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

Costa, B., Manzoni, C. ORCID: https://orcid.org/0000-0001-5367-4023, Bernal-Quiros, M., Kia, D. A., Aguilar, M., Alvarez, I., Alvarez, V., Andreassen, O. ORCID: https://orcid.org/0000-0002-4461-3568, Anfossi, M., Bagnoli, S., Benussi, L., Bernardi, L., Binetti, G., Blackburn, D., Boada, M., Borroni, B., Bowns, L., Bråthen, G. ORCID: https://orcid.org/0000-0003-3224-7983, Bruni, A. C., Chiang, H.-H., Clarimon, J., Colville, S., Conidi, M. E., Cope, T. E., Cruchaga, C., Cupidi, C., Di Battista, M. E., Diehl-Schmid, J., Diez-Fairen, M., Dols-Icardo, O., Durante, E., Flisar, D., Frangipane, F., Galimberti, D. ORCID: https://orcid.org/0000-0002-9284-5953, Gallo, M., Gallucci, M., Ghidoni, R. ORCID: https://orcid.org/0000-0002-7691-1957, Graff, C., Grafman, J. H., Grossman, M., Hardy, J., Hernández, I., Holloway, G. J. T., Huey, E. D., Illán-Gala, I. ORCID: https://orcid.org/0000-0002-5418-2052, Karydas, A., Khoshnood, B., Kramberger, M. G., Kristiansen, M., Lewis, P. A., Lleó, A., Madhan, G. K., Maletta, R., Maver, A., Menendez-Gonzalez, M., Milan, G., Miller, B., Mol, M. O. ORCID: https://orcid.org/0000-0003-2533-2530, Momeni, P., Moreno-Grau, S., Morris, C. M. ORCID: https://orcid.org/0000-0002-3749-0993, Nacmias, B. ORCID: https://orcid.org/0000-0001-9338-9040, Nilsson, C., Novelli, V., Öijerstedt, L., Padovani, A., Pal, S., Panchbhaya, Y., Pastor, P. ORCID: https://orcid.org/0000-0002-7493-8777, Peterlin, B., Piaceri, I., Pickering-Brown, S., Pijnenburg, Y. A. L. ORCID: https://orcid.org/0000-0003-2464-1905, Puca, A. A., Rainero, I., Rendina, A. ORCID: https://orcid.org/0000-0001-5331-2807, Richardson, A. M. T., Rogaeva, E., Rogelj, B. ORCID: https://orcid.org/0000-0003-3898-1943, Rollinson, S. ORCID: https://orcid.org/0000-0002-0921-4318, Rossi, G., Rossmeier, C., Rowe, J. B., Rubino, E. ORCID: https://orcid.org/0000-0002-7553-7553, Ruiz, A., Sanchez-Valle, R., Sando, S. B., Santillo, A. F., Saxon, J., Scarpini, E. ORCID: https://orcid.org/0000-0002-6395-2119, Serpente, M., Smirne, N., Sorbi, S., Suh, E., Tagliavini, F., Thompson, J. C., Trojanowski, J. Q., Van Deerlin, V. M., Van der Zee, J. ORCID: https://orcid.org/0000-0003-4381-8040, Van Broeckhoven, C. ORCID: https://orcid.org/0000-0003-0183-7665, van Rooij, J., Van Swieten, J. C., Veronesi, A., Vitale, E. ORCID: https://orcid.org/0000-0003-4651-3875, Waldö, M. L., Woodward, C., Yokoyama, J., Escott-Price, V., Polke, J. M. and Ferrari, R. (2020) C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts. Neurology, 95 (24). e3288-e3302. ISSN 0028-3878 doi: 10.1212/WNL.0000000000010914

Abstract/Summary

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.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/98068
Item Type	Article
Refereed	Yes
Divisions	Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Pharmacy Practice Research Group
Publisher	American Academy of Neurology
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