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

Abstract

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, dorsolateral prefrontal cortex and anterior cingulate cortex, 157 reference maps from neuronal, neuronal-depleted and bulk tissue chromatin for two histone marks associated with active promoters and enhancers, H3-trimethyl-lysine 4 (H3K4me3) and H3-acetyl-lysine 27 (H3K27ac). Differences between neuronal and neuronal-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 (hQTLs) were identified in neuronal and neuronal-depleted samples. Risk variants for schizophrenia, depressive symptoms and neuroticism were significantly overrepresented in neuronal H3K4me3 and H3K27ac landscapes. Our PsychENCODE and CommonMind sponsored resource highlights the critical role of cell-type specific signatures at regulatory and disease-associated non-coding sequences in the human frontal lobe.