Objective: We sought to characterise C9orf72 expansions in relation to genetic ancestry and age at onset (AAO), and to use these parameters to discriminate the behavioural 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=1396; bvFTD [n=800], PPA [n=495] and FTLD-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's Exact, ANOVA with Tukey post-hoc tests, and logistic and non-linear mixed-effects model regressions. Results: We found C9orf72 pathogenic expansions in 4% of all cases (56/1396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MNDs (11.9%), 40/800 bvFTDs (5%) and 4/495 of PPAs (0.8%). While addressing population-substructure through principal component 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 bvFTDs compared to PPAs (5% vs. 0.8% [p=2.17x10-5; OR=6.4; 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=1.1x10-2; 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 to complex genetic risk-architectures differently underpinning the behavioural and language variant syndromes.
C9orf72, AAO and ancestry help discriminating behavioural from language variants in FTLD cohorts / B. Costa, C. Manzoni, M. Bernal-Quiros, D.A. Kia, M. Aguilar, I. Alvarez, V. Alvarez, O. Andreassen, M. Anfossi, S. Bagnoli, L. Benussi, L. Bernardi, G. Binetti, D. Blackburn, M. Boada, B. Borroni, L. Bowns, G. Bråthen, A.C. Bruni, H. Chiang, J. 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. 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. 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. Pijnenburg, A.A. Puca, I. Rainero, A. Rendina, A.M. 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, E. Scarpini, M. Serpente, N. Smirne, S. Sorbi, E. Suh, F. Tagliavini, J.C. Thompson, J.Q. Trojanowski, V.M. Van Deerlin, J. Van der Zee, C. Van Broeckhoven, J. van Rooij, J.C. Van Swieten, A. Veronesi, E. Vitale, M.L. Waldö, C. Woodward, J. Yokoyama, V. Escott-Price, J.M. Polke, R. Ferrari. - In: NEUROLOGY. - ISSN 0028-3878. - (2020). [Epub ahead of print]
C9orf72, AAO and ancestry help discriminating behavioural from language variants in FTLD cohorts
D. Galimberti;E. Scarpini;M. Serpente;
2020
Abstract
Objective: We sought to characterise C9orf72 expansions in relation to genetic ancestry and age at onset (AAO), and to use these parameters to discriminate the behavioural 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=1396; bvFTD [n=800], PPA [n=495] and FTLD-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's Exact, ANOVA with Tukey post-hoc tests, and logistic and non-linear mixed-effects model regressions. Results: We found C9orf72 pathogenic expansions in 4% of all cases (56/1396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MNDs (11.9%), 40/800 bvFTDs (5%) and 4/495 of PPAs (0.8%). While addressing population-substructure through principal component 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 bvFTDs compared to PPAs (5% vs. 0.8% [p=2.17x10-5; OR=6.4; 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=1.1x10-2; 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 to complex genetic risk-architectures differently underpinning the behavioural and language variant syndromes.
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