Differential activity of transcribed enhancers in the prefrontal cortex of 537 cases with schizophrenia and controls.
Mol Psychiatry
; 24(11): 1685-1695, 2019 11.
Article
em En
| MEDLINE
| ID: mdl-29740122
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Esquizofrenia
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Elementos Facilitadores Genéticos
Tipo de estudo:
Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article