DNA methylation age-acceleration is associated with disease duration and age at onset in C9orf72 patients

Abstract

The repeat expansion in C9orf72 is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia. C9orf72 patients present with a wide range in disease duration and age of onset. The strongest risk factor for both syndromes is aging, which was linked to DNA methylation (DNAm) age based on the cumulative assessment of the methylation levels of 353 CpGs included on the genome-wide 450k BeadChip. DNAm age may reflect biological age better than chronological age. We conducted a genome-wide blood DNA methylation study of 46 unrelated C9orf72 patients. After correction for multiple testing, none of the CpGs demonstrated association between its methylation level and disease duration or age of onset. However, we detected a significant reverse correlation of DNAm age-acceleration with disease duration and age of onset, suggesting that for every 5-year increase in DNAm age-acceleration there is a 3.2-year earlier age of onset and 1.5-year shorter disease duration. The significant correlations remain after adjusting for gender, TMEM106B genotypes, disease phenotype and C9orf72 5′CpG island methylation status. A similar trend was observed for the blood DNA of affected members of an extended C9orf72 family; and tissues from the central nervous system of C9orf72 autopsy cases. For instance, regression analysis suggested that a 5-year increase in DNAm age-acceleration is linked to an earlier age of onset by 4.7 or 5.5 years for frontal cortex or spinal cord, respectively. Blood DNAm age may be a useful biomarker for biological age, because blood DNAm age-acceleration was similar to all investigated brain tissues, except for cerebellum that ages more slowly. In conclusion, DNA methylation analysis of C9orf72 patients revealed that increased DNAm age-acceleration is associated with a more severe disease phenotype with a shorter disease duration and earlier age of onset.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1713-y) contains supplementary material, which is available to authorized users.

Parkinsonism due to A53E α‐synuclein gene mutation: Clinical, genetic, epigenetic, and biochemical features

“…Disease age at onset varied widely among A53E carriers in this Canadian family (aged 25 to 58 years), similar to the published Finnish cases (aged 25 to 62 years) . We previously showed, in C9orf72 ‐related amyotrophic lateral sclerosis and/or frontotemporal dementia that disease age at onset correlated with DNAm age acceleration . To examine whether this epigenetic phenomenon occurs in the Canadian PD family, we determined DNAm age acceleration using blood DNA from 3 A53E carriers (Fig.…”

“…Genome‐wide DNAm analysis was performed with EPIC methylation BeadChip (Illumina, Illumina, San Diego, CA, USA) using blood genomic DNA from 3 family members with parkinsonism due to A53E. DNAm age was estimated as previously described . EPIC BeadChip is missing 10 of 353 CpGs originally used to estimate DNAm age from the discontinued 450K BeadChip without affecting the accuracy of estimating DNAm age …”

“…Phenotypic variability, particularly disease age at onset, is a common feature of PD due to α‐synuclein mutations among individuals with the same mutation including family members . Interestingly, our epigenetic analysis indicated that an earlier disease age at onset in A53E carriers is accompanied by increased DNAm age acceleration (similar to C9orf72 patients). It would be important to assess more SNCA families because the current study was limited to a single kindred.…”

“…Here, we report the first family outside Finland with parkinsonism because of A53E not inherited from the previously described founder. We examine the link between disease age at onset in this family and DNA methylation (DNAm) age, a potential epigenetic marker of biological aging . Furthermore, we characterize biochemical features of A53E α‐synuclein aggregation and its regulation by phosphorylation.…”

DNA methylation age acceleration is associated with ALS age of onset and survival

“…The cumulative assessment of DNAm levels at age-related CpGs allows the estimation of multi-tissue DNAm age (epigenetic clock), which could be more accurate for assessing biological age than chronological age. Hypermethylation of the CpG-island 5′ of the C9orf72-repeat and DNAm-age acceleration have been reported to be associated with C9orf72-disease duration and age of onset [9,10]. However, epigenetic modifiers in genetically unexplained ALS patients are largely unknown.…”