Journal
BRAIN
Volume 141, Issue -, Pages 2895-2907Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awy238
Keywords
C9orf72; genetic association; age of onset; amyotrophic lateral sclerosis; frontotemporal dementia
Categories
Funding
- Canadian Consortium on Neurodegeneration in Aging
- ALS Canada-Brain Canada
- James Hunter ALS Initiative
- Temerty Family Foundation
- Alzheimer's Society [284]
- Argentine National Research Council (CONICET) (EIS)
- ALS Canada Clinical Research Fellowship
- National Institutes of Health (NIH) [R35 NS097261, P50 AG016574, P01 NS084974]
- NIH [P01 NS084974, P01 AG019724, P01-AG-017586]
- JPND PreFrontALS [733051042]
- JPND RiMOD [733051024]
- Memorabel-FTD [733050103]
- Flemish Government initiated Impulse Program on Networks for Dementia Research (VIND)
- Methusalem Excellence Program
- Research Foundation Flanders (FWO)
- University of Antwerp
- Investissements d'avenir [ANR-10-IAIHU-06]
- Assistance Publique-Hopitaux de Paris (Clinical Research and Development Department)
- Programme Hospitalier de Recherche Clinique
- FTLD-exome [RCAOM-12123]
- ANR-PRTS PREV-DEMALS project
- MRC [MR/M008525/1]
- NIHR Rare Disease Translational Research Collaboration [BRC149/NS/MH]
- MRC UK GENFI grant [MR/M023664/1]
- Swedish Research Council [521-2010-3134, 529-2014-7504, 2015-02926]
- Alzheimer foundation Sweden
- Brain Foundation Sweden
- Swedish FTD Initiative
- Swedish Brain Power
- Karolinska Institutet
- Gamla tjanarinnor
- Stohnes foundation
- Dementia foundation Sweden
- Stockholm County Council
- Ricerca Corrente, Italian Ministry of Health
- National Health & Medical Research Council of Australia (NHMRC) [1138223]
- NHMRC [1079679, 1103258]
- Fondazione CRF [2015.0722]
- Italian Ministry of health [RF08900000]
- Ministero dell'Istruzione, dell'Universita e della Ricerca - MIUR
- Accion Estrategica en Salud, integrated in the Spanish National R + D + I Plan [PI13/02434, PI16/01861]
- ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion
- Fondo Europeo de Desarrollo Regional (FEDER- Una manera de Hacer Europa)
- European Union [115975]
- National Health and Medical Research Council of Australia [1138223] Funding Source: NHMRC
- MRC [G1100540, MC_UU_00024/1, MR/M023664/1, MC_U105597119, MC_UU_00005/12, G0900652, G0502157, G0400074] Funding Source: UKRI
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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.
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