A transcriptomic dimension of neuronal and immune gene programs within the subgenual anterior cingulate cortex in schizophrenia.

Many psychiatric disorders are heritable, but the molecular consequences of genetic risk remain difficult to resolve, in part due to environmental confounds and the complexity of transcriptomic data. This challenge impedes therapeutic development, which relies on integrating genetic and genomic insights. Here, we integrate diagnosis, toxicological exposure, and gene expression to clarify disease-associated transcriptomic patterns in the subgenual anterior cingulate cortex (sgACC), a brain region implicated in affective regulation and psychiatric illness. We applied group regularized canonical correlation analysis (GRCCA)-a multivariate regression method that models interdependent features-to deeply sequenced bulk RNA-seq data from individuals with bipolar disorder (BD; N = 35), major depression (MDD; N = 51), schizophrenia (SCZ; N = 44), and controls (N = 55). Toxicology data from 17 known compounds were included to assess the relative contribution of known environmental exposures. Case-control expression changes were also analyzed using traditional differential gene expression (DGE) analysis to compare biological interpretability across methods. Gene set enrichment analyses evaluated enrichments for neuropsychiatric risk genes, gene ontology pathways, and cell type markers. GRCCA identified a latent variable significantly associated with schizophrenia (p