Abstract
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 revealed changes in mitochondrial energy metabolism and synaptic function that converged across CNVs and cell types. For mirror CNVs, the direction of effects was often reversed between deletions and duplications and showed correlation with CNV gene dosage. These findings suggest that a shared pathophysiology underlies risk for convergent brain phenotypes across CNVs and point toward promising therapeutic targets.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Figure S10 revised. Supplemental file updated.
