The Neuronal Chromatin Landscape in Adult Schizophrenia Brains is Linked to Early Fetal Development

Overview

Journal Res Sq

Date 2023 Oct 27

PMID 37886514

Authors

Kiran Girdhar

Jaroslav Bendl

Andrew Baumgartner

Karen Therrien

Sanan Venkatesh

Deepika Mathur

Pengfei Dong

Samir Rahman

Steven P Kleopoulos

Ruth Misir

Sarah M Reach

Pavan K Auluck

Stefano Marenco

David A Lewis

Vahram Haroutunian

Cory Funk

Georgios Voloudakis

Gabriel E Hoffman

John F Fullard

Panos Roussos

Affiliations

Soon will be listed here.

Abstract

Non-coding variants increase risk of neuropsychiatric disease. However, our understanding of the cell-type specific role of the non-coding genome in disease is incomplete. We performed population scale (N=1,393) chromatin accessibility profiling of neurons and non-neurons from two neocortical brain regions: the anterior cingulate cortex and dorsolateral prefrontal cortex. Across both regions, we observed notable differences in neuronal chromatin accessibility between schizophrenia cases and controls. A per-sample disease pseudotime was positively associated with genetic liability for schizophrenia. Organizing chromatin into - and -regulatory domains, identified a prominent neuronal -regulatory domain (TRD1) active in immature glutamatergic neurons during fetal development. Polygenic risk score analysis using genetic variants within chromatin accessibility of TRD1 successfully predicted susceptibility to schizophrenia in the Million Veteran Program cohort. Overall, we present the most extensive resource to date of chromatin accessibility in the human cortex, yielding insights into the cell-type specific etiology of schizophrenia.

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