NEW YORK (GenomeWeb) – By comparing blood methylation profiles in identical twin pairs discordant for amyotrophic lateral sclerosis (ALS), an Australian research team has narrowed in on potential epigenetic contributors to the adult-onset motor neuron disease.
Using a combination of reduced-representation bisulfite sequencing and array-based methylation testing, the researchers characterized blood samples from five identical twin pairs, leading to thousands of differentially methylated regions in the individuals with ALS compared to their unaffected identical twins. In all but one of the twin pairs, the investigators also saw an uptick in age-related methylation marks in the individuals with ALS.
"[F]our of the five ALS-affected twins were epigenetically older than their co-twins, suggesting an acceleration of cell aging in this disease," co-corresponding authors Victor Chang Cardiac Research Institute researcher Catherine Suter and the University of Sydney's Roger Pamphlett, and their colleagues, wrote in a study published in PLOS One yesterday. "We also found a large number of differentially methylated sites between twins, most of which occurred at isolated CpGs and cluster in common genes and pathways relating to neurobiological functions."
The researchers used Illumina 450K Infinium methylation arrays and reduced-representation bisulfite sequencing to map methylation marks in peripheral blood samples from five individuals with sporadic ALS between the ages of 52 and 69 years old, including four with classic form of the disease and one individual with progressive muscular atrophy ALS.
When the team compared these methylation patterns with those in blood samples from each patient's identical twin, it did not see recurrent methylation shifts at promoters for documented ALS genes.
The same identical twin pairs had been profiled by whole-genome sequencing for a prior analysis that did not unearth telltale genetic differences between affected and unaffected individuals, the authors noted. However, the new methylation analysis did pick up some apparent epigenetic differences associated with ALS — the researchers pinned down more than 1,000 methylation disparities per twin pair.
Most of the methylation differences between ALS-affected and –unaffected twins occurred in individual twin pairs, the team reported, while a handful of the methylation changes recurrently fell in and around genes from the GABA signaling pathway or other signaling and/or neurobiology-related pathways.
The researchers cautioned that methylation differences between identical twins include epigenetic factors reflecting distinct environmental exposures and subtle physical differences between the twins that are not related to ALS. Even so, such results may eventually lead to methylation marks providing hints about the devastating disease and its development.
"[W]idespread changes in methylation patterns were found in ALS-affected co-twins, consistent with an epigenetic contribution to disease," the authors wrote. "These DNA methylation findings could be used to develop blood-based ALS biomarkers, gain insights into disease pathogenesis, and provide a reference for future large-scale ALS epigenetic studies."