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Mol Psychiatry. 2019 Nov;24(11):1685-1695. doi: 10.1038/s41380-018-0059-8. Epub 2018 May 8.

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

Author information

1
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
2
Department of Genetics and Genomic Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
3
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
4
Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark.
5
The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.
6
Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, USA.
7
Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA, USA.
8
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
9
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital Würzburg, Würzburg, Germany.
10
Systems Biology, Sage Bionetworks, Seattle, WA, USA.
11
Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy.
12
Centre for Computational and Systems Biology (COSBI), The Microsoft Research - University of Trento, Rovereto, Italy.
13
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
14
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
15
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. Panagiotis.roussos@mssm.edu.
16
Department of Genetics and Genomic Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. Panagiotis.roussos@mssm.edu.
17
Mental Illness Research, Education, and Clinical Center (VISN 2 South), James J. Peters VA Medical Center, Bronx, NY, USA. Panagiotis.roussos@mssm.edu.

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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