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

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

In: Neurology, Vol. 95, No. 24, 2020, p. E3288-E3302.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Costa, B, Manzoni, C, Bernal-Quiros, M, Kia, DA, Aguilar, M, Alvarez, I, Alvarez, V, Andreassen, OA, Anfossi, M, Bagnoli, S, Benussi, L, Bernardi, L, Binetti, G, Blackburn, DJ, Boada, M, Borroni, B, Bowns, L, Bråthen, G, Bruni, AC, Chiang, HH, Clarimon, J, Colville, S, Conidi, ME, Cope, TE, Cruchaga, C, Cupidi, C, Di Battista, ME, Diehl-Schmid, J, Diez-Fairen, M, Dols-Icardo, O, Durante, E, Flisar, D, Frangipane, F, Galimberti, D, Gallo, M, Gallucci, M, Ghidoni, R, Graff, C, Grafman, JH, Grossman, M, Hardy, J, Hernández, I, Holloway, GJT, Huey, ED, Illán-Gala, I, Karydas, A, Khoshnood, B, Kramberger, MG, Kristiansen, M, Lewis, PA, Lleó, A, Madhan, GK, Maletta, R, Maver, A, Menendez-Gonzalez, M, Milan, G, Miller, BL, Mol, MO, Momeni, P, Moreno-Grau, S, Morris, CM, Nacmias, B, Nilsson, C, Novelli, V, Öijerstedt, L, Padovani, A, Pal, S, Panchbhaya, Y, Pastor, P, Peterlin, B, Piaceri, I, Pickering-Brown, S, Pijnenburg, YAL, Puca, AA, Rainero, I, Rendina, A, Richardson, AMT, Rogaeva, E, Rogelj, B, Rollinson, S, Rossi, G, Roßmeier, C, Rowe, JB, Rubino, E, Ruiz, A, Sanchez-Valle, R, Sando, SB, Santillo, AF, Saxon, J, Scarpini, E, Serpente, M, Smirne, N, Sorbi, S, Suh, ER, Tagliavini, F, Thompson, JC, Trojanowski, JQ, van Deerlin, VM, van der Zee, J, van Broeckhoven, C, van Rooij, JGJ, van Swieten, JC, Veronesi, A, Vitale, E, Waldö, ML, Woodward, C, Yokoyama, JS, Escott-Price, V, Polke, JM & Ferrari, R 2020, 'C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts', Neurology, vol. 95, no. 24, pp. E3288-E3302. https://doi.org/10.1212/WNL.0000000000010914

APA

Costa, B., Manzoni, C., Bernal-Quiros, M., Kia, D. A., Aguilar, M., Alvarez, I., Alvarez, V., Andreassen, O. A., Anfossi, M., Bagnoli, S., Benussi, L., Bernardi, L., Binetti, G., Blackburn, D. J., Boada, M., Borroni, B., Bowns, L., Bråthen, G., Bruni, A. C., ... Ferrari, R. (2020). C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts. Neurology, 95(24), E3288-E3302. https://doi.org/10.1212/WNL.0000000000010914

Vancouver

Costa B, Manzoni C, Bernal-Quiros M, Kia DA, Aguilar M, Alvarez I et al. C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts. Neurology. 2020;95(24):E3288-E3302. https://doi.org/10.1212/WNL.0000000000010914

Author

Costa, Beatrice ; Manzoni, Claudia ; Bernal-Quiros, Manuel ; Kia, Demis A. ; Aguilar, Miquel ; Alvarez, Ignacio ; Alvarez, Victoria ; Andreassen, Ole A. ; Anfossi, Maria ; Bagnoli, Silvia ; Benussi, Luisa ; Bernardi, Livia ; Binetti, Giuliano ; Blackburn, Daniel J. ; Boada, Mercè ; Borroni, Barbara ; Bowns, Lucy ; Bråthen, Geir ; Bruni, Amalia C. ; Chiang, Huei Hsin ; Clarimon, Jordi ; Colville, Shuna ; Conidi, Maria E. ; Cope, Tom E. ; Cruchaga, Carlos ; Cupidi, Chiara ; Di Battista, Maria Elena ; Diehl-Schmid, Janine ; Diez-Fairen, Monica ; Dols-Icardo, Oriol ; Durante, Elisabetta ; Flisar, Dušan ; Frangipane, Francesca ; Galimberti, Daniela ; Gallo, Maura ; Gallucci, Maurizio ; Ghidoni, Roberta ; Graff, Caroline ; Grafman, Jordan H. ; Grossman, Murray ; Hardy, John ; Hernández, Isabel ; Holloway, Guy J.T. ; Huey, Edward D. ; Illán-Gala, Ignacio ; Karydas, Anna ; Khoshnood, Behzad ; Kramberger, Milica G. ; Kristiansen, Mark ; Lewis, Patrick A. ; Lleó, Alberto ; Madhan, Gaganjit K. ; Maletta, Raffaele ; Maver, Aleš ; Menendez-Gonzalez, Manuel ; Milan, Graziella ; Miller, Bruce L. ; Mol, Merel O. ; Momeni, Parastoo ; Moreno-Grau, Sonia ; Morris, Christopher M. ; Nacmias, Benedetta ; Nilsson, Christer ; Novelli, Valeria ; Öijerstedt, Linn ; Padovani, Alessandro ; Pal, Suvankar ; Panchbhaya, Yasmin ; Pastor, Pau ; Peterlin, Borut ; Piaceri, Irene ; Pickering-Brown, Stuart ; Pijnenburg, Yolande A.L. ; Puca, Annibale A. ; Rainero, Innocenzo ; Rendina, Antonella ; Richardson, Anna M.T. ; Rogaeva, Ekaterina ; Rogelj, Boris ; Rollinson, Sara ; Rossi, Giacomina ; Roßmeier, Carola ; Rowe, James B. ; Rubino, Elisa ; Ruiz, Agustín ; Sanchez-Valle, Raquel ; Sando, Sigrid B. ; Santillo, Alexander F. ; Saxon, Jennifer ; Scarpini, Elio ; Serpente, Maria ; Smirne, Nicoletta ; Sorbi, Sandro ; Suh, Eun Ran ; Tagliavini, Fabrizio ; Thompson, Jennifer C. ; Trojanowski, John Q. ; van Deerlin, Vivianna M. ; van der Zee, Julie ; van Broeckhoven, Christine ; van Rooij, Jeroen G.J. ; van Swieten, John C. ; Veronesi, Arianna ; Vitale, Emilia ; Waldö, Maria L. ; Woodward, Cathy ; Yokoyama, Jennifer S. ; Escott-Price, Valentina ; Polke, James M. ; Ferrari, Raffaele. / C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts. In: Neurology. 2020 ; Vol. 95, No. 24. pp. E3288-E3302.

Bibtex

@article{5003d4d1fafc4d5d8727fa29b3fd4f34,

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

abstract = "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.",

author = "Beatrice Costa and Claudia Manzoni and Manuel Bernal-Quiros and Kia, {Demis A.} and Miquel Aguilar and Ignacio Alvarez and Victoria Alvarez and Andreassen, {Ole A.} and Maria Anfossi and Silvia Bagnoli and Luisa Benussi and Livia Bernardi and Giuliano Binetti and Blackburn, {Daniel J.} and Merc{\`e} Boada and Barbara Borroni and Lucy Bowns and Geir Br{\aa}then and Bruni, {Amalia C.} and Chiang, {Huei Hsin} and Jordi Clarimon and Shuna Colville and Conidi, {Maria E.} and Cope, {Tom E.} and Carlos Cruchaga and Chiara Cupidi and {Di Battista}, {Maria Elena} and Janine Diehl-Schmid and Monica Diez-Fairen and Oriol Dols-Icardo and Elisabetta Durante and Du{\v s}an Flisar and Francesca Frangipane and Daniela Galimberti and Maura Gallo and Maurizio Gallucci and Roberta Ghidoni and Caroline Graff and Grafman, {Jordan H.} and Murray Grossman and John Hardy and Isabel Hern{\'a}ndez and Holloway, {Guy J.T.} and Huey, {Edward D.} and Ignacio Ill{\'a}n-Gala and Anna Karydas and Behzad Khoshnood and Kramberger, {Milica G.} and Mark Kristiansen and Lewis, {Patrick A.} and Alberto Lle{\'o} and Madhan, {Gaganjit K.} and Raffaele Maletta and Ale{\v s} Maver and Manuel Menendez-Gonzalez and Graziella Milan and Miller, {Bruce L.} and Mol, {Merel O.} and Parastoo Momeni and Sonia Moreno-Grau and Morris, {Christopher M.} and Benedetta Nacmias and Christer Nilsson and Valeria Novelli and Linn {\"O}ijerstedt and Alessandro Padovani and Suvankar Pal and Yasmin Panchbhaya and Pau Pastor and Borut Peterlin and Irene Piaceri and Stuart Pickering-Brown and Pijnenburg, {Yolande A.L.} and Puca, {Annibale A.} and Innocenzo Rainero and Antonella Rendina and Richardson, {Anna M.T.} and Ekaterina Rogaeva and Boris Rogelj and Sara Rollinson and Giacomina Rossi and Carola Ro{\ss}meier and Rowe, {James B.} and Elisa Rubino and Agust{\'i}n Ruiz and Raquel Sanchez-Valle and Sando, {Sigrid B.} and Santillo, {Alexander F.} and Jennifer Saxon and Elio Scarpini and Maria Serpente and Nicoletta Smirne and Sandro Sorbi and Suh, {Eun Ran} and Fabrizio Tagliavini and Thompson, {Jennifer C.} and Trojanowski, {John Q.} and {van Deerlin}, {Vivianna M.} and {van der Zee}, Julie and {van Broeckhoven}, Christine and {van Rooij}, {Jeroen G.J.} and {van Swieten}, {John C.} and Arianna Veronesi and Emilia Vitale and Wald{\"o}, {Maria L.} and Cathy Woodward and Yokoyama, {Jennifer S.} and Valentina Escott-Price and Polke, {James M.} and Raffaele Ferrari",

year = "2020",

doi = "10.1212/WNL.0000000000010914",

language = "English",

volume = "95",

pages = "E3288--E3302",

journal = "Neurology",

issn = "0028-3878",

publisher = "Lippincott Williams & Wilkins",

number = "24",

}

RIS

TY - JOUR

T1 - C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts

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 A.

AU - Anfossi, Maria

AU - Bagnoli, Silvia

AU - Benussi, Luisa

AU - Bernardi, Livia

AU - Binetti, Giuliano

AU - Blackburn, Daniel J.

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 L.

AU - Mol, Merel O.

AU - Momeni, Parastoo

AU - Moreno-Grau, Sonia

AU - Morris, Christopher 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, Eun Ran

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 G.J.

AU - van Swieten, John C.

AU - Veronesi, Arianna

AU - Vitale, Emilia

AU - Waldö, Maria L.

AU - Woodward, Cathy

AU - Yokoyama, Jennifer S.

AU - Escott-Price, Valentina

AU - Polke, James M.

AU - Ferrari, Raffaele

PY - 2020

Y1 - 2020

N2 - 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.

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.

U2 - 10.1212/WNL.0000000000010914

DO - 10.1212/WNL.0000000000010914

M3 - Journal article

C2 - 32943482

VL - 95

SP - E3288-E3302

JO - Neurology

JF - Neurology

SN - 0028-3878

IS - 24

ER -

ID: 286993021