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

Beatrice Costa, Christer Nilsson, Alexander F. Santillo, Maria L. Waldö, Raffaele Ferrari, International FTD-Genetics Consortium

Research output: Contribution to journalArticlepeer-review

2 Citations (SciVal)

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.

Original languageEnglish
Pages (from-to)E3288-E3302
JournalNeurology
Volume95
Issue number24
DOIs
Publication statusPublished - 2020

Bibliographical note

Funding Information:
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 Information:
The Article Processing Charge was funded by MRC and Wellcome Trust.

Funding Information:
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. Br?then 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-Sch?rling 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 Neurodegeneration 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 Acci?n Estrat?gica en Salud integrated in the Spanish National R + D + I Plan (grants PI13/02434 and PI16/01861), by ISCIII (Instituto de Salud Carlos III) Subdirecci?n General de Evaluaci?n, and by the Fondo Europeo de Desarrollo Regional (FEDER-Una manera de Hacer Europa). M. Boada and A. Ruiz are funded by Fundaci?n 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. Wald? is supported by the Elly Berggren Foundation. J. Yokoyama is funded by NIA K01 AG049152.

Publisher Copyright:
© 2020 Lippincott Williams and Wilkins. All rights reserved.

Subject classification (UKÄ)

  • Neurology
  • Neurosciences
  • Medical Genetics

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