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

Dong, P.; Bendl, J.; Misir, R.; Shao, Z.; Edelstien, J.; Davis, D. A.; Haroutunian, V.; Scott, W. K.; Acker, S.; Lawless, N.; Hoffman, G. E.; Fullard, J. F.; Roussos, P.

doi:10.1101/2022.09.02.506419

bioRxiv · 10.1101/2022.09.02.506419

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

Dong, P.·Bendl, J.·Misir, R.·Shao, Z.·Edelstien, J.·Davis, D. A.·Haroutunian, V.·Scott, W. K.·Acker, S.·Lawless, N.·Hoffman, G. E.·Fullard, J. F.·Roussos, P.

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Abstract

Brain region- and cell-specific transcriptomic and epigenomic molecular features are associated with heritability for neuropsychiatric traits, but a systematic view, considering cortical and subcortical regions, is lacking. Here, we provide an atlas of chromatin accessibility and gene expression in neuronal and non-neuronal nuclei across 25 distinct human cortical and subcortical brain regions from 6 neurotypical controls. We identified extensive gene expression and chromatin accessibility differences across brain regions, including variation in alternative promoter-isoform usage and enhancer-promoter interactions. Genes with distinct promoter-isoform usage across brain regions are strongly enriched for neuropsychiatric disease risk variants. Using an integrative approach, we characterized the function of the brain region-specific chromatin co-accessibility and gene-coexpression modules that are robustly associated with genetic risk for neuropsychiatric disorders. In addition, we identified a novel set of genes that is enriched for disease risk variants but is independent of cell-type specific gene expression and known susceptibility pathways. Our results provide a valuable resource for studying molecular regulation across multiple regions of the human brain and suggest a unique contribution of epigenetic modifications from subcortical areas to neuropsychiatric disorders.

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Dong, P., Bendl, J., Misir, R., Shao, Z., Edelstien, J., Davis, D. A., Haroutunian, V., Scott, W. K., Acker, S., Lawless, N., Hoffman, G. E., Fullard, J. F., Roussos, P.. 2022-09-04. Transcriptome and chromatin accessibility landscapes across 25 distinct human brain regions expand the susceptibility gene set for neuropsychiatric disorders. https://doi.org/10.1101/2022.09.02.506419

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