Epigenetic differences between monozygotic twins discordant for amyotrophic lateral sclerosis (ALS) provide clues to disease pathogenesis

PLoS One. 2017 Aug 10;12(8):e0182638. doi: 10.1371/journal.pone.0182638. eCollection 2017.


Amyotrophic lateral sclerosis (ALS) is a devastating late-onset neurodegenerative disorder in which only a small proportion of patients carry an identifiable causative genetic lesion. Despite high heritability estimates, a genetic etiology for most sporadic ALS remains elusive. Here we report the epigenetic profiling of five monozygotic twin pairs discordant for ALS, four with classic ALS and one with the progressive muscular atrophy ALS variant, in whom previous whole genome sequencing failed to uncover a genetic basis for their disease discordance. By studying cytosine methylation patterns in peripheral blood DNA we identified thousands of large between-twin differences at individual CpGs. While the specific sites of differences were mostly idiosyncratic to a twin pair, a proportion involving GABA signalling were common to all ALS individuals. For both idiosyncratic and common sites the differences occurred within genes and pathways related to neurobiological functions or dysfunctions, some of particular relevance to ALS such as glutamate metabolism and the Golgi apparatus. All four classic ALS patients were epigenetically older than their unaffected co-twins, suggesting accelerated aging in multiple tissues in this disease. In conclusion, widespread changes in methylation patterns were found in ALS-affected co-twins, consistent with an epigenetic contribution to disease. 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.

Publication types

  • Comparative Study
  • Twin Study

MeSH terms

  • Aged
  • Amyotrophic Lateral Sclerosis / genetics*
  • CpG Islands
  • DNA Methylation
  • Diseases in Twins / genetics*
  • Epigenesis, Genetic*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Signal Transduction
  • Twins, Monozygotic

Grant support

This study was supported by the Aimee Stacey Memorial and Ignatius Burnett bequests. Blood DNA samples were obtained from the Australian Motor Neuron Disease DNA Bank which was supported by an Australian National Health and Research Council Enabling Grant (APP402703) to RP. CMS is supported by an Australian Research Council Fellowship (FT120100097). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.