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

Abstract

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 −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.