DNA methylation study of Huntington’s disease and motor progression in patients and in animal models
Ake T. Lu, Pritika Narayan, Matthew J. Grant, Peter Langfelder, Nan Wang, Seung Kwak, Hilary Wilkinson, Richard Z. Chen, Jian Chen, C. Simon Bawden, Skye R. Rudiger, Marc Ciosi, Afroditi Chatzi, Alastair Maxwell, Timothy A. Hore, Jeff Aaronson, Jim Rosinski, Alicia Preiss, Thomas Vogt, Giovanni Coppola, Darren G. Monckton, Russell G. Snell, X. William Yang, Steve Horvath
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.