The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

How the 22q11.2 deletion predisposes to psychiatric disease is unclear. Here, the authors examine living human neuronal cells and show that 22q11.2 regulates the expression of genes linked to autism during early development, and genes linked to schizophrenia and synaptic biology in neurons. It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.

Automated summary

The mechanism by which the 22q11.2 deletion predisposes to psychiatric disease is not well understood. In this study, the authors investigated human neuronal cells and found that the deletion regulates the expression of genes associated with autism, schizophrenia, and synaptic biology. Using induced pluripotent stem cells and CRISPR/Cas9 technology, the researchers found that the deletion alters the abundance of transcripts associated with neurodevelopmental disorders during differentiation into neural progenitor cells. Furthermore, the altered transcripts in excitatory neurons were found to encode presynaptic factors and were associated with genetic risk for schizophrenia.