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

Kiran Girdhar; Gabriel E. Hoffman; Yan Jiang; Leanne Brown; Marija Kundakovic; Mads E. Hauberg; Nancy J. Francoeur; Ying chih Wang; Hardik Shah; David H. Kavanagh; Elizabeth Zharovsky; Rivka Jacobov; Jennifer R. Wiseman; Royce Park; Jessica S. Johnson; Bibi S. Kassim; Laura Sloofman; Eugenio Mattei; Zhiping Weng; Solveig K. Sieberts; Mette A. Peters; Brent T. Harris; Barbara K. Lipska; Pamela Sklar; Panos Roussos; Schahram Akbarian

doi:10.1038/s41593-018-0187-0

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

Kiran Girdhar, Gabriel E. Hoffman, Yan Jiang, Leanne Brown, Marija Kundakovic, Mads E. Hauberg, Nancy J. Francoeur, Ying chih Wang, Hardik Shah, David H. Kavanagh, Elizabeth Zharovsky, Rivka Jacobov, Jennifer R. Wiseman, Royce Park, Jessica S. Johnson, Bibi S. Kassim, Laura Sloofman, Eugenio Mattei, Zhiping Weng, Solveig K. SiebertsMette A. Peters, Brent T. Harris, Barbara K. Lipska, Pamela Sklar, Panos Roussos, Schahram Akbarian

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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.

Original language	English
Pages (from-to)	1126-1136
Number of pages	11
Journal	Nature Neuroscience
Volume	21
Issue number	8
DOIs	https://doi.org/10.1038/s41593-018-0187-0
State	Published - 1 Aug 2018

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Girdhar, K., Hoffman, G. E., Jiang, Y., Brown, L., Kundakovic, M., Hauberg, M. E., Francoeur, N. J., Wang, Y. C., Shah, H., Kavanagh, D. H., Zharovsky, E., Jacobov, R., Wiseman, J. R., Park, R., Johnson, J. S., Kassim, B. S., Sloofman, L., Mattei, E., Weng, Z., ... Akbarian, S. (2018). Cell-specific histone modification maps in the human frontal lobe link schizophrenia risk to the neuronal epigenome. Nature Neuroscience, 21(8), 1126-1136. https://doi.org/10.1038/s41593-018-0187-0

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title = "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, 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.",

author = "Kiran Girdhar and Hoffman, {Gabriel E.} and Yan Jiang and Leanne Brown and Marija Kundakovic and Hauberg, {Mads E.} and Francoeur, {Nancy J.} and Wang, {Ying chih} and Hardik Shah and Kavanagh, {David H.} and Elizabeth Zharovsky and Rivka Jacobov and Wiseman, {Jennifer R.} and Royce Park and Johnson, {Jessica S.} and Kassim, {Bibi S.} and Laura Sloofman and Eugenio Mattei and Zhiping Weng and Sieberts, {Solveig K.} and Peters, {Mette A.} and Harris, {Brent T.} and Lipska, {Barbara K.} and Pamela Sklar and Panos Roussos and Schahram Akbarian",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = aug,

day = "1",

doi = "10.1038/s41593-018-0187-0",

language = "English",

volume = "21",

pages = "1126--1136",

journal = "Nature Neuroscience",

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Girdhar, K , Hoffman, GE, Jiang, Y, Brown, L, Kundakovic, M, Hauberg, ME, Francoeur, NJ, Wang, YC, Shah, H, Kavanagh, DH, Zharovsky, E, Jacobov, R, Wiseman, JR, Park, R, Johnson, JS, Kassim, BS, Sloofman, L, Mattei, E, Weng, Z, Sieberts, SK, Peters, MA, Harris, BT, Lipska, BK, Sklar, P, Roussos, P & Akbarian, S 2018, 'Cell-specific histone modification maps in the human frontal lobe link schizophrenia risk to the neuronal epigenome', Nature Neuroscience, vol. 21, no. 8, pp. 1126-1136. https://doi.org/10.1038/s41593-018-0187-0

TY - JOUR

T1 - Cell-specific histone modification maps in the human frontal lobe link schizophrenia risk to the neuronal epigenome

AU - Girdhar, Kiran

AU - Hoffman, Gabriel E.

AU - Jiang, Yan

AU - Brown, Leanne

AU - Kundakovic, Marija

AU - Hauberg, Mads E.

AU - Francoeur, Nancy J.

AU - Wang, Ying chih

AU - Shah, Hardik

AU - Kavanagh, David H.

AU - Zharovsky, Elizabeth

AU - Jacobov, Rivka

AU - Wiseman, Jennifer R.

AU - Park, Royce

AU - Johnson, Jessica S.

AU - Kassim, Bibi S.

AU - Sloofman, Laura

AU - Mattei, Eugenio

AU - Weng, Zhiping

AU - Sieberts, Solveig K.

AU - Peters, Mette A.

AU - Harris, Brent T.

AU - Lipska, Barbara K.

AU - Sklar, Pamela

AU - Roussos, Panos

AU - Akbarian, Schahram

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85050528650&partnerID=8YFLogxK

U2 - 10.1038/s41593-018-0187-0

DO - 10.1038/s41593-018-0187-0

M3 - Article

C2 - 30038276

AN - SCOPUS:85050528650

SN - 1097-6256

VL - 21

SP - 1126

EP - 1136

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 8

ER -

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

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