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Contrasting genetic predisposition and diagnosis in psychiatric disorders: A multi-omic single-nucleus analysis of the human OFC.
Sci. Adv. 11:eadq2290 (2025)
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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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Genome-wide Association; Chromatin; Schizophrenia; Expression; Microglia; Insights; Channel; Stress; Impact; Focus
ISSN (print) / ISBN
2375-2548
e-ISSN
2375-2548
Journal
Science Advances
Quellenangaben
Volume: 11,
Issue: 10,
Article Number: eadq2290
Publisher
American Association for the Advancement of Science (AAAS)
Publishing Place
Washington, DC [u.a.]
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Computational Biology (ICB)
Grants
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
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