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

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

Author information

1
Department of Genetics and Genomic Sciences, Icahn Institute of Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
2
Department of Genetics and Genomic Sciences, Icahn Institute of Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. gabriel.hoffman@mssm.edu.
3
Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
4
Department of Biological Sciences, Fordham University, Bronx, NY, USA.
5
iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.
6
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
7
Program in Bioinformatics and Integrative Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA.
8
Systems Biology, Sage Bionetworks, Seattle, WA, USA.
9
Department of Neurology, Georgetown University, Washington, DC, USA.
10
Human Brain Collection Core, NIMH, Bethesda, MD, USA.
11
Department of Genetics and Genomic Sciences, Icahn Institute of Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. panagiotis.roussos@mssm.edu.
12
Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. panagiotis.roussos@mssm.edu.
13
Mental Illness Research, Education, and Clinical Center, James J. Peters VA Medical Center, Bronx, NY, USA. panagiotis.roussos@mssm.edu.
14
Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. schahram.akbarian@mssm.edu.

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, 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.

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