In psychiatric disorders, common and rare genetic variants cause widespread dysfunction of cells and their interactions, especially in the prefrontal cortex, giving rise to psychiatric symptoms. To better understand these processes, we traced the effects of common and rare genetics, and cumulative disease risk scores, to their molecular footprints in human cortical single-cell types. We demonstrated that examining gene expression at single-exon resolution is crucial for understanding the cortical dysregulation associated with diagnosis and genetic risk derived from common variants. We then used disease risk scores to identify a core set of genes that serve as a footprint of common and rare variants in the cortex. Pathways enriched in these genes included dopamine regulation, circadian entrainment, and hormone regulation. Single-nuclei-RNA-sequencing pinpointed these enriched genes to excitatory cortical neurons. This study highlights the importance of studying sub-gene-level genetic architecture to classify psychiatric disorders based on biology rather than symptomatology, to identify novel targets for treatment development.
Overall design
Profiles of gene expression based on resolution of single exons of postmortem dorsolateral prefrontal cortex (DLPFC) of Brodmann area 9 (BA 9) from 169 adult subjects aged 18-87 years with schizophrenia (SCZ; n = 68), bipolar disorder (BD; n = 15), and major depressive disorder (MDD; n = 24) and matched controls (n = 62). Replicates were removed. Demographic, clinical, and pharmacologic data were collected as part of a medical history survey using the Diagnostic Instrument for Brain Studies (DIBS). Samples were hybridized to Affymetrix Human Exon 1.0 ST v2 arrays.
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