Abstract
| Original language | English |
|---|---|
| Pages (from-to) | E3288-E3302 |
| Journal | Neurology |
| Volume | 95 |
| Issue number | 24 |
| DOIs | |
| Publication status | Published - 2020 |
Keywords
- 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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C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts. / 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.; 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.; Gallo, M.; Gallucci, M.; Ghidoni, R.; Graff, C.; Grafman, J.H.; Grossman, M.; Hardy, J.; Hernández, I.; Holloway, G.J.T.; Huey, E.D.; Illán-Gala, I.; 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.L.; Mol, M.O.; Momeni, P.; Moreno-Grau, S.; Morris, C.M.; Nacmias, B.; Nilsson, C.; Novelli, V.; Öijerstedt, L.; Padovani, A.; Pal, S.; Panchbhaya, Y.; Pastor, P.; Peterlin, B.; Piaceri, I.; Pickering-Brown, S.; Pijnenburg, Y.A.L.; Puca, A.A.; Rainero, I.; Rendina, A.; Richardson, A.M.T.; Rogaeva, E.; Rogelj, B.; Rollinson, S.; Rossi, G.; Roßmeier, C.; Rowe, J.B.; Rubino, E.; Ruiz, A.; Sanchez-Valle, R.; Sando, S.B.; Santillo, A.F.; Saxon, J.; Serpente, M.; Smirne, N.; Scarpini, E.; Sorbi, S.; Suh, E.; Tagliavini, F.; Thompson, J.C.; Trojanowski, J.Q.; van Deerlin, V.M.; van der Zee, J.; van Broeckhoven, C.; van Rooij, J.G.J.; van Swieten, J.C.; Veronesi, A.; Vitale, E.; Waldö, M.L.; Woodward, C.; Yokoyama, J.S.; Escott-Price, V.; Polke, J.M.; Ferrari, R.; Consortium, International FTD-Genetics.
In: Neurology, Vol. 95, No. 24, 2020, p. E3288-E3302.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts
AU - Costa, B.
AU - Manzoni, C.
AU - Bernal-Quiros, M.
AU - Kia, D.A.
AU - Aguilar, M.
AU - Alvarez, I.
AU - Alvarez, V.
AU - Andreassen, O.A.
AU - Anfossi, M.
AU - Bagnoli, S.
AU - Benussi, L.
AU - Bernardi, L.
AU - Binetti, G.
AU - Blackburn, D.J.
AU - Boada, M.
AU - Borroni, B.
AU - Bowns, L.
AU - Bråthen, G.
AU - Bruni, A.C.
AU - Chiang, H.-H.
AU - Clarimon, J.
AU - Colville, S.
AU - Conidi, M.E.
AU - Cope, T.E.
AU - Cruchaga, C.
AU - Cupidi, C.
AU - Di Battista, M.E.
AU - Diehl-Schmid, J.
AU - Diez-Fairen, M.
AU - Dols-Icardo, O.
AU - Durante, E.
AU - Flisar, D.
AU - Frangipane, F.
AU - Galimberti, D.
AU - Gallo, M.
AU - Gallucci, M.
AU - Ghidoni, R.
AU - Graff, C.
AU - Grafman, J.H.
AU - Grossman, M.
AU - Hardy, J.
AU - Hernández, I.
AU - Holloway, G.J.T.
AU - Huey, E.D.
AU - Illán-Gala, I.
AU - Karydas, A.
AU - Khoshnood, B.
AU - Kramberger, M.G.
AU - Kristiansen, M.
AU - Lewis, P.A.
AU - Lleó, A.
AU - Madhan, G.K.
AU - Maletta, R.
AU - Maver, A.
AU - Menendez-Gonzalez, M.
AU - Milan, G.
AU - Miller, B.L.
AU - Mol, M.O.
AU - Momeni, P.
AU - Moreno-Grau, S.
AU - Morris, C.M.
AU - Nacmias, B.
AU - Nilsson, C.
AU - Novelli, V.
AU - Öijerstedt, L.
AU - Padovani, A.
AU - Pal, S.
AU - Panchbhaya, Y.
AU - Pastor, P.
AU - Peterlin, B.
AU - Piaceri, I.
AU - Pickering-Brown, S.
AU - Pijnenburg, Y.A.L.
AU - Puca, A.A.
AU - Rainero, I.
AU - Rendina, A.
AU - Richardson, A.M.T.
AU - Rogaeva, E.
AU - Rogelj, B.
AU - Rollinson, S.
AU - Rossi, G.
AU - Roßmeier, C.
AU - Rowe, J.B.
AU - Rubino, E.
AU - Ruiz, A.
AU - Sanchez-Valle, R.
AU - Sando, S.B.
AU - Santillo, A.F.
AU - Saxon, J.
AU - Serpente, M.
AU - Smirne, N.
AU - Scarpini, E.
AU - Sorbi, S.
AU - Suh, E.
AU - Tagliavini, F.
AU - Thompson, J.C.
AU - Trojanowski, J.Q.
AU - van Deerlin, V.M.
AU - van der Zee, J.
AU - van Broeckhoven, C.
AU - van Rooij, J.G.J.
AU - van Swieten, J.C.
AU - Veronesi, A.
AU - Vitale, E.
AU - Waldö, M.L.
AU - Woodward, C.
AU - Yokoyama, J.S.
AU - Escott-Price, V.
AU - Polke, J.M.
AU - Ferrari, R.
AU - Consortium, International FTD-Genetics
N1 - Export Date: 22 February 2021 CODEN: NEURA Correspondence Address: Manzoni, C.; School of Pharmacy, United Kingdom; email: c.manzoni@ucl.ac.uk Correspondence Address: Ferrari, R.; Department of Neurodegenerative Disease, United Kingdom; email: r.ferrari@ucl.ac.uk Chemicals/CAS: C9orf72 Protein; C9orf72 protein, human Funding details: PI 15/00878 Funding details: 20143810, AG09215 Funding details: RF-2016-02361492 Funding details: G0400074 Funding details: PI13/02434, PI16/01861 Funding details: AG017586, AG054519, P30 AG10124, U01 AG062418 Funding details: National Institutes of Health, NIH, P01 AG026276, R01AG044546, R01AG058501, RF1AG053303, U01AG058922 Funding details: National Institute on Aging, NIA, K01 AG049152 Funding details: U.S. Bureau of Land Management, BLM Funding details: Wellcome Trust, WT, 202903/Z/16/Z Funding details: EU Joint Programme – Neurodegenerative Disease Research, JPND, AC14/00013 Funding details: European Federation of Pharmaceutical Industries and Associations, EFPIA, 115975 Funding details: Associazione Fatebenefratelli per la Ricerca, AFaR, P01-AG1972403, P50-AG023501 Funding details: Medical Research Council, MRC, MR/N026004/1, SUAG004/91365 Funding details: National Institute for Health Research, NIHR, RG64473 Funding details: University College London, UCL Funding details: Newcastle University Funding details: European Commission, EC Funding details: Alzheimer’s Research UK, ARUK Funding details: Fonds Wetenschappelijk Onderzoek, FWO Funding details: Newcastle upon Tyne Hospitals NHS Foundation Trust Funding details: Karolinska Institutet, KI Funding details: Javna Agencija za Raziskovalno Dejavnost RS, ARRS, 103838, J3-8201, J3-9263, P4-0127 Funding details: Vetenskapsrådet, VR, 2015-02926, 2018-02754, 529-2014-7504 Funding details: Instituto de Salud Carlos III, ISCIII Funding details: Norges Forskningsråd, 223273 Funding details: Horizon 2020 Funding details: Universiteit Antwerpen Funding details: European Regional Development Fund, FEDER Funding details: Innovative Medicines Initiative, IMI Funding details: NIHR Newcastle Biomedical Research Centre Funding details: Nasjonalforeningen for Folkehelsen Funding details: Alzheimer’s Society, 284, 447 Funding details: UK Dementia Research Institute, UK DRI Funding details: NIHR Cambridge Biomedical Research Centre Funding text 1: R. Ferrari and B. Costa are supported by funding from the Alzheimer’s Society (grants 284 and 447). V. Alvarez and M. Menendez-Gonzalez are supported by the Fondos Feder (grant PI 15/00878). O. Andreassen is supported by the Research Council of Norway (grant 223273), Norwegian Health Association, and the KG Jebsen Stiftelsen. L. Benussi, R. Ghidoni, G. Rossi, and F. Tagliavini are supported by the Italian Ministry of Health–Ricerca Corrente. G. Bråthen and R. Ghidoni are supported by the Italian Ministry of Health (grant RF-2016-02361492). D. Blackburn is supported by the Sheffield Biomedical Research Centre. L. Bernardi is supported by the National Institute for Health Research Cambridge Biomedical Research Centre and Biomedical Research Unit in Dementia (NIHR, grant RG64473). T.E. Cope is supported by the Association of British Neurologists; the recruitment and clinical characterization of research participants at Washington University were supported by NIH (grants R01AG044546, RF1AG053303, R01AG058501, U01AG058922, P50 AG05681, P01 AG03991, and P01 AG026276). F. Frangipane is supported by ONLUS Lamezia Terme. C. Graff is supported by grants from JPND Prefrontals Swedish Research Council (VR) 529-2014-7504, Swedish Research Council (VR) 2015-02926, Swedish Research Council (VR) 2018-02754, Swedish FTD Initiative-Schörling Foundation, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Karolinska Institutet Doctoral Funding, and StratNeuro, Swedish Demensfonden. M. Gallo is supported by the NIH (grant AG054519). M. Gallucci, E. Scarpini, J.C. Thompson and V.M. Van Deerlin are supported by the NIH (grant AG017586, and P30 AG10124 and U01 AG062418). J. Hardy and P.A. Lewis are supported by an MRC Programme grant (MR/N026004/1). J. Hardy is supported by the UK Dementia Research Institute, which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK, Wellcome Trust (award 202903/Z/16/Z), Dolby Family Fund, National Institute for Health Research University College London Hospitals Biomedical Research Centre, BRCNIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust, and University College London. R. Maletta is supported by the Associazione per la Ricerca Neurogenetica. B. Miller is supported by the NIH (grants P50-AG023501 and P01-AG1972403) (BLM). C.M. Morris is supported by the Newcastle Brain Tissue Resource, the UK Medical Research Council (grant G0400074), the NIHR Newcastle Biomedical Research Centre awarded to the Newcastle upon Tyne NHS Foundation Trust and Newcastle University, and a grant from the Alzheimer’s Society and Alzheimer’s Research UK as part of the Brains for Dementia Research Project. B. Nacmias and S.B. Sando are supported by the Ricerca di Ateneo 2019. E. Rogaeva is supported by the Canadian Consortium on Neuro-degeneration in Aging. B. Rogelj is supported by grants from the Slovenian Research Agency (grants P4-0127, J3-8201, J3-9263). J. van Rooij is supported by the Wellcome Trust (grant 103838), by the Medical Research Council (grant number SUAG004/91365), and by the National Institute for Health Research Cambridge Biomedical Research Centre and Biomedical Research Unit in Dementia (NIHR, grant RG64473). A. Rendina is supported by the Innovative Medicines Initiative 2 Joint Undertaking, which receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA (grant 115975), by Acción Estratégica en Salud integrated in the Spanish National R + D + I Plan (grants PI13/02434 and PI16/01861), by ISCIII (Instituto de Salud Carlos III) Subdirección General de Evaluación, and by the Fondo Europeo de Desarrollo Regional (FEDER-Una manera de Hacer Europa). M. Boada and A. Ruiz are funded by Fundación bancaria La Caixa and Grifols SA (GR@ACE project). R. Sanchez-Valle is funded by the Spanish National Institute of Health Carlos III (ISCIII) under the aegis of the EU Joint Programme–Neurodegenerative Disease Research (JPND) (grant AC14/00013) and Fundacio Marato de TV3 (20143810) (RSV). J.Q. Trojanowski is supported by the NIH (grant AG09215). C. Van Broeckhoven and J. Van der Zee are supported by the Flemish Government initiated Impulse Program on Networks for Dementia Research (VIND) and the Methusalem Excellence Program, by the Research Foundation Flanders (FWO), and by the University of Antwerp Research Fund (Belgium). M.L. Waldö is supported by the Elly Berggren Foundation. J. Yokoyama is funded by NIA K01 AG049152. Funding text 2: The Article Processing Charge was funded by MRC and Wellcome Trust. 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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. © 2020 Lippincott Williams and Wilkins. All rights reserved.
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. © 2020 Lippincott Williams and Wilkins. All rights reserved.
KW - analysis of variance
KW - ancestry group
KW - Article
KW - Central European
KW - cohort analysis
KW - correlation analysis
KW - diagnostic accuracy
KW - Fisher exact test
KW - frontal variant frontotemporal dementia
KW - frontotemporal dementia
KW - genetic association
KW - genetic risk
KW - genotype
KW - haplotype
KW - human
KW - intermethod comparison
KW - logistic regression analysis
KW - major clinical study
KW - motor neuron disease
KW - nonlinear system
KW - Northern European
KW - nucleotide repeat
KW - onset age
KW - polymerase chain reaction
KW - post hoc analysis
KW - prediction
KW - primary progressive aphasia
KW - principal component analysis
KW - priority journal
KW - regression analysis
KW - Southern European
KW - statistical analysis
KW - aged
KW - clinical trial
KW - Europe
KW - female
KW - genetics
KW - geography
KW - male
KW - middle aged
KW - multicenter study
KW - pathophysiology
KW - Scandinavia
KW - Southern Europe
KW - syndrome
KW - very elderly
KW - C9orf72 protein, human
KW - guanine nucleotide exchange C9orf72
KW - repetitive DNA
KW - Age of Onset
KW - Aged
KW - Aged, 80 and over
KW - Aphasia, Primary Progressive
KW - C9orf72 Protein
KW - Cohort Studies
KW - DNA Repeat Expansion
KW - Female
KW - Frontotemporal Dementia
KW - Frontotemporal Lobar Degeneration
KW - Geography
KW - Humans
KW - Male
KW - Mediterranean Region
KW - Middle Aged
KW - Principal Component Analysis
KW - Scandinavian and Nordic Countries
KW - Syndrome
U2 - 10.1212/WNL.0000000000010914
DO - 10.1212/WNL.0000000000010914
M3 - Article
VL - 95
SP - E3288-E3302
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 24
ER -