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, John Sherwood, Danielle 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 Lilliehook, Outi Kuismin, Eija Hamalainen, Mitja Kurki, Christina M. Hultman, Anna K. Kähler, Joao A. Paulo, Andrea Ganna, Jon Madison, Bruce Cohen, Donna McPhie, Rolf Adolfsson, Roy Perlis, Ricardo Dolmetsch, Samouil Farhi, Steven McCarroll, Steven Hyman, Ben Neale, Lindy E. Barrett, Wade Harper, Aarno Palotie, Mark Daly and Kevin Eggan ()
Additional contact information
Ralda Nehme: Broad Institute of Harvard and MIT
Olli Pietiläinen: Broad Institute of Harvard and MIT
Mykyta Artomov: Broad Institute of Harvard and MIT
Matthew Tegtmeyer: Broad Institute of Harvard and MIT
Vera Valakh: Broad Institute of Harvard and MIT
Leevi Lehtonen: University of Helsinki
Christina Bell: Blavatnik Institute of Harvard Medical School
Tarjinder Singh: Broad Institute of Harvard and MIT
Aditi Trehan: Broad Institute of Harvard and MIT
John Sherwood: Broad Institute of Harvard and MIT
Danielle Manning: Broad Institute of Harvard and MIT
Emily Peirent: Broad Institute of Harvard and MIT
Rhea Malik: Harvard University
Ellen J. Guss: Harvard University
Derek Hawes: Broad Institute of Harvard and MIT
Amanda Beccard: Broad Institute of Harvard and MIT
Anne M. Bara: Broad Institute of Harvard and MIT
Dane Z. Hazelbaker: Broad Institute of Harvard and MIT
Emanuela Zuccaro: Harvard University
Giulio Genovese: Broad Institute of Harvard and MIT
Alexander A. Loboda: Broad Institute of Harvard and MIT
Anna Neumann: Broad Institute of Harvard and MIT
Christina Lilliehook: Broad Institute of Harvard and MIT
Outi Kuismin: Massachusetts General Hospital
Eija Hamalainen: University of Helsinki
Mitja Kurki: Broad Institute of Harvard and MIT
Christina M. Hultman: Karolinska Institutet
Anna K. Kähler: Karolinska Institutet
Joao A. Paulo: Blavatnik Institute of Harvard Medical School
Andrea Ganna: Broad Institute of Harvard and MIT
Jon Madison: Broad Institute of Harvard and MIT
Bruce Cohen: McLean Hospital
Donna McPhie: McLean Hospital
Rolf Adolfsson: Umea University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry
Roy Perlis: Massachusetts General Hospital
Ricardo Dolmetsch: Novartis Institutes for Biomedical Research, Novartis
Samouil Farhi: Broad Institute of Harvard and MIT
Steven McCarroll: Broad Institute of Harvard and MIT
Steven Hyman: Broad Institute of Harvard and MIT
Ben Neale: Broad Institute of Harvard and MIT
Lindy E. Barrett: Broad Institute of Harvard and MIT
Wade Harper: Blavatnik Institute of Harvard Medical School
Aarno Palotie: Broad Institute of Harvard and MIT
Mark Daly: Broad Institute of Harvard and MIT
Kevin Eggan: Broad Institute of Harvard and MIT

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31436-8

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