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Gerstner, N. ; Fröhlich, A.S.* ; Matosin, N.* ; Gagliardi, M.* ; Cruceanu, C.* ; Ködel, M.* ; Rex-Haffner, M.* ; Tu, X.* ; Mostafavi, S.* ; Ziller, M.J.* ; Binder, E.B.* ; Knauer-Arloth, J.

Contrasting genetic predisposition and diagnosis in psychiatric disorders: A multi-omic single-nucleus analysis of the human OFC.

Sci. Adv. 11:eadq2290 (2025)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Psychiatric disorders like schizophrenia, bipolar disorder, and major depressive disorder exhibit substantial genetic and clinical overlap. However, their molecular architecture remains elusive due to their polygenic nature and complex brain cell interactions. We integrated clinical data with genetic susceptibility to investigate gene expression and chromatin accessibility in the orbitofrontal cortex of 92 postmortem human brain samples at the single-nucleus (sn) level. Using snRNA-seq and snATAC-seq, we analyzed ~800,000 and 400,000 nuclei, respectively. We observed cell-type-specific dysregulation related to clinical diagnosis and genetic risk. Dysregulation in gene expression and chromatin accessibility associated with diagnosis was pronounced in excitatory neurons. Conversely, genetic risk predominantly affected glial and endothelial cells. Notably, INO80E and HCN2 genes exhibited dysregulation in excitatory neurons' superficial layers 2/3 influenced by schizophrenia polygenic risk. This study unveils the complex genetic and epigenetic landscape of psychiatric disorders, emphasizing the importance of cell-type-specific analyses in understanding their pathogenesis and contrasting genetic predisposition with clinical diagnosis.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Genome-wide Association; Chromatin; Schizophrenia; Expression; Microglia; Insights; Channel; Stress; Impact; Focus
Sprache englisch
Veröffentlichungsjahr 2025
HGF-Berichtsjahr 2025
ISSN (print) / ISBN 2375-2548
e-ISSN 2375-2548
Zeitschrift Science Advances
Quellenangaben Band: 11, Heft: 10, Seiten: , Artikelnummer: eadq2290 Supplement: ,
Verlag American Association for the Advancement of Science (AAAS)
Verlagsort Washington, DC [u.a.]
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Computational Biology (ICB)
POF Topic(s) 30205 - Bioengineering and Digital Health
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-503800-001
Förderungen Joachim Herz Foundation
National Institute of Alcohol Abuse and Alcoholism of the National Institutes of Health
Alexander von Humboldt Foundation
BMBF eMED program grant DINGS
Hope for Depression Research Foundation
DOI 10.1126/sciadv.adq2290
WOS ID 001439265400010
Scopus ID 86000336395
PubMed ID 40053590
Erfassungsdatum 2025-05-06
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