Title :

A c6orf10/loc101929163 locus is associated with age of onset in c9orf72 carriers

Author(s) :

Zhang, Ming [Auteur]
Ferrari, Raffaele [Auteur]
Tartaglia, Maria Carmela [Auteur]
Keith, Julia [Auteur]
Surace, Ezequiel I. [Auteur]
Wolf, Uri [Auteur]
Sato, Christine [Auteur]
Grinberg, Mark [Auteur]
Liang, Yan [Auteur]
Xi, Zhengrui [Auteur]
Dupont, Kyle [Auteur]
Mcgoldrick, Philip [Auteur]
Weichert, Anna [Auteur]
Mckeever, Paul M. [Auteur]
Schneider, Raphael [Auteur]
Mccorkindale, Michael D. [Auteur]
Manzoni, Claudia [Auteur]
Rademakers, Rosa [Auteur]
Graff-Radford, Neill R. [Auteur]
Dickson, Dennis W. [Auteur]
Parisi, Joseph E. [Auteur]
Boeve, Bradley F. [Auteur]
Petersen, Ronald C. [Auteur]
Miller, Bruce L. [Auteur]
Seeley, William W. [Auteur]
Van Swieten, John C. [Auteur]
Van Rooij, Jeroen G J. [Auteur]
Pijnenburg, Yolande [Auteur]
Van Der Zee, Julie [Auteur]
Van Broeckhoven, Christine [Auteur]
Le Ber, Isabelle [Auteur]
Van Deerlin, Vivianna M. [Auteur]
Suh, Eunran [Auteur]
Rohrer, Jonathan D. [Auteur]
Mead, Simon [Auteur]
Graff, Caroline [Auteur]
Oijerstedt, Linn [Auteur]
Pickering-Brown, Stuart [Auteur]
Rollinson, Sara [Auteur]
Rossi, Giacomina [Auteur]
Tagliavini, Fabrizio [Auteur]
Brooks, William S. [Auteur]
Dobson-Stone, Carol [Auteur]
Halliday, Glenda M. [Auteur]
Hodges, John R. [Auteur]
Piguet, Olivier [Auteur]
Binetti, Giuliano [Auteur]
Benussi, Luisa [Auteur]
Ghidoni, Roberta [Auteur]
Nacmias, Benedetta [Auteur]
Sorbi, Sandro [Auteur]
Bruni, Amalia Cecilia [Auteur]
Galimberti, Daniela [Auteur]
Scarpini, Elio [Auteur]
Rainero, Innocenzo [Auteur]
Rubino, Elisa [Auteur]
Clarimon, Jordi [Auteur]
Lleo, Alberto [Auteur]
Ruiz, Agustin [Auteur]
Hernandez, Isabel [Auteur]
Pastor, Pau [Auteur]
Diez-Fairen, Monica [Auteur]
Borroni, Barbara [Auteur]
Pasquier, Florence [Auteur]
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Troubles cognitifs dégénératifs et vasculaires - U1171
Deramecourt, Vincent [Auteur]

Lille Neurosciences & Cognition (LilNCog) - U 1172
Lebouvier, Thibaud [Auteur]
Perneczky, Robert [Auteur]
Diehl-Schmid, Janine [Auteur]
Grafman, Jordan [Auteur]
Huey, Edward D. [Auteur]
Mayeux, Richard [Auteur]
Nalls, Michael A. [Auteur]
Hernandez, Dena G. [Auteur]
Singleton, Andrew B. [Auteur]
Momeni, Parastoo [Auteur]
Zeng, Zhen [Auteur]
Hardy, John [Auteur]
Robertson, Janice [Auteur]
Zinman, Lorne [Auteur]
Rogaeva, Ekaterina [Auteur]

Journal title :

Brain . a journal of neurology

Abbreviated title :

Brain

Volume number :

141

Pages :

2895-2907

Publication date :

2018-10-01

ISSN :

1460-2156

English keyword(s) :

genetic association
age of onset
C9orf72
frontotemporal dementia
amyotrophic lateral sclerosis

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

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, ...
Show more >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.Show less >

Language :

Anglais

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

CHU Lille
CNRS
Inserm
Université de Lille

Collections :

• Lille Neurosciences & Cognition (LilNCog) - U 1172

Research team(s) :

Alzheimer et Tauopathies
Troubles cognitifs dégénératifs et vasculaires

Submission date :

2019-11-27T14:35:28Z