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

Cell Line DiGeorge Syndrome / genetics Humans Induced Pluripotent Stem Cells Neurons RNA Schizophrenia / genetics

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
27 06 2022
Historique:
received: 22 09 2021
accepted: 08 06 2022
entrez: 27 6 2022
pubmed: 28 6 2022
medline: 30 6 2022
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-022-31436-8 PMID: 35760976 PMC: PMC9237031
pubmed: 35760976
doi: 10.1038/s41467-022-31436-8
pii: 10.1038/s41467-022-31436-8
pmc: PMC9237031
doi:

Substances chimiques

RNA 63231-63-0

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

3690

Subventions

Organisme : NIMH NIH HHS
ID : U01 MH105669
Pays : United States
Organisme : NINDS NIH HHS
ID : R37 NS083524
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH115727
Pays : United States

Informations de copyright

© 2022. The Author(s).

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Auteurs

Ralda Nehme (R)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA. rnehme@broadinstitute.org.
Department of Stem Cell and Regenerative Biology, and the Harvard Institute for Stem Cell Biology, Harvard University, Cambridge, MA, 02138, USA. rnehme@broadinstitute.org.
ORCID: 0000-0001-7215-3311

Olli Pietiläinen (O)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA. ollip@broadinstitute.org.
Department of Stem Cell and Regenerative Biology, and the Harvard Institute for Stem Cell Biology, Harvard University, Cambridge, MA, 02138, USA. ollip@broadinstitute.org.
ORCID: 0000-0003-4387-1861

Mykyta Artomov (M)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
ORCID: 0000-0001-5282-8764

Matthew Tegtmeyer (M)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
Department of Stem Cell and Regenerative Biology, and the Harvard Institute for Stem Cell Biology, Harvard University, Cambridge, MA, 02138, USA.

Vera Valakh (V)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
Department of Stem Cell and Regenerative Biology, and the Harvard Institute for Stem Cell Biology, Harvard University, Cambridge, MA, 02138, USA.

Leevi Lehtonen (L)

Institute for Molecular Medicine Finland, University of Helsinki, FI-00014, Helsinki, Finland.

Christina Bell (C)

Department of Cell Biology, Blavatnik Institute of Harvard Medical School, Boston, MA, USA.

Tarjinder Singh (T)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
ORCID: 0000-0003-0601-6815

Aditi Trehan (A)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
Department of Stem Cell and Regenerative Biology, and the Harvard Institute for Stem Cell Biology, Harvard University, Cambridge, MA, 02138, USA.

John Sherwood (J)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
Department of Stem Cell and Regenerative Biology, and the Harvard Institute for Stem Cell Biology, Harvard University, Cambridge, MA, 02138, USA.

Danielle Manning (D)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.

Emily Peirent (E)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
Department of Stem Cell and Regenerative Biology, and the Harvard Institute for Stem Cell Biology, Harvard University, Cambridge, MA, 02138, USA.
ORCID: 0000-0002-3226-7127

Rhea Malik (R)

Department of Stem Cell and Regenerative Biology, and the Harvard Institute for Stem Cell Biology, Harvard University, Cambridge, MA, 02138, USA.

Ellen J Guss (EJ)

Department of Stem Cell and Regenerative Biology, and the Harvard Institute for Stem Cell Biology, Harvard University, Cambridge, MA, 02138, USA.
ORCID: 0000-0002-2579-8712

Derek Hawes (D)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
Department of Stem Cell and Regenerative Biology, and the Harvard Institute for Stem Cell Biology, Harvard University, Cambridge, MA, 02138, USA.

Amanda Beccard (A)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.

Anne M Bara (AM)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
Department of Stem Cell and Regenerative Biology, and the Harvard Institute for Stem Cell Biology, Harvard University, Cambridge, MA, 02138, USA.

Dane Z Hazelbaker (DZ)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.

Emanuela Zuccaro (E)

Department of Stem Cell and Regenerative Biology, and the Harvard Institute for Stem Cell Biology, Harvard University, Cambridge, MA, 02138, USA.

Giulio Genovese (G)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
ORCID: 0000-0003-3066-5575

Alexander A Loboda (AA)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
ITMO University, St. Petersburg, Russia.
Almazov National Medical Research Centre, Saint-Petersburg, Russia.

Anna Neumann (A)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
ORCID: 0000-0001-7115-8305

Christina Lilliehook (C)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.

Outi Kuismin (O)

Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA.
PEDEGO Research Unit, University of Oulu, FI-90014, Oulu, Finland.
Medical Research Center, Oulu University Hospital, FI-90014, Oulu, Finland.
Department of Clinical Genetics, Oulu University Hospital, 90220, Oulu, Finland.

Eija Hamalainen (E)

Institute for Molecular Medicine Finland, University of Helsinki, FI-00014, Helsinki, Finland.

Mitja Kurki (M)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
Institute for Molecular Medicine Finland, University of Helsinki, FI-00014, Helsinki, Finland.
Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA.

Christina M Hultman (CM)

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77, Stockholm, Sweden.

Anna K Kähler (AK)

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77, Stockholm, Sweden.

Joao A Paulo (JA)

Department of Cell Biology, Blavatnik Institute of Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0002-4291-413X

Andrea Ganna (A)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
ORCID: 0000-0002-8147-240X

Jon Madison (J)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.

Bruce Cohen (B)

Department of Psychiatry, McLean Hospital, Belmont, MA, 02478, USA.
ORCID: 0000-0002-8861-6285

Donna McPhie (D)

Department of Psychiatry, McLean Hospital, Belmont, MA, 02478, USA.

Rolf Adolfsson (R)

Umea University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry, 901 85, Umea, Sweden.

Roy Perlis (R)

Psychiatry Dept., Massachusetts General Hospital, Boston, MA, 02114, USA.

Ricardo Dolmetsch (R)

Novartis Institutes for Biomedical Research, Novartis, Cambridge, MA, 02139, USA.

Samouil Farhi (S)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
ORCID: 0000-0003-1359-4568

Steven McCarroll (S)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.

Steven Hyman (S)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
Department of Stem Cell and Regenerative Biology, and the Harvard Institute for Stem Cell Biology, Harvard University, Cambridge, MA, 02138, USA.

Ben Neale (B)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
ORCID: 0000-0003-1513-6077

Lindy E Barrett (LE)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
Department of Stem Cell and Regenerative Biology, and the Harvard Institute for Stem Cell Biology, Harvard University, Cambridge, MA, 02138, USA.
ORCID: 0000-0002-3229-4774

Wade Harper (W)

Department of Cell Biology, Blavatnik Institute of Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0002-6944-7236

Aarno Palotie (A)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
Institute for Molecular Medicine Finland, University of Helsinki, FI-00014, Helsinki, Finland.
Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA.
Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.
ORCID: 0000-0002-2527-5874

Mark Daly (M)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
Institute for Molecular Medicine Finland, University of Helsinki, FI-00014, Helsinki, Finland.
Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA.
Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.
ORCID: 0000-0002-0949-8752

Kevin Eggan (K)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA. kevin.eggan@bmrn.com.
Department of Stem Cell and Regenerative Biology, and the Harvard Institute for Stem Cell Biology, Harvard University, Cambridge, MA, 02138, USA. kevin.eggan@bmrn.com.
BioMarin Pharmaceutical, San Rafael, CA, 94901, USA. kevin.eggan@bmrn.com.
ORCID: 0000-0003-4436-8467

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Classifications MeSH

questionsmedicales.fr › Cellules › Cellules cultivées › Lignée cellulaire › The 22q11.2 region regulates presynaptic...
questionsmedicales.fr › Maladies endocriniennes › Maladies de la parathyroïde › Hypoparathyroïdie › Syndrome de délétion 22q11 › Syndrome de DiGeorge › The 22q11.2 region regulates presynaptic...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The 22q11.2 region regulates presynaptic...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches pluripotentes › Cellules souches pluripotentes induites › The 22q11.2 region regulates presynaptic...
questionsmedicales.fr › Cellules › Neurones › The 22q11.2 region regulates presynaptic...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › The 22q11.2 region regulates presynaptic...
questionsmedicales.fr › Troubles mentaux › Schizophrénie et troubles avec traits psychotiques › Schizophrénie › The 22q11.2 region regulates presynaptic...