Cargando…

The neuronal chromatin landscape in adult schizophrenia brains is linked to early fetal development

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Girdhar, Kiran, Bendl, Jaroslav, Baumgartner, Andrew, 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, Voloudakis, Georgios, Hoffman, Gabriel E., Fullard, John F., Roussos, Panos
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Journal Experts 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10602154/
https://www.ncbi.nlm.nih.gov/pubmed/37886514
http://dx.doi.org/10.21203/rs.3.rs-3393581/v1
_version_ 1785126337018593280
author Girdhar, Kiran
Bendl, Jaroslav
Baumgartner, Andrew
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
Voloudakis, Georgios
Hoffman, Gabriel E.
Fullard, John F.
Roussos, Panos
author_facet Girdhar, Kiran
Bendl, Jaroslav
Baumgartner, Andrew
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
Voloudakis, Georgios
Hoffman, Gabriel E.
Fullard, John F.
Roussos, Panos
author_sort Girdhar, Kiran
collection PubMed
description 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.
format Online
Article
Text
id pubmed-10602154
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher American Journal Experts
record_format MEDLINE/PubMed
spelling pubmed-106021542023-10-27 The neuronal chromatin landscape in adult schizophrenia brains is linked to early fetal development Girdhar, Kiran Bendl, Jaroslav Baumgartner, Andrew 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 Voloudakis, Georgios Hoffman, Gabriel E. Fullard, John F. Roussos, Panos Res Sq Article 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. American Journal Experts 2023-10-02 /pmc/articles/PMC10602154/ /pubmed/37886514 http://dx.doi.org/10.21203/rs.3.rs-3393581/v1 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Girdhar, Kiran
Bendl, Jaroslav
Baumgartner, Andrew
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
Voloudakis, Georgios
Hoffman, Gabriel E.
Fullard, John F.
Roussos, Panos
The neuronal chromatin landscape in adult schizophrenia brains is linked to early fetal development
title The neuronal chromatin landscape in adult schizophrenia brains is linked to early fetal development
title_full The neuronal chromatin landscape in adult schizophrenia brains is linked to early fetal development
title_fullStr The neuronal chromatin landscape in adult schizophrenia brains is linked to early fetal development
title_full_unstemmed The neuronal chromatin landscape in adult schizophrenia brains is linked to early fetal development
title_short The neuronal chromatin landscape in adult schizophrenia brains is linked to early fetal development
title_sort neuronal chromatin landscape in adult schizophrenia brains is linked to early fetal development
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10602154/
https://www.ncbi.nlm.nih.gov/pubmed/37886514
http://dx.doi.org/10.21203/rs.3.rs-3393581/v1
work_keys_str_mv AT girdharkiran theneuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT bendljaroslav theneuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT baumgartnerandrew theneuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT therrienkaren theneuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT venkateshsanan theneuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT mathurdeepika theneuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT dongpengfei theneuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT rahmansamir theneuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT kleopoulosstevenp theneuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT misirruth theneuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT reachsarahm theneuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT auluckpavank theneuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT marencostefano theneuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT lewisdavida theneuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT haroutunianvahram theneuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT funkcory theneuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT voloudakisgeorgios theneuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT hoffmangabriele theneuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT fullardjohnf theneuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT roussospanos theneuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT girdharkiran neuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT bendljaroslav neuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT baumgartnerandrew neuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT therrienkaren neuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT venkateshsanan neuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT mathurdeepika neuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT dongpengfei neuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT rahmansamir neuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT kleopoulosstevenp neuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT misirruth neuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT reachsarahm neuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT auluckpavank neuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT marencostefano neuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT lewisdavida neuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT haroutunianvahram neuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT funkcory neuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT voloudakisgeorgios neuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT hoffmangabriele neuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT fullardjohnf neuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment
AT roussospanos neuronalchromatinlandscapeinadultschizophreniabrainsislinkedtoearlyfetaldevelopment