Common schizophrenia risk variants are enriched in open chromatin regions of human glutamatergic neurons

Mads E. Hauberg, Jordi Creus-Muncunill, Jaroslav Bendl, Alexey Kozlenkov, Biao Zeng, Chuhyon Corwin, Sarah Chowdhury, Harald Kranz, Yasmin L. Hurd, Michael Wegner, Anders D. Børglum, Stella Dracheva, Michelle E. Ehrlich, John F. Fullard and Panos Roussos ()
Additional contact information
Mads E. Hauberg: Icahn School of Medicine at Mount Sinai
Jordi Creus-Muncunill: Icahn School of Medicine at Mount Sinai
Jaroslav Bendl: Icahn School of Medicine at Mount Sinai
Alexey Kozlenkov: Icahn School of Medicine at Mount Sinai
Biao Zeng: Icahn School of Medicine at Mount Sinai
Chuhyon Corwin: Icahn School of Medicine at Mount Sinai
Sarah Chowdhury: Icahn School of Medicine at Mount Sinai
Harald Kranz: Gene Bridges, Im Neuenheimer Feld 584
Yasmin L. Hurd: Icahn School of Medicine at Mount Sinai
Michael Wegner: Emil-Fischer-Zentrum, Friedrich-Alexander Universität Erlangen-Nürnberg
Anders D. Børglum: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Stella Dracheva: Icahn School of Medicine at Mount Sinai
Michelle E. Ehrlich: Icahn School of Medicine at Mount Sinai
John F. Fullard: Icahn School of Medicine at Mount Sinai
Panos Roussos: Icahn School of Medicine at Mount Sinai

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract The chromatin landscape of human brain cells encompasses key information to understanding brain function. Here we use ATAC-seq to profile the chromatin structure in four distinct populations of cells (glutamatergic neurons, GABAergic neurons, oligodendrocytes, and microglia/astrocytes) from three different brain regions (anterior cingulate cortex, dorsolateral prefrontal cortex, and primary visual cortex) in human postmortem brain samples. We find that chromatin accessibility varies greatly by cell type and, more moderately, by brain region, with glutamatergic neurons showing the largest regional variability. Transcription factor footprinting implicates cell-specific transcriptional regulators and infers cell-specific regulation of protein-coding genes, long intergenic noncoding RNAs and microRNAs. In vivo transgenic mouse experiments validate the cell type specificity of several of these human-derived regulatory sequences. We find that open chromatin regions in glutamatergic neurons are enriched for neuropsychiatric risk variants, particularly those associated with schizophrenia. Integration of cell-specific chromatin data with a bulk tissue study of schizophrenia brains increases statistical power and confirms that glutamatergic neurons are most affected. These findings illustrate the utility of studying the cell-type-specific epigenome in complex tissues like the human brain, and the potential of such approaches to better understand the genetic basis of human brain function.

Date: 2020
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DOI: 10.1038/s41467-020-19319-2

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