The neuronal chromatin landscape in adult schizophrenia brains is linked to early fetal development.
Document Type
Article
Publication Date
10-2-2023
Publication Title
Res Sq
Keywords
washington; isb; genomics
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 cis- and trans-regulatory domains, identified a prominent neuronal trans-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.
Clinical Institute
Mental Health
Clinical Institute
Neurosciences (Brain & Spine)
Clinical Institute
Women & Children
Department
Behavioral Health
Department
Institute for Systems Biology
Department
Perinatology/Neonatology
Recommended Citation
Girdhar, Kiran; Bendl, Jaroslav; Baumgartner, Andrew M; Therrien, Karen; Venkatesh, Sanan; Mathur, Deepika; Dong, Pengfei; Rahman, Samir; Kleopoulos, Steven P; Misir, Ruth; Reach, Sarah M; Auluck, Pavan K; Marenco, Stefano; Lewis, David A; Haroutunian, Vahram; Funk, Cory C; Voloudakis, Georgios; Hoffman, Gabriel E; Fullard, John F; and Roussos, Panos, "The neuronal chromatin landscape in adult schizophrenia brains is linked to early fetal development." (2023). Articles, Abstracts, and Reports. 8082.
https://digitalcommons.providence.org/publications/8082
