DNA methylation study of Huntington’s disease and motor progression in patients and in animal models

Although 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.