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.