Nature Research, Nature Communications, 1(11), 2020
DOI: 10.1038/s41467-020-18255-5
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AbstractAlthough Huntington’s disease (HD) is a well studied Mendelian genetic disorder, less is known about its associated epigenetic changes. Here, we characterize DNA methylation levels in six different tissues from 3 species: a mouse huntingtin (Htt) gene knock-in model, a transgenic HTT sheep model, and humans. Our epigenome-wide association study (EWAS) of human blood reveals that HD mutation status is significantly (p < 10−7) associated with 33 CpG sites, including the HTT gene (p = 6.5 × 10−26). These Htt/HTT associations were replicated in the Q175 Htt knock-in mouse model (p = 6.0 × 10−8) and in the transgenic sheep model (p = 2.4 × 10−88). We define a measure of HD motor score progression among manifest HD cases based on multiple clinical assessments. EWAS of motor progression in manifest HD cases exhibits significant (p < 10−7) associations with methylation levels at three loci: near PEX14 (p = 9.3 × 10−9), GRIK4 (p = 3.0 × 10−8), and COX4I2 (p = 6.5 × 10−8). We conclude that HD is accompanied by profound changes of DNA methylation levels in three mammalian species.