Contrasting genetic predisposition and diagnosis in psychiatric disorders: a multi-omic single-nucleus analysis of the human orbitofrontal cortex

Psychiatric disorders like schizophrenia, bipolar disorder, and major depressive disorder exhibit significant genetic and clinical overlap. However, their molecular architecture remains elusive due to their polygenic nature and complex brain cell interactions. Here, 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-cell level. Through single-nucleus (sn) RNA-seq and snATAC-seq, we analyzed approximately 800,000 and 400,000 nuclei, respectively. We observed cell type-specific dysregulation related to clinical diagnosis and genetic risk across cortical cell types. Dysregulation in gene expression and chromatin accessibility associated with diagnosis was pronounced in excitatory neurons. Conversely, genetic risk predominantly impacted 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Hope for Depression Research Foundation and the Federal Ministry of Education and Research of Germany. Human brain tissue acquisition was funded by the Alexander von Humboldt Foundation research support package awarded to Dr. Natalie Matosin. Nathalie Gerstner is supported by the Joachim Herz Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Ludwig Maximilians-Universitaet (22-0523) and the Human Research Ethics Committees at the University of Wollongong (HE2018/351) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Significant results from differential analysis of gene expression and chromatin accessibility between cases and controls as well as high and low risk individuals are available in Table S4-S9. Complete result lists can be obtained from . Preprocessed and raw single-nuclei data are available upon reasonable request to the authors.