TY - JOUR
T1 - Differential activity of transcribed enhancers in the prefrontal cortex of 537 cases with schizophrenia and controls
AU - the CommonMind Consortium
AU - Hauberg, Mads E.
AU - Fullard, John F.
AU - Zhu, Lingxue
AU - Cohain, Ariella T.
AU - Giambartolomei, Claudia
AU - Misir, Ruth
AU - Reach, Sarah
AU - Johnson, Jessica S.
AU - Wang, Minghui
AU - Mattheisen, Manuel
AU - Børglum, Anders Dupont
AU - Zhang, Bin
AU - Sieberts, Solveig K.
AU - Peters, Mette A.
AU - Domenici, Enrico
AU - Schadt, Eric E.
AU - Devlin, Bernie
AU - Sklar, Pamela
AU - Roeder, Kathryn
AU - Roussos, Panos
N1 - Publisher Copyright:
© 2018, Macmillan Publishers Limited, part of Springer Nature.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85046668816&partnerID=8YFLogxK
U2 - 10.1038/s41380-018-0059-8
DO - 10.1038/s41380-018-0059-8
M3 - Article
C2 - 29740122
AN - SCOPUS:85046668816
SN - 1359-4184
VL - 24
SP - 1685
EP - 1695
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 11
ER -