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

B. Costa, C. Manzoni, M. Bernal-Quiros, D.A. Kia, M. Aguilar, I. Alvarez, V. Alvarez, O.A. Andreassen, M. Anfossi, S. Bagnoli, L. Benussi, L. Bernardi, G. Binetti, D.J. Blackburn, M. Boada, B. Borroni, L. Bowns, G. Bråthen, A.C. Bruni, H.-H. ChiangJ. Clarimon, S. Colville, M.E. Conidi, T.E. Cope, C. Cruchaga, C. Cupidi, M.E. Di Battista, J. Diehl-Schmid, M. Diez-Fairen, O. Dols-Icardo, E. Durante, D. Flisar, F. Frangipane, D. Galimberti, M. Gallo, M. Gallucci, R. Ghidoni, C. Graff, J.H. Grafman, M. Grossman, J. Hardy, I. Hernández, G.J.T. Holloway, E.D. Huey, I. Illán-Gala, A. Karydas, B. Khoshnood, M.G. Kramberger, M. Kristiansen, P.A. Lewis, A. Lleó, G.K. Madhan, R. Maletta, A. Maver, M. Menendez-Gonzalez, G. Milan, B.L. Miller, M.O. Mol, P. Momeni, S. Moreno-Grau, C.M. Morris, B. Nacmias, C. Nilsson, V. Novelli, L. Öijerstedt, A. Padovani, S. Pal, Y. Panchbhaya, P. Pastor, B. Peterlin, I. Piaceri, S. Pickering-Brown, Y.A.L. Pijnenburg, A.A. Puca, I. Rainero, A. Rendina, A.M.T. Richardson, E. Rogaeva, B. Rogelj, S. Rollinson, G. Rossi, C. Roßmeier, J.B. Rowe, E. Rubino, A. Ruiz, R. Sanchez-Valle, S.B. Sando, A.F. Santillo, J. Saxon, M. Serpente, N. Smirne, E. Scarpini, S. Sorbi, E. Suh, F. Tagliavini, J.C. Thompson, J.Q. Trojanowski, V.M. van Deerlin, J. van der Zee, C. van Broeckhoven, J.G.J. van Rooij, J.C. van Swieten, A. Veronesi, E. Vitale, M.L. Waldö, C. Woodward, J.S. Yokoyama, V. Escott-Price, J.M. Polke, R. Ferrari, International FTD-Genetics Consortium

Research output: Contribution to journalArticlepeer-review


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. © 2020 Lippincott Williams and Wilkins. All rights reserved.
Original languageEnglish
Pages (from-to)E3288-E3302
Issue number24
Publication statusPublished - 2020


  • analysis of variance
  • ancestry group
  • Article
  • Central European
  • cohort analysis
  • correlation analysis
  • diagnostic accuracy
  • Fisher exact test
  • frontal variant frontotemporal dementia
  • frontotemporal dementia
  • genetic association
  • genetic risk
  • genotype
  • haplotype
  • human
  • intermethod comparison
  • logistic regression analysis
  • major clinical study
  • motor neuron disease
  • nonlinear system
  • Northern European
  • nucleotide repeat
  • onset age
  • polymerase chain reaction
  • post hoc analysis
  • prediction
  • primary progressive aphasia
  • principal component analysis
  • priority journal
  • regression analysis
  • Southern European
  • statistical analysis
  • aged
  • clinical trial
  • Europe
  • female
  • genetics
  • geography
  • male
  • middle aged
  • multicenter study
  • pathophysiology
  • Scandinavia
  • Southern Europe
  • syndrome
  • very elderly
  • C9orf72 protein, human
  • guanine nucleotide exchange C9orf72
  • repetitive DNA
  • Age of Onset
  • Aged
  • Aged, 80 and over
  • Aphasia, Primary Progressive
  • C9orf72 Protein
  • Cohort Studies
  • DNA Repeat Expansion
  • Female
  • Frontotemporal Dementia
  • Frontotemporal Lobar Degeneration
  • Geography
  • Humans
  • Male
  • Mediterranean Region
  • Middle Aged
  • Principal Component Analysis
  • Scandinavian and Nordic Countries
  • Syndrome


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