High-risk neuropsychiatric copy number variants are associated with convergent transcriptomic changes in human brain cells

Large, recurrent copy number variants (CNVs) are among the strongest risk factors for neuropsychiatric conditions, contributing to multiple phenotypes with overlapping psychiatric and cognitive symptoms. However, the molecular basis of this convergent risk remains unknown. We evaluated the human brain transcriptome in carriers of nine high-risk neuropsychiatric CNVs and matched non-carriers using single nucleus RNA-sequencing. Brain tissue from carriers displayed widespread disruptions of gene expression, with deletions showing greater changes than the reciprocal duplications. Functional enrichment analysis of differentially expressed genes revealed changes in mitochondrial energy metabolism and synaptic function that converged across CNVs and cell types. The direction of effects correlated with CNV gene dosage for mirror CNVs. These findings suggest that a shared pathophysiology underlies risk for convergent brain phenotypes across CNVs and point toward promising therapeutic targets.