-Genetics Consortium
AU - Costa, Beatrice
AU - Manzoni, Claudia
AU - Bernal-Quiros, Manuel
AU - Kia, Demis A.
AU - Aguilar, Miquel
AU - Alvarez, Ignacio
AU - Alvarez, Victoria
AU - Andreassen, Ole A.
AU - Anfossi, Maria
AU - Bagnoli, Silvia
AU - Benussi, Luisa
AU - Bernardi, Livia
AU - Binetti, Giuliano
AU - Blackburn, Daniel J.
AU - Boada, Mercè
AU - Borroni, Barbara
AU - Bowns, Lucy
AU - Bråthen, Geir
AU - Bruni, Amalia C.
AU - Chiang, Huei Hsin
AU - Clarimon, Jordi
AU - Colville, Shuna
AU - Conidi, Maria E.
AU - Cope, Tom E.
AU - Cruchaga, Carlos
AU - Cupidi, Chiara
AU - Di Battista, Maria Elena
AU - Diehl-Schmid, Janine
AU - Diez-Fairen, Monica
AU - Dols-Icardo, Oriol
AU - Durante, Elisabetta
AU - Flisar, Dušan
AU - Frangipane, Francesca
AU - Galimberti, Daniela
AU - Gallo, Maura
AU - Gallucci, Maurizio
AU - Ghidoni, Roberta
AU - Graff, Caroline
AU - Grafman, Jordan H.
AU - Grossman, Murray
AU - Hardy, John
AU - Hernández, Isabel
AU - Holloway, Guy J.T.
AU - Huey, Edward D.
AU - Illán-Gala, Ignacio
AU - Karydas, Anna
AU - Khoshnood, Behzad
AU - Kramberger, Milica G.
AU - Kristiansen, Mark
AU - Lewis, Patrick A.
N1 - Publisher Copyright:
© 2020 Lippincott Williams and Wilkins. All rights reserved.
PY - 2020/12/15
Y1 - 2020/12/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85098531165&partnerID=8YFLogxK
U2 - 10.1212/WNL.0000000000010914
DO - 10.1212/WNL.0000000000010914
M3 - Article
C2 - 32943482
AN - SCOPUS:85098531165
SN - 0028-3878
VL - 95
SP - E3288-E3302
JO - Neurology
JF - Neurology
IS - 24
ER -