A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers

Ming Zhang; Raffaele Ferrari; Maria Carmela Tartaglia; Julia Keith; Ezequiel I. Surace; Uri Wolf; Christine Sato; Mark Grinberg; Yan Liang; Zhengrui Xi; Kyle Dupont; Philip McGoldrick; Anna Weichert; Paul M. McKeever; Raphael Schneider; Michael D. McCorkindale; Claudia Manzoni; Rosa Rademakers; Neill R. Graff-Radford; Dennis W. Dickson; Joseph E. Parisi; Bradley F. Boeve; Ronald C. Petersen; Bruce L. Miller; William W. Seeley; John C. van Swieten; Jeroen van Rooij; Yolande Pijnenburg; Julie van der Zee; Christine Van Broeckhoven; Isabelle Le Ber; Vivianna Van Deerlin; EunRan Suh; Jonathan D. Rohrer; Simon Mead; Caroline Graff; Linn Oijerstedt; Stuart Pickering-Brown; Sara Rollinson; Giacomina Rossi; Fabrizio Tagliavini; William S. Brooks; Carol Dobson-Stone; Glenda M. Halliday; John R. Hodges; Olivier Piguet; Giuliano Binetti; Luisa Benussi; Roberta Ghidoni; Benedetta Nacmias; Sandro Sorbi; Amalia C. Bruni; Daniela Galimberti; Elio Scarpini; Innocenzo Rainero; Elisa Rubino; Jordi Clarimon; Alberto Lleo; Agustin Ruiz; Isabel Hernandez; Pau Pastor; Monica Diez-Fairen; Barbara Borroni; Florence Pasquier; Vincent Deramecourt; Thibaud Lebouvier; Robert Perneczky; Janine Diehl-Schmid; Jordan Grafman; Edward D. Huey; Richard Mayeux; Michael A. Nalls; Dena Hernandez; Andrew Singleton; Parastoo Momeni; Zhen Zeng; John Hardy; Janice Robertson; Lorne Zinman; Ekaterina Rogaeva; International FTD-Genomics Consortium (IFGC); Timothy Griffiths

doi:10.1093/brain/awy238

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A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers

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A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers

Ming Zhang, Raffaele Ferrari, Maria Carmela Tartaglia, Julia Keith, Ezequiel I. Surace, Uri Wolf, Christine Sato, Mark Grinberg, Yan Liang, Zhengrui Xi, …

Brain (London, England : 1878), Vol.141(10), pp.2895-2907

10/01/2018

DOI: 10.1093/brain/awy238

PMCID: PMC6158742

PMID: 30252044

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Abstract

The G(4)C(2)-repeat expansion C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9o7f72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.

Clinical Neurology

Life Sciences & Biomedicine

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Neurosciences & Neurology

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Title: Subtitle: A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers
Creators: Ming Zhang - Tongji University
Raffaele Ferrari - National Hospital for Neurology and Neurosurgery
Maria Carmela Tartaglia - University of Toronto
Julia Keith - Canada Research Chairs
Ezequiel I. Surace - Inst Invest Neurol Dr Raul Carrea FLENI, Dept Neuropatol, Mol Biol Lab, Buenos Aires, DF, Argentina
Uri Wolf - Canada Research Chairs
Christine Sato - University of Toronto
Mark Grinberg - University of Toronto
Yan Liang - University of Toronto
Zhengrui Xi - University of Toronto
Kyle Dupont - University of Toronto
Philip McGoldrick - University of Toronto
Anna Weichert - University of Toronto
Paul M. McKeever - University of Toronto
Raphael Schneider - University of Toronto
Michael D. McCorkindale - National Hospital for Neurology and Neurosurgery
Claudia Manzoni - University of Reading
Rosa Rademakers - Mayo Clinic in Florida
Neill R. Graff-Radford - Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA
Dennis W. Dickson - Mayo Clinic in Florida
Joseph E. Parisi - Mayo Clinic
Bradley F. Boeve - Mayo Clinic
Ronald C. Petersen - Mayo Clinic
Bruce L. Miller - University of California, San Francisco
William W. Seeley - University of California, San Francisco
John C. van Swieten - Erasmus MC
Jeroen van Rooij - Erasmus MC, Dept Neurol, Rotterdam, Netherlands
Yolande Pijnenburg - University of Amsterdam
Julie van der Zee - University of Antwerp
Christine Van Broeckhoven - University of Antwerp
Isabelle Le Ber - Institut du Cerveau
Vivianna Van Deerlin - Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA
EunRan Suh - Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA
Jonathan D. Rohrer - UCL Inst Neurol, Dept Neurodegenerat Dis, Dementia Res Ctr, London, England
Simon Mead - MRC Prion Unit
Caroline Graff - Karolinska Institutet
Linn Oijerstedt - Karolinska Institutet
Stuart Pickering-Brown - University of Manchester
Sara Rollinson - University of Manchester
Giacomina Rossi - Fondazione IRCCS Istituto Neurologico Carlo Besta
Fabrizio Tagliavini - Fondazione IRCCS Istituto Neurologico Carlo Besta
William S. Brooks - UNSW Sydney
Carol Dobson-Stone - The University of Sydney
Glenda M. Halliday - The University of Sydney
John R. Hodges - The University of Sydney
Olivier Piguet - The University of Sydney
Giuliano Binetti - Centro San Giovanni di Dio Fatebenefratelli
Luisa Benussi - Centro San Giovanni di Dio Fatebenefratelli
Roberta Ghidoni - Centro San Giovanni di Dio Fatebenefratelli
Benedetta Nacmias - University of Florence
Sandro Sorbi - University of Florence
Amalia C. Bruni - Azienda Sanit Prov Catanzaro, Reg Neurogenet Ctr, Lamezia Terme, Italy
Daniela Galimberti - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Elio Scarpini - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Innocenzo Rainero - University of Turin
Elisa Rubino - University of Turin
Jordi Clarimon - Biomedical Research Networking Center on Neurodegenerative Diseases
Alberto Lleo - Biomedical Research Networking Center on Neurodegenerative Diseases
Agustin Ruiz - Universitat Internacional de Catalunya
Isabel Hernandez - Universitat Internacional de Catalunya
Pau Pastor - Hosp Univ Mutua de Terrassa, Memory Disorders Unit, Dept Neurol, Barcelona, Spain
Monica Diez-Fairen - Hosp Univ Mutua de Terrassa, Memory Disorders Unit, Dept Neurol, Barcelona, Spain
Barbara Borroni - University of Brescia
Florence Pasquier - Université de Lille
Vincent Deramecourt - Université de Lille
Thibaud Lebouvier - Université de Lille
Robert Perneczky - Technical University of Munich
Janine Diehl-Schmid - Tech Univ Munich, Dept Psychiat & Psychotherapy, Munich, Germany
Jordan Grafman - Northwestern University
Edward D. Huey - Columbia University Irving Medical Center
Richard Mayeux - Columbia University Irving Medical Center
Michael A. Nalls - National Institute on Aging
Dena Hernandez - National Institute on Aging
Andrew Singleton - National Institute on Aging
Parastoo Momeni - RONA
Zhen Zeng - Merck & Co., Inc., Rahway, NJ, USA
John Hardy - UCL, Dept Mol Neurosci, Inst Neurol, London, England
Janice Robertson - University of Toronto
Lorne Zinman - Sunnybrook Health Science Centre
Ekaterina Rogaeva - University of Toronto
International FTD-Genomics Consortium (IFGC)
Timothy Griffiths (Contributor) - Psychological and Brain Sciences
Resource Type: Journal article
Publication Details: Brain (London, England : 1878), Vol.141(10), pp.2895-2907
DOI: 10.1093/brain/awy238
PMID: 30252044
PMCID: PMC6158742
NLM abbreviation: Brain
ISSN: 0006-8950
eISSN: 1460-2156
Publisher: Oxford Univ Press
Number of pages: 13
Grant note: 521-2010-3134; 529-2014-7504; 2015-02926 / Swedish Research Council PI13/02434; PI16/01861 / Accion Estrategica en Salud, integrated in the Spanish National R + D + I Plan Gamla tjanarinnor ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion 284 / Alzheimer's Society ANR-PRTS PREV-DEMALS project BRC149/NS/MH / NIHR Rare Disease Translational Research Collaboration Stohnes foundation Methusalem Excellence Program 1079679; 1103258 / NHMRC; National Health & Medical Research Council (NHMRC) of Australia 733051042 / JPND PreFrontALS MR/M008525/1 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Dementia foundation Sweden 115975 / European Union; European Union (EU) MC_UU_00005/12; MC_U105597119; G0502157; G0400074; G1100540; MC_UU_00024/1; MR/M023664/1; G0900652 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Ministero dell'Istruzione, dell'Universita e della Ricerca - MIUR; Ministry of Education, Universities and Research (MIUR) 733051024 / JPND RiMOD James Hunter ALS Initiative Argentine National Research Council (CONICET) (EIS) University of Antwerp Karolinska Institutet Ricerca Corrente, Italian Ministry of Health; Ministry of Health, Italy Stockholm County Council ANR-10-IAIHU-06 / Investissements d'avenir; Agence Nationale de la Recherche (ANR) 1138223 / National Health and Medical Research Council of Australia; National Health & Medical Research Council (NHMRC) of Australia ALS Canada Clinical Research Fellowship Brain Foundation Sweden P01 NS084974; P01 AG019724; P01-AG-017586 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Swedish Brain Power Research Foundation Flanders (FWO); FWO Canadian Consortium on Neurodegeneration in Aging Flemish Government initiated Impulse Program on Networks for Dementia Research (VIND) Swedish FTD Initiative Assistance Publique-Hopitaux de Paris (Clinical Research and Development Department) RCAOM-12123 / FTLD-exome 1138223 / National Health & Medical Research Council of Australia (NHMRC); National Health & Medical Research Council (NHMRC) of Australia 2015.0722 / Fondazione CRF Fondo Europeo de Desarrollo Regional (FEDER- "Una manera de Hacer Europa"); European Union (EU) Alzheimer foundation Sweden MR/M023664/1 / MRC UK GENFI grant; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Programme Hospitalier de Recherche Clinique Temerty Family Foundation 733050103 / Memorabel-FTD RF08900000 / Italian Ministry of health; Ministry of Health, Italy ALS Canada-Brain Canada R35 NS097261; P50 AG016574; P01 NS084974 / National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
Language: English
Date published: 10/01/2018
Academic Unit: Psychological and Brain Sciences
Record Identifier: 9984627187202771

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