Differential activity of transcribed enhancers in the prefrontal cortex of 537 cases with schizophrenia and controls
Year: 2018
Type: article
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.
Source: Molecular Psychiatry
Authors: Mads E. Hauberg, John F. Fullard, Lingxue Zhu, Ariella T. Cohain, Claudia Giambartolomei, Ruth Misir, Sarah Reach, Jessica S. Johnson, Minghui Wang, Manuel Mattheisen, Anders Dupont Børglum, Bin Zhang, Solveig K. Sieberts, Mette A. Peters, Enrico Domenici, Eric E. Schadt, Bernie Devlin, Pamela Sklar, Kathryn Roeder, Panos Roussos
Institutions: Aarhus University, Lundbeck Foundation, Icahn School of Medicine at Mount Sinai, Carnegie Mellon University, University of Würzburg, Karolinska Institutet, Universitätsklinikum Würzburg, Sage Bionetworks, University of Trento, The Microsoft Research - University of Trento Centre for Computational and Systems Biology, University of Pittsburgh, James J. Peters VA Medical Center
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Awards: G1226976794, G1228824270, G1327529060, G1363864812, G1496609009, Identifying therapeutic targets for autism using Shank3-deficient mice, G214445032, G2362047122, White Matter Abnormalities in Schizophrenia, Transforming Genomics with 5 PB Big Omics Data Engine Cray CS300-AC Supercomputer, G3246699782, G3322638211, G3421941850, Alzheimer's Disease Research Center, Risk genetic variants and cis regulation of gene expression in Bipolar Disorder, G3987400284, International Cohort Collection for Bipolar Disorder, Genetics Association in Schizophrenia and Other Disorders, G5014262244, G5669340364, G590325742, 1/3-Networks from Multidimensional Data for Schizophrenia and Related Disorders, G648333902, G6846248770, Plasma and CSF Abeta peptides in late-onset major depression, G817915945, G883029084, G9000229553
OpenAlex ID: W2800216885