RT Journal Article
SR Electronic
T1 <em>C9orf72</em>, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts
JF Neurology
JO Neurology
FD Lippincott Williams &amp; Wilkins
SP e3288
OP e3302
DO 10.1212/WNL.0000000000010914
VO 95
IS 24
A1 Costa, Beatrice
A1 Manzoni, Claudia
A1 Bernal-Quiros, Manuel
A1 Kia, Demis A.
A1 Aguilar, Miquel
A1 Alvarez, Ignacio
A1 Alvarez, Victoria
A1 Andreassen, Ole
A1 Anfossi, Maria
A1 Bagnoli, Silvia
A1 Benussi, Luisa
A1 Bernardi, Livia
A1 Binetti, Giuliano
A1 Blackburn, Daniel
A1 Boada, Mercè
A1 Borroni, Barbara
A1 Bowns, Lucy
A1 Bråthen, Geir
A1 Bruni, Amalia C.
A1 Chiang, Huei-Hsin
A1 Clarimon, Jordi
A1 Colville, Shuna
A1 Conidi, Maria E.
A1 Cope, Tom E.
A1 Cruchaga, Carlos
A1 Cupidi, Chiara
A1 Di Battista, Maria Elena
A1 Diehl-Schmid, Janine
A1 Diez-Fairen, Monica
A1 Dols-Icardo, Oriol
A1 Durante, Elisabetta
A1 Flisar, Dušan
A1 Frangipane, Francesca
A1 Galimberti, Daniela
A1 Gallo, Maura
A1 Gallucci, Maurizio
A1 Ghidoni, Roberta
A1 Graff, Caroline
A1 Grafman, Jordan H.
A1 Grossman, Murray
A1 Hardy, John
A1 Hernández, Isabel
A1 Holloway, Guy J.T.
A1 Huey, Edward D.
A1 Illán-Gala, Ignacio
A1 Karydas, Anna
A1 Khoshnood, Behzad
A1 Kramberger, Milica G.
A1 Kristiansen, Mark
A1 Lewis, Patrick A.
A1 Lleó, Alberto
A1 Madhan, Gaganjit K.
A1 Maletta, Raffaele
A1 Maver, Aleš
A1 Menendez-Gonzalez, Manuel
A1 Milan, Graziella
A1 Miller, Bruce
A1 Mol, Merel O.
A1 Momeni, Parastoo
A1 Moreno-Grau, Sonia
A1 Morris, Chris M.
A1 Nacmias, Benedetta
A1 Nilsson, Christer
A1 Novelli, Valeria
A1 Öijerstedt, Linn
A1 Padovani, Alessandro
A1 Pal, Suvankar
A1 Panchbhaya, Yasmin
A1 Pastor, Pau
A1 Peterlin, Borut
A1 Piaceri, Irene
A1 Pickering-Brown, Stuart
A1 Pijnenburg, Yolande A.L.
A1 Puca, Annibale A.
A1 Rainero, Innocenzo
A1 Rendina, Antonella
A1 Richardson, Anna M.T.
A1 Rogaeva, Ekaterina
A1 Rogelj, Boris
A1 Rollinson, Sara
A1 Rossi, Giacomina
A1 Rossmeier, Carola
A1 Rowe, James B.
A1 Rubino, Elisa
A1 Ruiz, Agustín
A1 Sanchez-Valle, Raquel
A1 Sando, Sigrid B.
A1 Santillo, Alexander F.
A1 Saxon, Jennifer
A1 Scarpini, Elio
A1 Serpente, Maria
A1 Smirne, Nicoletta
A1 Sorbi, Sandro
A1 Suh, EunRan
A1 Tagliavini, Fabrizio
A1 Thompson, Jennifer C.
A1 Trojanowski, John Q.
A1 Van Deerlin, Vivianna M.
A1 Van der Zee, Julie
A1 Van Broeckhoven, Christine
A1 van Rooij, Jeroen
A1 Van Swieten, John C.
A1 Veronesi, Arianna
A1 Vitale, Emilia
A1 Waldö, Maria L.
A1 Woodward, Cathy
A1 Yokoyama, Jennifer
A1 Escott-Price, Valentina
A1 Polke, James M.
A1 Ferrari, Raffaele
A1 ,
YR 2020
UL http://n.neurology.org/content/95/24/e3288.abstract
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