Population-level variation of enhancer expression identifies novel disease mechanisms in the human brain

Abstract

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.

Transcriptome and chromatin accessibility landscapes across 25 distinct human brain regions expand the susceptibility gene set for neuropsychiatric disorders

“…The recently developed activity-by-contact (ABC) model integrating chromatin states and 3D contacts accurately predicts the experimentally validated promoter-enhancer interactions 35 . With our brain-region-specific chromatin accessibility information and cell-type-specific Hi-C contacts 18,36 , we built brain-region-specific ABC models and found the majority of EP links located within 50kb of transcriptional start sites (TSS) ( Fig. S6a and Supplementary Table 8 ).…”

“…b , Epigenomic profiles around major interior promoters and non-major 5’ promoters. The shadow shows the 95% confidence intervals.ChIP-seq profiles derived from Dong et al 2022 18 . c , Spearman correlation coefficient (SCC) between the log2 fold change of gene and promoter-isoform expressions of all promoter-isoforms (upper panel) and non-concordant promoter-isoforms (bottom panel).…”

“…The prevailing view is that non-coding risk variants exert their effects by altering CRE function and disrupting gene-regulatory circuits 6,13 . Large-scale efforts have been fruitful in generating CRE regulatory atlases 8,9,[14][15][16] and mapping chromatin quantitative trait loci (QTL) 7,17,18 in the human brain to decipher the function of neuropsychiatric risk variants.…”

Acetylated Chromatin Domains Link Chromosomal Organization to Cell- and Circuit-level Dysfunction in Schizophrenia and Bipolar Disorder

“…Integrating neuron-specific chromosomal conformation assayed by Hi-C from NeuN + sorted nuclei from PFC from a set of reference brains (N=6; 3F/3M) 23,26 , allowed us to evaluate whether CRDs provide a submodular organization within higher-order chromatin structures such as the topologically associating domains (TADs) computed from Hi-C chromosomal conformation mappings. Examining Hi-C and H3K27ac CRD structure in the 2MB of sequence surrounding GATB (Glutamyl-TRNA Amidotransferase Subunit B), a locus contributing to the heritability of cognitive traits and educational attainment 27 , reveals CRD landscapes embedded in the chromosomal TAD architecture (Figure 3C).…”

Sex significantly impacts the function of major depression-linked variantsin vivo

“…Instead, these SNPs are found in probable regulatory elements (REs), including transcriptional-regulatory sequences predicted from measures such as chromatin marks, accessibility, and conformation. Specific brain regions and cell types are enriched for such measures at-and in putative regulatory target genes of-MDD-associated loci, including the hippocampus (7,11) and excitatory neurons (12)(13)(14)(15)(16), suggesting sites of action for these REs. In particular, there has been long-standing interest in the hippocampus regarding both MDD pathology and sex differences in the brain.…”