Literature DB >> 32943482

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

Beatrice Costa1, Claudia Manzoni2, Manuel Bernal-Quiros1, Demis A Kia1, Miquel Aguilar1, Ignacio Alvarez1, Victoria Alvarez1, Ole Andreassen1, Maria Anfossi1, Silvia Bagnoli1, Luisa Benussi1, Livia Bernardi1, Giuliano Binetti1, Daniel Blackburn1, Mercè Boada1, Barbara Borroni1, Lucy Bowns1, Geir Bråthen1, Amalia C Bruni1, Huei-Hsin Chiang1, Jordi Clarimon1, Shuna Colville1, Maria E Conidi1, Tom E Cope1, Carlos Cruchaga1, Chiara Cupidi1, Maria Elena Di Battista1, Janine Diehl-Schmid1, Monica Diez-Fairen1, Oriol Dols-Icardo1, Elisabetta Durante1, Dušan Flisar1, Francesca Frangipane1, Daniela Galimberti1, Maura Gallo1, Maurizio Gallucci1, Roberta Ghidoni1, Caroline Graff1, Jordan H Grafman1, Murray Grossman1, John Hardy1, Isabel Hernández1, Guy J T Holloway1, Edward D Huey1, Ignacio Illán-Gala1, Anna Karydas1, Behzad Khoshnood1, Milica G Kramberger1, Mark Kristiansen1, Patrick A Lewis1, Alberto Lleó1, Gaganjit K Madhan1, Raffaele Maletta1, Aleš Maver1, Manuel Menendez-Gonzalez1, Graziella Milan1, Bruce Miller1, Merel O Mol1, Parastoo Momeni1, Sonia Moreno-Grau1, Chris M Morris1, Benedetta Nacmias1, Christer Nilsson1, Valeria Novelli1, Linn Öijerstedt1, Alessandro Padovani1, Suvankar Pal1, Yasmin Panchbhaya1, Pau Pastor1, Borut Peterlin1, Irene Piaceri1, Stuart Pickering-Brown1, Yolande A L Pijnenburg1, Annibale A Puca1, Innocenzo Rainero1, Antonella Rendina1, Anna M T Richardson1, Ekaterina Rogaeva1, Boris Rogelj1, Sara Rollinson1, Giacomina Rossi1, Carola Rossmeier1, James B Rowe1, Elisa Rubino1, Agustín Ruiz1, Raquel Sanchez-Valle1, Sigrid B Sando1, Alexander F Santillo1, Jennifer Saxon1, Elio Scarpini1, Maria Serpente1, Nicoletta Smirne1, Sandro Sorbi1, EunRan Suh1, Fabrizio Tagliavini1, Jennifer C Thompson1, John Q Trojanowski1, Vivianna M Van Deerlin1, Julie Van der Zee1, Christine Van Broeckhoven1, Jeroen van Rooij1, John C Van Swieten1, Arianna Veronesi1, Emilia Vitale1, Maria L Waldö1, Cathy Woodward1, Jennifer Yokoyama1, Valentina Escott-Price1, James M Polke1, Raffaele Ferrari2.   

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.
Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

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Year:  2020        PMID: 32943482      PMCID: PMC7836664          DOI: 10.1212/WNL.0000000000010914

Source DB:  PubMed          Journal:  Neurology        ISSN: 0028-3878            Impact factor:   9.910


  38 in total

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Authors:  Alan E Renton; Elisa Majounie; Adrian Waite; Javier Simón-Sánchez; Sara Rollinson; J Raphael Gibbs; Jennifer C Schymick; Hannu Laaksovirta; John C van Swieten; Liisa Myllykangas; Hannu Kalimo; Anders Paetau; Yevgeniya Abramzon; Anne M Remes; Alice Kaganovich; Sonja W Scholz; Jamie Duckworth; Jinhui Ding; Daniel W Harmer; Dena G Hernandez; Janel O Johnson; Kin Mok; Mina Ryten; Danyah Trabzuni; Rita J Guerreiro; Richard W Orrell; James Neal; Alex Murray; Justin Pearson; Iris E Jansen; David Sondervan; Harro Seelaar; Derek Blake; Kate Young; Nicola Halliwell; Janis Bennion Callister; Greg Toulson; Anna Richardson; Alex Gerhard; Julie Snowden; David Mann; David Neary; Michael A Nalls; Terhi Peuralinna; Lilja Jansson; Veli-Matti Isoviita; Anna-Lotta Kaivorinne; Maarit Hölttä-Vuori; Elina Ikonen; Raimo Sulkava; Michael Benatar; Joanne Wuu; Adriano Chiò; Gabriella Restagno; Giuseppe Borghero; Mario Sabatelli; David Heckerman; Ekaterina Rogaeva; Lorne Zinman; Jeffrey D Rothstein; Michael Sendtner; Carsten Drepper; Evan E Eichler; Can Alkan; Ziedulla Abdullaev; Svetlana D Pack; Amalia Dutra; Evgenia Pak; John Hardy; Andrew Singleton; Nigel M Williams; Peter Heutink; Stuart Pickering-Brown; Huw R Morris; Pentti J Tienari; Bryan J Traynor
Journal:  Neuron       Date:  2011-09-21       Impact factor: 17.173

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Journal:  Brain       Date:  2018-10-01       Impact factor: 13.501

10.  Screening a UK amyotrophic lateral sclerosis cohort provides evidence of multiple origins of the C9orf72 expansion.

Authors:  Pietro Fratta; James M Polke; Jia Newcombe; Sarah Mizielinska; Tammaryn Lashley; Mark Poulter; Jon Beck; Elisavet Preza; Anny Devoy; Katie Sidle; Robin Howard; Andrea Malaspina; Richard W Orrell; Jan Clarke; Ching-Hua Lu; Kin Mok; Toby Collins; Maryam Shoaii; Tina Nanji; Selina Wray; Gary Adamson; Alan Pittman; Alan E Renton; Bryan J Traynor; Mary G Sweeney; Tamas Revesz; Henry Houlden; Simon Mead; Adrian M Isaacs; Elizabeth M C Fisher
Journal:  Neurobiol Aging       Date:  2014-08-01       Impact factor: 4.673

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