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.
Highlights
Most patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have a sporadic form of the disease suggesting the contribution of several small-effect genetic and environmental risk factors that could be linked to DNA methylation changes [1]
We conducted a genome-wide DNA methylation profiling of blood DNA from 46 unrelated C9orf72 patients (Table 1) to estimate if a difference in methylation level at any single CpG site on the 450k BeadChip is associated with age of onset or disease duration
The DNA methylation (DNAm) age-acceleration was similar between blood and central nervous system (CNS) tissues (p > 0.05), except for cerebellum (p < 0.01), which has significantly lower DNAm ageacceleration compared to the other tissues: by 7.6 years vs. blood (p < 0.01), and 7.2 years vs. spinal cord (p = 0.02) (Fig. 6)
Summary
Most patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have a sporadic form of the disease suggesting the contribution of several small-effect genetic and environmental risk factors that could be linked to DNA methylation changes [1]. In addition to variable syndromes, the phenotypic heterogeneity in C9orf patients includes a wide range in disease duration (0.5–22 years) and age of onset (27–74 years) [5, 21]. Only variations in ATXN2 and TMEM106B have been suggested as genetic modifiers in C9orf carriers. Intermediate ATXN2 alleles (27–33 CAG-repeats) were reported as modifiers in C9orf carriers, rendering susceptibility to ALS [29]; and homozygosity for the minor allele (G) of rs3173615 in TMEM106B was reported to protect against developing FTD in C9orf patients [30], while the major allele (A) of rs1990622 in TMEM106B was associated with a later age of onset in C9orf FTD patients [8]
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