The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia
Ralda Nehme, Olli Pietiläinen, Mykyta Artomov, Matthew Tegtmeyer, Vera Valakh, Leevi Lehtonen, Christina Bell, Tarjinder Singh, Aditi Trehan, J. L. Sherwood, Danielle K. Manning, Emily Peirent, Rhea Malik, Ellen J. Guss, Derek Hawes, Amanda Beccard, Anne M. Bara, Dane Z. Hazelbaker, Emanuela Zuccaro, Giulio Genovese, Alexander A. Loboda, Anna Neumann, Christina Lilliehöök, Outi Kuismin, Eija Hämäläinen, Mitja Kurki, Christina M. Hultman, Anna K. Kähler, João A. Paulo, Andrea Ganna, Jon M. Madison, Bruce M. Cohen, Donna L. McPhie, Rolf Adolfsson, Roy H. Perlis, Ricardo E. Dolmetsch, Samouil L. Farhi, Steven A. McCarroll, Steven E. Hyman, Ben Neale, Lindy E. Barrett, J. Wade Harper, Aarno Palotie, Mark J. Daly, Kevin Eggan
Abstract
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.