PT  - JOURNAL ARTICLE
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
AU  - Anfossi, Maria
AU  - Bagnoli, Silvia
AU  - Benussi, Luisa
AU  - Bernardi, Livia
AU  - Binetti, Giuliano
AU  - Blackburn, Daniel
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.
AU  - Lleó, Alberto
AU  - Madhan, Gaganjit K.
AU  - Maletta, Raffaele
AU  - Maver, Aleš
AU  - Menendez-Gonzalez, Manuel
AU  - Milan, Graziella
AU  - Miller, Bruce
AU  - Mol, Merel O.
AU  - Momeni, Parastoo
AU  - Moreno-Grau, Sonia
AU  - Morris, Chris M.
AU  - Nacmias, Benedetta
AU  - Nilsson, Christer
AU  - Novelli, Valeria
AU  - Öijerstedt, Linn
AU  - Padovani, Alessandro
AU  - Pal, Suvankar
AU  - Panchbhaya, Yasmin
AU  - Pastor, Pau
AU  - Peterlin, Borut
AU  - Piaceri, Irene
AU  - Pickering-Brown, Stuart
AU  - Pijnenburg, Yolande A.L.
AU  - Puca, Annibale A.
AU  - Rainero, Innocenzo
AU  - Rendina, Antonella
AU  - Richardson, Anna M.T.
AU  - Rogaeva, Ekaterina
AU  - Rogelj, Boris
AU  - Rollinson, Sara
AU  - Rossi, Giacomina
AU  - Rossmeier, Carola
AU  - Rowe, James B.
AU  - Rubino, Elisa
AU  - Ruiz, Agustín
AU  - Sanchez-Valle, Raquel
AU  - Sando, Sigrid B.
AU  - Santillo, Alexander F.
AU  - Saxon, Jennifer
AU  - Scarpini, Elio
AU  - Serpente, Maria
AU  - Smirne, Nicoletta
AU  - Sorbi, Sandro
AU  - Suh, EunRan
AU  - Tagliavini, Fabrizio
AU  - Thompson, Jennifer C.
AU  - Trojanowski, John Q.
AU  - Van Deerlin, Vivianna M.
AU  - Van der Zee, Julie
AU  - Van Broeckhoven, Christine
AU  - van Rooij, Jeroen
AU  - Van Swieten, John C.
AU  - Veronesi, Arianna
AU  - Vitale, Emilia
AU  - Waldö, Maria L.
AU  - Woodward, Cathy
AU  - Yokoyama, Jennifer
AU  - Escott-Price, Valentina
AU  - Polke, James M.
AU  - Ferrari, Raffaele
AU  - , 
TI  - <em>C9orf72</em>, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts
AID  - 10.1212/WNL.0000000000010914
DP  - 2020 Dec 15
TA  - Neurology
PG  - e3288--e3302
VI  - 95
IP  - 24
4099  - http://n.neurology.org/content/95/24/e3288.short
4100  - http://n.neurology.org/content/95/24/e3288.full
SO  - Neurology2020 Dec 15; 95
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.AAO=age at onset; bvFTD=behavioral variant frontotemporal dementia; FTLD=frontotemporal lobar degeneration; IFGC=International FTD Genetics Consortium; LOOCV=leave-one-out cross-validation; MND=motor neuron disease; PCA=principal components analysis; PNFA=progressive nonfluent aphasia; PPA=primary progressive aphasia; rc=repeat counts; SNP=single nucleotide polymorphism