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

• Published in: Nature neuroscience Vol. 21; no. 8; pp. 1126 - 1136
• Main Authors: Girdhar, Kiran, Hoffman, Gabriel E., Jiang, Yan, Brown, Leanne, Kundakovic, Marija, Hauberg, Mads E., Francoeur, Nancy J., Wang, Ying-chih, Shah, Hardik, Kavanagh, David H., Zharovsky, Elizabeth, Jacobov, Rivka, Wiseman, Jennifer R., Park, Royce, Johnson, Jessica S., Kassim, Bibi S., Sloofman, Laura, Mattei, Eugenio, Weng, Zhiping, Sieberts, Solveig K., Peters, Mette A., Harris, Brent T., Lipska, Barbara K., Sklar, Pamela, Roussos, Panos, Akbarian, Schahram
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2018; Nature Publishing Group
• Subjects: 45; 45/15; 45/23; 631/114/1314; 692/699/476/1799; Alzheimer Disease - genetics; Animal Genetics and Genomics; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Brain; Brain Mapping; Brain research; Chromatin; Chromatin - genetics; Corporate sponsorship; Cortex (cingulate); Depletion; Depression - genetics; Depression - pathology; Educational Status; Enhancers; Epigenesis, Genetic - genetics; Epigenetic inheritance; Frontal lobe; Frontal Lobe - metabolism; Frontal Lobe - pathology; Frontal lobes; Gene mapping; Genetic aspects; Genetic Predisposition to Disease - genetics; Genetic Variation; Genome-Wide Association Study; Gyrus Cinguli - pathology; Health aspects; Histones; Histones - genetics; Humans; Landscape; Legal liability; Liability; Medical schools; Mental disorders; Methylation; Molecular neurobiology; Neurobiology; Neurogenetics; Neurons; Neurosciences; Neurosis; Neurotic Disorders - genetics; Neurotic Disorders - pathology; Physiological aspects; Post-translational modifications; Prefrontal cortex; Prefrontal Cortex - pathology; Psychosis; Quantitative genetics; Quantitative trait loci; Resource; Risk; Risk factors; Schizophrenia; Schizophrenia - genetics; Schizophrenia - metabolism
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/s41593-018-0187-0

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. This PsychENCODE resource presents 157 reference maps for open-chromatin-associated histone methylation and acetylation in prefrontal and anterior cingulate cortex, linking the neuronal epigenome to the genetic risk architecture of schizophrenia.