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

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

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Division of Molecular Structural and Computational Biology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.
Discipline of Pathology, Sydney Medical School, Brain and Mind Research Institute, The University of Sydney, Camperdown, NSW, Australia.
Department of Neuropathology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia.


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.

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