A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers
Ming Zhang
(1, 2)
,
Raffaele Ferrari
(3)
,
Maria Carmela Tartaglia
(2, 4, 5)
,
Julia Keith
(5)
,
Ezequiel I Surace
,
Uri Wolf
(5)
,
Christine Sato
(2)
,
Mark Grinberg
(2)
,
Yan Liang
(2)
,
Zhengrui Xi
(2)
,
Kyle Dupont
(2)
,
Philip Mcgoldrick
(2)
,
Anna Weichert
(2)
,
Paul M Mckeever
(2)
,
Raphael Schneider
(2)
,
Michael D Mccorkindale
(3)
,
Claudia Manzoni
(6)
,
Rosa Rademakers
(7)
,
Neill R Graff-Radford
(7)
,
Dennis W Dickson
(7)
,
Joseph E Parisi
(8)
,
Bradley F Boeve
(8)
,
Ronald C Petersen
(8)
,
Bruce L Miller
(9)
,
William W Seeley
(9)
,
John C van Swieten
(10)
,
Jeroen van Rooij
(10)
,
Yolande a L Pijnenburg
(11)
,
Julie van der Zee
(12)
,
Christine van Broeckhoven
(12)
,
Isabelle Le Ber
(13, 14)
,
Vivianna van Deerlin
(15)
,
Eunran Suh
(15)
,
Jonathan D Rohrer
(16)
,
Simon Mead
(17)
,
Caroline Graff
(18, 19)
,
Linn Öijerstedt
(18, 19)
,
Stuart Pickering-Brown
(20)
,
Sara Rollinson
(20)
,
Giacomina Rossi
(21)
,
Fabrizio Tagliavini
(21)
,
William S Brooks
(22)
,
Carol Dobson-Stone
(23, 22)
,
Glenda M Halliday
(23)
,
John R Hodges
(23)
,
Olivier Piguet
(23)
,
Giuliano Binetti
(24)
,
Luisa Benussi
(24)
,
Roberta Ghidoni
(24)
,
Benedetta Nacmias
(25)
,
Sandro Sorbi
(25)
,
Amalia C Bruni
,
Daniela Galimberti
(26)
,
Elio Scarpini
(26)
,
Innocenzo Rainero
(27)
,
Elisa Rubino
(27)
,
Jordi Clarimon
(28, 29, 30)
,
Alberto Lleó
(28, 29, 30)
,
Agustin Ruiz
(31)
,
Isabel Hernández
(31)
,
Pau Pastor
(32)
,
Monica Diez-Fairen
(32)
,
Barbara Borroni
(33)
,
Florence Pasquier
(34)
,
Vincent Deramecourt
(34)
,
Thibaud Lebouvier
(34)
,
Robert Perneczky
(35)
,
Janine Diehl-Schmid
(35)
,
Jordan Grafman
(36, 37)
,
Edward D Huey
(38)
,
Richard Mayeux
(38)
,
Michael A Nalls
(39)
,
Dena Hernandez
(39)
,
Andrew B Singleton
(39)
,
Parastoo Momeni
,
Zhen Zeng
,
John Hardy
(16)
,
Janice Robertson
(2)
,
Lorne Zinman
(5, 40)
,
Ekaterina Rogaeva
(2, 5)
1
Tongji University
2 Tanz Center Research in Neurodegenerative Diseases [Toronto]
3 UCL Institute of Neurology, Queen Square [London]
4 Toronto Western Hospital
5 University of Toronto
6 UOR - University of Reading
7 Mayo Clinic [Jacksonville]
8 Mayo Clinic [Rochester]
9 UC San Francisco - University of California [San Francisco]
10 Erasmus MC - Erasmus University Medical Center [Rotterdam]
11 Alzheimer Center Amsterdam
12 UA - University of Antwerp
13 ICM - Institut du Cerveau = Paris Brain Institute
14 CHU Pitié-Salpêtrière [AP-HP]
15 Perelman School of Medicine
16 Institute of Neurology [London]
17 MRC Prion Unit [London]
18 Karolinska Institutet [Stockholm]
19 Karolinska University Hospital [Stockholm]
20 University of Manchester [Manchester]
21 Fondazione IRCCS Istituto Neurologico "Carlo Besta"
22 UNSW - University of New South Wales [Sydney]
23 The University of Sydney
24 Istituto Centro San Giovanni di Dio Fatebenefratelli
25 UniFI - Università degli Studi di Firenze = University of Florence = Université de Florence
26 Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
27 UNITO - Università degli studi di Torino = University of Turin
28 Hospital de la Santa Creu i Sant Pau
29 UAB - Universitat Autònoma de Barcelona = Autonomous University of Barcelona = Universidad Autónoma de Barcelona
30 CIBERNED - Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas
31 UIC - Universitat Internacional de Catalunya [Barcelona]
32 Hospital Universitari Mútua de Terrassa
33 UniBs - Università degli Studi di Brescia = University of Brescia
34 TCDV - Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046
35 TUM - Technische Universität Munchen - Technical University Munich - Université Technique de Munich
36 Northwestern University [Chicago, Ill. USA]
37 Feinberg School of Medicine
38 CUMC - Columbia University Medical Center
39 NIA - National Institute on Aging [Bethesda, USA]
40 Sunnybrook - Sunnybrook Health Sciences Centre [Toronto]
2 Tanz Center Research in Neurodegenerative Diseases [Toronto]
3 UCL Institute of Neurology, Queen Square [London]
4 Toronto Western Hospital
5 University of Toronto
6 UOR - University of Reading
7 Mayo Clinic [Jacksonville]
8 Mayo Clinic [Rochester]
9 UC San Francisco - University of California [San Francisco]
10 Erasmus MC - Erasmus University Medical Center [Rotterdam]
11 Alzheimer Center Amsterdam
12 UA - University of Antwerp
13 ICM - Institut du Cerveau = Paris Brain Institute
14 CHU Pitié-Salpêtrière [AP-HP]
15 Perelman School of Medicine
16 Institute of Neurology [London]
17 MRC Prion Unit [London]
18 Karolinska Institutet [Stockholm]
19 Karolinska University Hospital [Stockholm]
20 University of Manchester [Manchester]
21 Fondazione IRCCS Istituto Neurologico "Carlo Besta"
22 UNSW - University of New South Wales [Sydney]
23 The University of Sydney
24 Istituto Centro San Giovanni di Dio Fatebenefratelli
25 UniFI - Università degli Studi di Firenze = University of Florence = Université de Florence
26 Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
27 UNITO - Università degli studi di Torino = University of Turin
28 Hospital de la Santa Creu i Sant Pau
29 UAB - Universitat Autònoma de Barcelona = Autonomous University of Barcelona = Universidad Autónoma de Barcelona
30 CIBERNED - Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas
31 UIC - Universitat Internacional de Catalunya [Barcelona]
32 Hospital Universitari Mútua de Terrassa
33 UniBs - Università degli Studi di Brescia = University of Brescia
34 TCDV - Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046
35 TUM - Technische Universität Munchen - Technical University Munich - Université Technique de Munich
36 Northwestern University [Chicago, Ill. USA]
37 Feinberg School of Medicine
38 CUMC - Columbia University Medical Center
39 NIA - National Institute on Aging [Bethesda, USA]
40 Sunnybrook - Sunnybrook Health Sciences Centre [Toronto]
Ming Zhang
- Fonction : Auteur
- PersonId : 1373832
Ezequiel I Surace
- Fonction : Auteur
Carol Dobson-Stone
- Fonction : Auteur
Amalia C Bruni
- Fonction : Auteur
Parastoo Momeni
- Fonction : Auteur
Zhen Zeng
- Fonction : Auteur
Ekaterina Rogaeva
- Fonction : Auteur
- PersonId : 921847
Résumé
The G4C2-repeat expansion in 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 450 k 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 124.7 kb 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 C9orf72 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.
Origine : Publication financée par une institution
Licence : CC BY - Paternité
Licence : CC BY - Paternité