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Differential activity of transcribed enhancers in the prefrontal cortex of 537 cases with schizophrenia and controls

Molecular Psychiatry volume 24, pages 1685–1695 (2019)Cite this article

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Abstract

Transcription at enhancers is a widespread phenomenon which produces so-called enhancer RNA (eRNA) and occurs in an activity-dependent manner. However, the role of eRNA and its utility in exploring disease-associated changes in enhancer function, and the downstream coding transcripts that they regulate, is not well established. We used transcriptomic and epigenomic data to interrogate the relationship of eRNA transcription to disease status and how genetic variants alter enhancer transcriptional activity in the human brain. We combined RNA-seq data from 537 postmortem brain samples from the CommonMind Consortium with cap analysis of gene expression and enhancer identification, using the assay for transposase-accessible chromatin followed by sequencing (ATACseq). We find 118 differentially transcribed eRNAs in schizophrenia and identify schizophrenia-associated gene/eRNA co-expression modules. Perturbations of a key module are associated with the polygenic risk scores. Furthermore, we identify genetic variants affecting expression of 927 enhancers, which we refer to as enhancer expression quantitative loci or eeQTLs. Enhancer expression patterns are consistent across studies, including differentially expressed eRNAs and eeQTLs. Combining eeQTLs with a genome-wide association study of schizophrenia identifies a genetic variant that alters enhancer function and expression of its target gene, GOLPH3L. Our novel approach to analyzing enhancer transcription is adaptable to other large-scale, non-poly-A depleted, RNA-seq studies.

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Acknowledgements

This work was supported by the National Institutes of Health—R01AG050986 (Roussos), R01MH109677 (Roussos), R37MH057881 (Devlin, Roeder) and R01MH109900 (Roeder)—Brain Behavior Research Foundation (20540 Roussos), Alzheimer’s Association (NIRG-340998 Roussos) and the Veterans Affairs (Merit grant BX002395 Roussos). This study was additionally funded by The Lundbeck Foundation, Denmark (Grant number R102-A9118). Further, this work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. This paper is dedicated to the memory of PS. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. RNA-seq and genotyping data were generated as part of the CommonMind Consortium supported by funding from Takeda Pharmaceuticals Company Limited, F. Hoffman-La Roche Ltd. and NIH grants R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, R01-MH-075916, P50M096891, P50MH084053S1, R37MH057881 and R37MH057881S1, HHSN271201300031C, AG02219, AG05138 and MH06692. Brain tissue for the study was obtained from the following brain bank collections: the Mount Sinai NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer’s Disease Core Center, the University of Pittsburgh NeuroBioBank and Brain and Tissue Repositories and the NIMH Human Brain Collection Core. CMC Leadership: PS, Joseph Buxbaum (Icahn School of Medicine at Mount Sinai), BD, David Lewis (University of Pittsburgh), Raquel Gur, Chang-Gyu Hahn (University of Pennsylvania), Keisuke Hirai, Hiroyoshi Toyoshiba (Takeda Pharmaceuticals Company Limited), ED, Laurent Essioux (F. Hoffman-La Roche Ltd.), Lara Mangravite, MP (Sage Bionetworks), Thomas Lehner, Barbara Lipska (NIMH).

The CommonMind Consortium

Menachem Fromer, Douglas M Ruderfer, Hardik R Shah, Lambertus L Klei, Kristen K Dang, Thanneer M Perumal, Benjamin A Logsdon, Milind C Mahajan, Lara M Mangravite, Laurent Essioux, Hiroyoshi Toyoshiba, Raquel E Gur, Chang-Gyu Hahn, David A Lewis, Vahram Haroutunian, Barbara K Lipska, Joseph D Buxbaum, Keisuke Hirai

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  1. These authors contributed equally: Mads E. Hauberg, John F. Fullard.

Authors and Affiliations

  1. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Mads E. Hauberg, John F. Fullard, Claudia Giambartolomei, Ruth Misir, Sarah Reach, Jessica S. Johnson, Pamela Sklar & Panos Roussos

  2. Department of Genetics and Genomic Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Mads E. Hauberg, John F. Fullard, Ariella T. Cohain, Ruth Misir, Sarah Reach, Jessica S. Johnson, Minghui Wang, Bin Zhang, Eric E. Schadt, Pamela Sklar & Panos Roussos

  3. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Mads E. Hauberg, Manuel Mattheisen & Anders Dupont Børglum

  4. Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark

    Mads E. Hauberg, Manuel Mattheisen & Anders Dupont Børglum

  5. The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark

    Mads E. Hauberg, Manuel Mattheisen & Anders Dupont Børglum

  6. Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, USA

    Lingxue Zhu & Kathryn Roeder

  7. Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA, USA

    Lingxue Zhu & Kathryn Roeder

  8. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Manuel Mattheisen

  9. Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital Würzburg, Würzburg, Germany

    Manuel Mattheisen

  10. Systems Biology, Sage Bionetworks, Seattle, WA, USA

    Solveig K. Sieberts & Mette A. Peters

  11. Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy

    Enrico Domenici

  12. Centre for Computational and Systems Biology (COSBI), The Microsoft Research - University of Trento, Rovereto, Italy

    Enrico Domenici

  13. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    Bernie Devlin

  14. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Pamela Sklar

  15. Mental Illness Research, Education, and Clinical Center (VISN 2 South), James J. Peters VA Medical Center, Bronx, NY, USA

    Panos Roussos

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  1. Mads E. Hauberg
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Correspondence to Panos Roussos.

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Hauberg, M.E., Fullard, J.F., Zhu, L. et al. Differential activity of transcribed enhancers in the prefrontal cortex of 537 cases with schizophrenia and controls. Mol Psychiatry 24, 1685–1695 (2019). https://doi.org/10.1038/s41380-018-0059-8

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