Abstract:
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<sup>-7</sup>) associated with 33 CpG sites, including the HTT gene (p = 6.5 × 10<sup>-26</sup>). These Htt/HTT associations were replicated in the Q175 Htt knock-in mouse model (p = 6.0 × 10<sup>-8</sup>) and in the transgenic sheep model (p = 2.4 × 10<sup>-88</sup>). 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<sup>-7</sup>) associations with methylation levels at three loci: near PEX14 (p = 9.3 × 10<sup>-9</sup>), GRIK4 (p = 3.0 × 10<sup>-8</sup>), and COX4I2 (p = 6.5 × 10<sup>-8</sup>). We conclude that HD is accompanied by profound changes of DNA methylation levels in three mammalian species.