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Research Paper|Volume 8, Issue 7|pp 1485—1512

Huntington's disease accelerates epigenetic aging of human brain and disrupts DNA methylation levels

Steve Horvath1,2, Peter Langfelder1, Seung Kwak3, Jeff Aaronson3, Jim Rosinski3, Thomas F. Vogt3, Marika Eszes4,5, Richard L.M. Faull4,5, Maurice A. Curtis4,5, Henry J. Waldvogel4,5, Oi-Wa Choi6, Spencer Tung7, Harry V. Vinters7, Giovanni Coppola6,8,9, X. William Yang6,8,9
  • 1Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
  • 2Biostatistics, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA 90095, USA
  • 3CHDI Management/CHDI Foundation, Princeton, NJ 08540, USA
  • 4Department of Anatomy and Medical Imaging, Faculty of Medical and Health Science (FMHS), University of Auckland, Auckland, New Zealand
  • 5Centre for Brain Research, Faculty of Medical and Health Science (FMHS), University of Auckland, Auckland, New Zealand
  • 6Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
  • 7Pathology and Laboratory Medicine, and Neurology, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA
  • 8Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
  • 9UCLA Brain Research Institute, Los Angeles, CA 90095, USA
Received: May 5, 2016Accepted: July 12, 2016Published: July 27, 2016

Copyright: © 2016 Horvath et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Age of Huntington's disease (HD) motoric onset is strongly related to the number of CAG trinucleotide repeats in the huntingtin gene, suggesting that biological tissue age plays an important role in disease etiology. Recently, a DNA methylation based biomarker of tissue age has been advanced as an epigenetic aging clock. We sought to inquire if HD is associated with an accelerated epigenetic age. DNA methylation data was generated for 475 brain samples from various brain regions of 26 HD cases and 39 controls. Overall, brain regions from HD cases exhibit a significant epigenetic age acceleration effect (p=0.0012). A multivariate model analysis suggests that HD status increases biological age by 3.2 years. Accelerated epigenetic age can be observed in specific brain regions (frontal lobe, parietal lobe, and cingulate gyrus). After excluding controls, we observe a negative correlation (r=−0.41, p=5.5×10−8) between HD gene CAG repeat length and the epigenetic age of HD brain samples. Using correlation network analysis, we identify 11 co-methylation modules with a significant association with HD status across 3 broad cortical regions. In conclusion, HD is associated with an accelerated epigenetic age of specific brain regions and more broadly with substantial changes in brain methylation levels.