Cell-specific histone modification maps in the human frontal lobe link schizophrenia risk to the neuronal epigenome

Nat Neurosci. 2018 Aug;21(8):1126-1136. doi: 10.1038/s41593-018-0187-0. Epub 2018 Jul 23.


Risk variants for schizophrenia affect more than 100 genomic loci, yet cell- and tissue-specific roles underlying disease liability remain poorly characterized. We have generated for two cortical areas implicated in psychosis, the dorsolateral prefrontal cortex and anterior cingulate cortex, 157 reference maps from neuronal, neuron-depleted and bulk tissue chromatin for two histone marks associated with active promoters and enhancers, H3-trimethyl-Lys4 (H3K4me3) and H3-acetyl-Lys27 (H3K27ac). Differences between neuronal and neuron-depleted chromatin states were the major axis of variation in histone modification profiles, followed by substantial variability across subjects and cortical areas. Thousands of significant histone quantitative trait loci were identified in neuronal and neuron-depleted samples. Risk variants for schizophrenia, depressive symptoms and neuroticism were significantly over-represented in neuronal H3K4me3 and H3K27ac landscapes. Our Resource, sponsored by PsychENCODE and CommonMind, highlights the critical role of cell-type-specific signatures at regulatory and disease-associated noncoding sequences in the human frontal lobe.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Brain Mapping
  • Chromatin / genetics
  • Depression / genetics
  • Depression / pathology
  • Educational Status
  • Epigenesis, Genetic / genetics*
  • Frontal Lobe / metabolism*
  • Frontal Lobe / pathology*
  • Genetic Predisposition to Disease / genetics
  • Genetic Variation
  • Genome-Wide Association Study
  • Gyrus Cinguli / pathology
  • Histones / genetics*
  • Humans
  • Neurotic Disorders / genetics
  • Neurotic Disorders / pathology
  • Prefrontal Cortex / pathology
  • Risk
  • Schizophrenia / genetics*
  • Schizophrenia / metabolism*


  • Chromatin
  • Histones