Manuel Mattheisen

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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Mads E. Hauberg
  • John F. Fullard, Icahn School of Medicine at Mount Sinai
  • ,
  • Lingxue Zhu, Carnegie Mellon University
  • ,
  • Ariella T. Cohain, Icahn School of Medicine at Mount Sinai
  • ,
  • Claudia Giambartolomei, Icahn School of Medicine at Mount Sinai
  • ,
  • Ruth Misir, Icahn School of Medicine at Mount Sinai
  • ,
  • Sarah Reach, Icahn School of Medicine at Mount Sinai
  • ,
  • Jessica S. Johnson, Icahn School of Medicine at Mount Sinai
  • ,
  • Minghui Wang, Icahn School of Medicine at Mount Sinai
  • ,
  • Manuel Mattheisen
  • Anders Dupont Børglum
  • Bin Zhang, Icahn School of Medicine at Mount Sinai
  • ,
  • Solveig K. Sieberts, Sage Bionetworks
  • ,
  • Mette A. Peters, Sage Bionetworks
  • ,
  • Enrico Domenici, University of Trento
  • ,
  • Eric E. Schadt, Icahn School of Medicine at Mount Sinai
  • ,
  • Bernie Devlin, University of Pittsburgh
  • ,
  • Pamela Sklar, Icahn School of Medicine at Mount Sinai
  • ,
  • Kathryn Roeder, Carnegie Mellon University
  • ,
  • Panos Roussos, Icahn School of Medicine at Mount Sinai, VA Boston Healthcare System
  • ,
  • the CommonMind Consortium

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.

Original languageEnglish
JournalMolecular Psychiatry
Volume24
Issue11
Pages (from-to)1685-1695
Number of pages11
ISSN1359-4184
DOIs
Publication statusPublished - Nov 2019

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