84. FROM HIGH-RISK CNVS TO BRAIN BIOLOGY: CELL TYPE-SPECIFIC TRANSCRIPTOMICS ACROSS NINE CNVS IMPLICATE CONVERGENT ENERGY METABOLISM CHANGES IN POSTMORTEM HUMAN BRAIN

Background High-risk copy number variants (CNVs) confer substantial risk for neuropsychiatric disorders, yet the mechanisms linking these variants to convergent psychiatric and cognitive phenotypes remain unclear. Using a genetics-first approach, we investigated how recurrent CNVs impact gene expression across distinct brain cell types and assessed their potential relevance to broader clinical populations. Methods Postmortem dorsolateral prefrontal cortex and anterior cingulate cortex from 15 CNV carriers (deletions and duplications at 22q11.2, 1q21.1, 16p11.2, 15q11.2, and 7q11.23 deletions) along with matched non-carrier controls across three brain banks (total n=66) were analyzed using bulk and single-nucleus RNA-sequencing. Bulk data were quantified with RSEM and analyzed with Dream, while single-nucleus data were processed in CellRanger, quality-controlled in Seurat, and annotated using Azimuth. Differential expression analyses were performed across nine major cell types with Dreamlet. Functional enrichment analyses were used to identify shared biological pathways across CNVs. In a separate exploratory postmortem schizophrenia cohort with existing bulk transcriptome and mitochondrial assays (mtDNA copy number and Complex I activity), transcriptome-wide case-control contrasts were used for correlation-based clustering analyses. Results CNV carriers showed dosage-dependent changes in gene expression, with deletions producing greater transcriptomic disruption than reciprocal duplications. Single-nucleus analyses revealed cell type-specific effects: astrocytes were most affected in 22q11.2 deletions, while excitatory neurons were preferentially affected in 7q11.23 deletions. Across CNVs and cell types, the most frequently implicated signal was disruption of cellular energy metabolism, particularly oxidative phosphorylation, with synaptic pathways also enriched and partially correlated with metabolic changes. Notably, 22q11.2 deletions displayed upregulation of glycolytic pathways, most prominently in astrocytes, suggesting cell type-specific metabolic remodelingIn the exploratory schizophrenia cohort, we identified an additional 22q11.2 deletion carrier exhibiting markedly elevated mtDNA copy number (Cohen’s d = 4.05) and reduced Complex I activity (Cohen’s d = 0.56), along with a distinct transcriptome-wide profile. Correlation-based clustering identified two additional schizophrenia cases with similar gene expression changes, indicating that CNV-associated transcriptional signatures may extend to a subset of clinically defined cases. Discussion This study provides the first large-scale cell type-resolved transcriptomic analysis of multiple high-risk neuropsychiatric CNVs, revealing both CNV-specific and convergent molecular effects. The results highlight disruption of cellular energy metabolism as a central and shared feature across CNVs. These findings further suggest that transcriptomic signatures derived from CNV carriers may help define biologically meaningful subgroups within heterogeneous psychiatric populations. Future work will expand sample size, incorporate additional brain regions, refine cell type resolution, and validate these signatures in independent cohorts while quantifying the contribution of specific pathways to disease stratification.