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. 

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

Objectives: Copy number variants (CNVs) are well-known genetic pleiotropic risk factors for multiple neurodevelopmental and psychiatric disorders (NPDs) including autism (ASD) and schizophrenia (SZ). Overall, little is known about how different CNVs conferring risk for the same condition may affect subcortical brain structures and how these alterations relate to the level of disease risk conferred by CNVs. To fill this gap, we investigated gross volume, and vertex level thickness and surface maps of subcortical structures in 11 different CNVs and 6 different NPDs. Methods: Subcortical structures were characterized using harmonized ENIGMA protocols in 675 CNV carriers (at the following loci: 1q21.1, TAR, 13q12.12, 15q11.2, 16p11.2, 16p13.11, and 22q11.2) and 782 controls (Male/Female: 727/730; age-range: 6-80 years) as well as ENIGMA summary-statistics for ASD, SZ, ADHD, Obsessive-Compulsive-Disorder, Bipolar-Disorder, and Major-Depression. Results: Nine of the 11 CNVs affected volume of at least one subcortical structure. The hippocampus and amygdala were affected by five CNVs. Effect sizes of CNVs on subcortical volume, thickness and local surface area were correlated with their previously reported effect sizes on cognition and risk for ASD and SZ. Shape analyses were able to identify subregional alterations that were averaged out in volume analyses. We identified a common latent dimension - characterized by opposing effects on basal ganglia and limbic structures - across CNVs and across NPDs. Conclusion: Our findings demonstrate that subcortical alterations associated with CNVs show varying levels of similarities with those associated with neuropsychiatric conditions. We also observed distinct effects with some CNVs clustering with adult conditions while others clustered with ASD. This large cross-CNV and NPDs analysis provide insight into the long-standing questions of why CNVs at different genomic loci increase the risk for the same NPD, as well as why a single CNV increases the risk for a diverse set of NPDs.

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Subcortical brain alterations in carriers of genomic copy number variants

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Subcortical brain alterations in carriers of genomic copy number variants