Summary
Enhancer RNAs (eRNAs) constitute an important tissue- and cell-type-specific layer of the regulome. Identification of risk variants for neuropsychiatric diseases within enhancers underscores the importance of understanding the population-level variation of eRNAs in the human brain. We jointly analyzed cell type-specific transcriptome and regulome data to identify 30,795 neuronal and 23,265 non-neuronal eRNAs, expanding the catalog of known human brain eRNAs by an order of magnitude. Examination of the population-level variation of the transcriptome and regulome in 1,382 brain samples identified reproducible changes affecting cis- and trans-co-regulation of eRNA-gene modules in schizophrenia. We show that 13% of schizophrenia heritability is jointly mediated in cis by brain gene and eRNA expression. Inclusion of eRNAs in transcriptome-wide association studies facilitated fine-mapping and functional interpretation of disease loci. Overall, our study characterizes the eRNA-gene regulome and genetic mechanisms in the human cortex in both healthy and disease states.
Highlights
Catalog and characterize cell-type-specific transcribed enhancers in the human cerebral cortex.
Cis- and trans-eRNA-gene co-expression networks dissect cell-type-specific dysregulations of regulome in schizophrenia.
Adding eRNA to the analysis of gene expression data increases the explained heritability mediated in cis-regulation of expression by more than 50% when compared to genes alone.
Joint eRNA-gene transcriptome-wide association study facilitates functional characterization of schizophrenia risk loci.
Competing Interest Statement
The authors have declared no competing interest.