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Lu, Ake T.; Narayan, Pritika; Grant, Matthew J.; Langfelder, Peter; Wang, Nan; Kwak, Seung; Wilkinson, Hilary; Chen, Richard Z.; Chen, Jian; Simon Bawden, C.; Rudiger, Skye R.; Ciosi, Marc; Chatzi, Afroditi; Maxwell, Alastair; Hore, Timothy A.; Aaronson, Jeff; Rosinski, Jim; Preiss, Alicia; Vogt, Thomas F.; Coppola, Giovanni; Monckton, Darren; Snell, Russell G.; William Yang, X.; Horvath, Steve

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

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  • Media type: E-Article
  • Title: DNA methylation study of Huntington’s disease and motor progression in patients and in animal models
  • Contributor: Lu, Ake T.; Narayan, Pritika; Grant, Matthew J.; Langfelder, Peter; Wang, Nan; Kwak, Seung; Wilkinson, Hilary; Chen, Richard Z.; Chen, Jian; Simon Bawden, C.; Rudiger, Skye R.; Ciosi, Marc; Chatzi, Afroditi; Maxwell, Alastair; Hore, Timothy A.; Aaronson, Jeff; Rosinski, Jim; Preiss, Alicia; Vogt, Thomas F.; Coppola, Giovanni; Monckton, Darren; Snell, Russell G.; William Yang, X.; Horvath, Steve
  • Published: Springer Science and Business Media LLC, 2020
  • Published in: Nature Communications, 11 (2020) 1
  • Language: English
  • DOI: 10.1038/s41467-020-18255-5
  • ISSN: 2041-1723
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>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 <jats:italic>huntingtin</jats:italic> (Htt) gene knock-in model, a transgenic <jats:italic>HTT</jats:italic> sheep model, and humans. Our epigenome-wide association study (EWAS) of human blood reveals that HD mutation status is significantly (<jats:italic>p</jats:italic> &lt; 10<jats:sup>−7</jats:sup>) associated with 33 CpG sites, including the <jats:italic>HTT</jats:italic> gene (<jats:italic>p</jats:italic> = 6.5 × 10<jats:sup>−26</jats:sup>). These <jats:italic>Htt/HTT</jats:italic> associations were replicated in the Q175 <jats:italic>Htt</jats:italic> knock-in mouse model (<jats:italic>p</jats:italic> = 6.0 × 10<jats:sup>−8</jats:sup>) and in the transgenic sheep model (<jats:italic>p</jats:italic> = 2.4 × 10<jats:sup>−88</jats: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 (<jats:italic>p</jats:italic> &lt; 10<jats:sup>−7</jats:sup>) associations with methylation levels at three loci: near <jats:italic>PEX14</jats:italic> (<jats:italic>p</jats:italic> = 9.3 × 10<jats:sup>−9</jats:sup>), <jats:italic>GRIK4</jats:italic> (<jats:italic>p</jats:italic> = 3.0 × 10<jats:sup>−8</jats:sup>), and <jats:italic>COX4I2</jats:italic> (<jats:italic>p</jats:italic> = 6.5 × 10<jats:sup>−8</jats:sup>). We conclude that HD is accompanied by profound changes of DNA methylation levels in three mammalian species.</jats:p>
  • Access State: Open Access