19Amyotrophic lateral sclerosis (ALS) is a devastating late-onset neurodegenerative disorder in 20 which only a small proportion of patients carry an identifiable causative genetic lesion. Despite 21 high heritability estimates, a genetic etiology for most sporadic ALS remains elusive. Here we 22 report the epigenetic profiling of five monozygotic twin pairs discordant for ALS in whom 23 previous genome sequencing excluded a genetic basis for their disease discordance. By studying 24 cytosine methylation patterns in peripheral blood DNA we identified thousands of large 25 between-twin differences at individual CpGs. While the specific sites of difference were largely 26 idiosyncratic to a twin pair, a proportion (involving GABA signalling) were common to all 27 affected individuals. In both instances the differences occurred within genes and pathways 28 related to neurobiological function and dysfunction. Our findings reveal widespread changes in 29 epigenetic marks in ALS patients, consistent with an epigenetic contribution to disease. These 30 findings may be exploited to develop blood-based biomarkers of ALS and develop further 31 insight into disease pathogenesis. We expect that our findings will provide a useful point of 32 reference for further large-scale studies of sporadic ALS. 33
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