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Nat Commun DOI:10.1038/s41467-022-31436-8

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

Publication TypeJournal Article
Year of Publication2022
AuthorsNehme, R, Pietilainen, O, Artomov, M, Tegtmeyer, M, Valakh, V, Lehtonen, L, Bell, C, Singh, T, Trehan, A, Sherwood, J, Manning, D, Peirent, E, Malik, R, Guss, EJ, Hawes, D, Beccard, A, Bara, AM, Hazelbaker, DZ, Zuccaro, E, Genovese, G, Loboda, AA, Neumann, A, Lilliehook, C, Kuismin, O, Hämäläinen, E, Kurki, M, Hultman, CM, Kähler, AK, Paulo, JA, Ganna, A, Madison, J, Cohen, B, McPhie, D, Adolfsson, R, Perlis, R, Dolmetsch, R, Farhi, S, McCarroll, S, Hyman, S, Neale, B, Barrett, LE, Harper, W, Palotie, A, Daly, M, Eggan, K
JournalNat Commun
Date Published2022 Jun 27
KeywordsCell Line, DiGeorge Syndrome, Humans, Induced Pluripotent Stem Cells, Neurons, RNA, Schizophrenia

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.


Alternate JournalNat Commun
PubMed ID35760976
Grant ListU01MH105669 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /