title: Huntington's disease accelerates epigenetic aging of human brain and disrupts DNA methylation levels.
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.
authors.affiliation: Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.|Biostatistics, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Horvath
authors.affiliation: Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Langfelder
authors.affiliation: CHDI Management/CHDI Foundation, Princeton, NJ 08540, USA.
authors.forename: Seung
authors.initials: S
authors.lastname: Kwak
authors.affiliation: CHDI Management/CHDI Foundation, Princeton, NJ 08540, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Aaronson
authors.affiliation: CHDI Management/CHDI Foundation, Princeton, NJ 08540, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Rosinski
authors.affiliation: CHDI Management/CHDI Foundation, Princeton, NJ 08540, USA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Vogt
authors.affiliation: Department of Anatomy and Medical Imaging, Faculty of Medical and Health Science (FMHS), University of Auckland, Auckland, New Zealand.|Centre for Brain Research, Faculty of Medical and Health Science (FMHS), University of Auckland, Auckland, New Zealand.
authors.forename: Marika
authors.initials: M
authors.lastname: Eszes
authors.affiliation: Department of Anatomy and Medical Imaging, Faculty of Medical and Health Science (FMHS), University of Auckland, Auckland, New Zealand.|Centre for Brain Research, Faculty of Medical and Health Science (FMHS), University of Auckland, Auckland, New Zealand.
authors.forename: Richard L M
authors.initials: RL
authors.lastname: Faull
authors.affiliation: Department of Anatomy and Medical Imaging, Faculty of Medical and Health Science (FMHS), University of Auckland, Auckland, New Zealand.|Centre for Brain Research, Faculty of Medical and Health Science (FMHS), University of Auckland, Auckland, New Zealand.
authors.forename: Maurice A
authors.initials: MA
authors.lastname: Curtis
authors.affiliation: Department of Anatomy and Medical Imaging, Faculty of Medical and Health Science (FMHS), University of Auckland, Auckland, New Zealand.|Centre for Brain Research, Faculty of Medical and Health Science (FMHS), University of Auckland, Auckland, New Zealand.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Waldvogel
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors.forename: Oi-Wa
authors.initials: OW
authors.lastname: Choi
authors.affiliation: Pathology and Laboratory Medicine, and Neurology, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA.
authors.forename: Spencer
authors.initials: S
authors.lastname: Tung
authors.affiliation: Pathology and Laboratory Medicine, and Neurology, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA.
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.|Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.|UCLA Brain Research Institute, Los Angeles, CA 90095, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.|Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.|UCLA Brain Research Institute, Los Angeles, CA 90095, USA.
authors.forename: X William
authors.initials: XW
authors.lastname: Yang
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D017668:Age of Onset; D000368:Aged; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D019175:DNA Methylation; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D055815:Young Adult
keywords: DNA methylation; Huntington's disease; biomarker of aging; brain; epigenetic clock; epigenetics