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Cell-type specific open chromatin profiling in human postmortem brain infers functional roles for non-coding schizophrenia loci

By John F. Fullard, Claudia Giambartolomei, Mads E Hauberg, Ke Xu, Christopher Bare, Joel T. Dudley, Manuel Mattheisen, Sarah E. Medland, Vahram Haroutunian, Panos Roussos

Posted 07 Jul 2016
bioRxiv DOI: 10.1101/062513 (published DOI: 10.1093/hmg/ddx103)

To better understand the role of cis regulatory elements in neuropsychiatric disorders we applied ATAC-seq to neuronal and non-neuronal nuclei isolated from frozen postmortem human brain. Most of the identified open chromatin regions (OCRs) are differentially accessible between neurons and non-neurons, and show enrichment with known cell type markers, promoters and enhancers. Relative to those of non-neurons, neuronal OCRs are more evolutionarily conserved and are enriched in distal regulatory elements. Our data reveals sex differences in chromatin accessibility and identifies novel OCRs that escape X chromosome inactivation, with implications for intellectual disability. Transcription factor footprinting analysis identifies differences in the regulome between neuronal and non-neuronal cells and ascribes putative functional roles to 16 non-coding schizophrenia risk variants. These results represent the first analysis of cell-type-specific OCRs and TF binding sites in postmortem human brain and further our understanding of the regulome and the impact of neuropsychiatric disease-associated genetic risk variants.

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