IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-31436-8.html
   My bibliography  Save this article

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

Author

Listed:
  • Ralda Nehme

    (Broad Institute of Harvard and MIT
    Harvard University)

  • Olli Pietiläinen

    (Broad Institute of Harvard and MIT
    Harvard University)

  • Mykyta Artomov

    (Broad Institute of Harvard and MIT
    Massachusetts General Hospital)

  • Matthew Tegtmeyer

    (Broad Institute of Harvard and MIT
    Harvard University)

  • Vera Valakh

    (Broad Institute of Harvard and MIT
    Harvard University)

  • 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
    Harvard University)

  • John Sherwood

    (Broad Institute of Harvard and MIT
    Harvard University)

  • Danielle Manning

    (Broad Institute of Harvard and MIT)

  • Emily Peirent

    (Broad Institute of Harvard and MIT
    Harvard University)

  • Rhea Malik

    (Harvard University)

  • Ellen J. Guss

    (Harvard University)

  • Derek Hawes

    (Broad Institute of Harvard and MIT
    Harvard University)

  • Amanda Beccard

    (Broad Institute of Harvard and MIT)

  • Anne M. Bara

    (Broad Institute of Harvard and MIT
    Harvard University)

  • 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
    Massachusetts General Hospital
    ITMO University
    Almazov National Medical Research Centre)

  • Anna Neumann

    (Broad Institute of Harvard and MIT)

  • Christina Lilliehook

    (Broad Institute of Harvard and MIT)

  • Outi Kuismin

    (Massachusetts General Hospital
    University of Oulu
    Oulu University Hospital
    Oulu University Hospital)

  • Eija Hamalainen

    (University of Helsinki)

  • Mitja Kurki

    (Broad Institute of Harvard and MIT
    University of Helsinki
    Massachusetts General Hospital)

  • 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
    Harvard University)

  • Ben Neale

    (Broad Institute of Harvard and MIT)

  • Lindy E. Barrett

    (Broad Institute of Harvard and MIT
    Harvard University)

  • Wade Harper

    (Blavatnik Institute of Harvard Medical School)

  • Aarno Palotie

    (Broad Institute of Harvard and MIT
    University of Helsinki
    Massachusetts General Hospital
    Massachusetts General Hospital)

  • Mark Daly

    (Broad Institute of Harvard and MIT
    Massachusetts General Hospital
    University of Helsinki
    Massachusetts General Hospital)

  • Kevin Eggan

    (Broad Institute of Harvard and MIT
    Harvard University
    BioMarin Pharmaceutical)

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.

Suggested Citation

  • Ralda Nehme & Olli Pietiläinen & Mykyta Artomov & Matthew Tegtmeyer & Vera Valakh & Leevi Lehtonen & Christina Bell & Tarjinder Singh & Aditi Trehan & John Sherwood & Danielle Manning & Emily Peirent , 2022. "The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31436-8
    DOI: 10.1038/s41467-022-31436-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-31436-8
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-31436-8?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Monkol Lek & Konrad J. Karczewski & Eric V. Minikel & Kaitlin E. Samocha & Eric Banks & Timothy Fennell & Anne H. O’Donnell-Luria & James S. Ware & Andrew J. Hill & Beryl B. Cummings & Taru Tukiainen , 2016. "Analysis of protein-coding genetic variation in 60,706 humans," Nature, Nature, vol. 536(7616), pages 285-291, August.
    2. Tarjinder Singh & Timothy Poterba & David Curtis & Huda Akil & Mariam Al Eissa & Jack D. Barchas & Nicholas Bass & Tim B. Bigdeli & Gerome Breen & Evelyn J. Bromet & Peter F. Buckley & William E. Bunn, 2022. "Rare coding variants in ten genes confer substantial risk for schizophrenia," Nature, Nature, vol. 604(7906), pages 509-516, April.
    3. Xianglong Zhang & Ying Zhang & Xiaowei Zhu & Carolin Purmann & Michael S. Haney & Thomas Ward & Arineh Khechaduri & Jie Yao & Sherman M. Weissman & Alexander E. Urban, 2018. "Local and global chromatin interactions are altered by large genomic deletions associated with human brain development," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    4. Menachem Fromer & Andrew J. Pocklington & David H. Kavanagh & Hywel J. Williams & Sarah Dwyer & Padhraig Gormley & Lyudmila Georgieva & Elliott Rees & Priit Palta & Douglas M. Ruderfer & Noa Carrera &, 2014. "De novo mutations in schizophrenia implicate synaptic networks," Nature, Nature, vol. 506(7487), pages 179-184, February.
    5. Christiaan A de Leeuw & Joris M Mooij & Tom Heskes & Danielle Posthuma, 2015. "MAGMA: Generalized Gene-Set Analysis of GWAS Data," PLOS Computational Biology, Public Library of Science, vol. 11(4), pages 1-19, April.
    6. Björn Schwanhäusser & Dorothea Busse & Na Li & Gunnar Dittmar & Johannes Schuchhardt & Jana Wolf & Wei Chen & Matthias Selbach, 2011. "Global quantification of mammalian gene expression control," Nature, Nature, vol. 473(7347), pages 337-342, May.
    7. Shaun M. Purcell & Jennifer L. Moran & Menachem Fromer & Douglas Ruderfer & Nadia Solovieff & Panos Roussos & Colm O’Dushlaine & Kimberly Chambert & Sarah E. Bergen & Anna Kähler & Laramie Duncan & El, 2014. "A polygenic burden of rare disruptive mutations in schizophrenia," Nature, Nature, vol. 506(7487), pages 185-190, February.
    8. Alan Hutson, 1999. "Calculating nonparametric confidence intervals for quantiles using fractional order statistics," Journal of Applied Statistics, Taylor & Francis Journals, vol. 26(3), pages 343-353.
    9. Vassily Trubetskoy & Antonio F. Pardiñas & Ting Qi & Georgia Panagiotaropoulou & Swapnil Awasthi & Tim B. Bigdeli & Julien Bryois & Chia-Yen Chen & Charlotte A. Dennison & Lynsey S. Hall & Max Lam & K, 2022. "Mapping genomic loci implicates genes and synaptic biology in schizophrenia," Nature, Nature, vol. 604(7906), pages 502-508, April.
    10. Cagla Eroglu & Ben A. Barres, 2010. "Regulation of synaptic connectivity by glia," Nature, Nature, vol. 468(7321), pages 223-231, November.
    11. Ellis Chika Onwordi & Els F. Halff & Thomas Whitehurst & Ayla Mansur & Marie-Caroline Cotel & Lisa Wells & Hannah Creeney & David Bonsall & Maria Rogdaki & Ekaterina Shatalina & Tiago Reis Marques & E, 2020. "Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    12. Hreinn Stefansson & Andreas Meyer-Lindenberg & Stacy Steinberg & Brynja Magnusdottir & Katrin Morgen & Sunna Arnarsdottir & Gyda Bjornsdottir & G. Bragi Walters & Gudrun A. Jonsdottir & Orla M. Doyle , 2014. "CNVs conferring risk of autism or schizophrenia affect cognition in controls," Nature, Nature, vol. 505(7483), pages 361-366, January.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Ruoyu Tian & Tian Ge & Hyeokmoon Kweon & Daniel B. Rocha & Max Lam & Jimmy Z. Liu & Kritika Singh & Daniel F. Levey & Joel Gelernter & Murray B. Stein & Ellen A. Tsai & Hailiang Huang & Christopher F., 2024. "Whole-exome sequencing in UK Biobank reveals rare genetic architecture for depression," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Charley Xia & Sarah J. Pickett & David C. M. Liewald & Alexander Weiss & Gavin Hudson & W. David Hill, 2023. "The contributions of mitochondrial and nuclear mitochondrial genetic variation to neuroticism," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Yash Patel & Jean Shin & Eeva Sliz & Ariana Tang & Aniket Mishra & Rui Xia & Edith Hofer & Hema Sekhar Reddy Rajula & Ruiqi Wang & Frauke Beyer & Katrin Horn & Max Riedl & Jing Yu & Henry Völzke & Rob, 2024. "Genetic risk factors underlying white matter hyperintensities and cortical atrophy," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    4. Eva-Maria Stauffer & Richard A. I. Bethlehem & Lena Dorfschmidt & Hyejung Won & Varun Warrier & Edward T. Bullmore, 2023. "The genetic relationships between brain structure and schizophrenia," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    5. Sophie A. Riesmeijer & Zoha Kamali & Michael Ng & Dmitriy Drichel & Bram Piersma & Kerstin Becker & Thomas B. Layton & Jagdeep Nanchahal & Michael Nothnagel & Ahmad Vaez & Hans Christian Hennies & Pau, 2024. "A genome-wide association meta-analysis implicates Hedgehog and Notch signaling in Dupuytren’s disease," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    6. Yunfeng Huang & Dora Bodnar & Chia-Yen Chen & Gabriela Sanchez-Andrade & Mark Sanderson & Jun Shi & Katherine G. Meilleur & Matthew E. Hurles & Sebastian S. Gerety & Ellen A. Tsai & Heiko Runz, 2023. "Rare genetic variants impact muscle strength," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    7. Alan Selewa & Kaixuan Luo & Michael Wasney & Linsin Smith & Xiaotong Sun & Chenwei Tang & Heather Eckart & Ivan P. Moskowitz & Anindita Basu & Xin He & Sebastian Pott, 2023. "Single-cell genomics improves the discovery of risk variants and genes of atrial fibrillation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    8. Kynon J. M. Benjamin & Ria Arora & Arthur S. Feltrin & Geo Pertea & Hunter H. Giles & Joshua M. Stolz & Laura D’Ignazio & Leonardo Collado-Torres & Joo Heon Shin & William S. Ulrich & Thomas M. Hyde &, 2024. "Sex affects transcriptional associations with schizophrenia across the dorsolateral prefrontal cortex, hippocampus, and caudate nucleus," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    9. Max Lam & Chia-Yen Chen & W. David Hill & Charley Xia & Ruoyu Tian & Daniel F. Levey & Joel Gelernter & Murray B. Stein & Alexander S. Hatoum & Hailiang Huang & Anil K. Malhotra & Heiko Runz & Tian Ge, 2022. "Collective genomic segments with differential pleiotropic patterns between cognitive dimensions and psychopathology," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    10. Yuni Kay & Linda Tsan & Elizabeth A. Davis & Chen Tian & Léa Décarie-Spain & Anastasiia Sadybekov & Anna N. Pushkin & Vsevolod Katritch & Scott E. Kanoski & Bruce E. Herring, 2022. "Schizophrenia-associated SAP97 mutations increase glutamatergic synapse strength in the dentate gyrus and impair contextual episodic memory in rats," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    11. Rebecca Sebastian & Kang Jin & Narciso Pavon & Ruby Bansal & Andrew Potter & Yoonjae Song & Juliana Babu & Rafael Gabriel & Yubing Sun & Bruce Aronow & ChangHui Pak, 2023. "Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    12. Karen Perez Arce & Adema Ribic & Dhrubajyoti Chowdhury & Katherine Watters & Garth J. Thompson & Basavaraju G. Sanganahalli & Elizabeth T. C. Lippard & Astrid Rohlmann & Stephen M. Strittmatter & Mark, 2023. "Concerted roles of LRRTM1 and SynCAM 1 in organizing prefrontal cortex synapses and cognitive functions," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    13. Leonardo Sportelli & Daniel P. Eisenberg & Roberta Passiatore & Enrico D’Ambrosio & Linda A. Antonucci & Jasmine S. Bettina & Qiang Chen & Aaron L. Goldman & Michael D. Gregory & Kira Griffiths & Thom, 2024. "Dopamine signaling enriched striatal gene set predicts striatal dopamine synthesis and physiological activity in vivo," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    14. Ji Min Lee & Henrik M. Hammarén & Mikhail M. Savitski & Sung Hee Baek, 2023. "Control of protein stability by post-translational modifications," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    15. Mohammad Soltani & Cesar A Vargas-Garcia & Duarte Antunes & Abhyudai Singh, 2016. "Intercellular Variability in Protein Levels from Stochastic Expression and Noisy Cell Cycle Processes," PLOS Computational Biology, Public Library of Science, vol. 12(8), pages 1-23, August.
    16. Dick Schijven & Sourena Soheili-Nezhad & Simon E. Fisher & Clyde Francks, 2024. "Exome-wide analysis implicates rare protein-altering variants in human handedness," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    17. Shahram Bahrami & Kaja Nordengen & Jaroslav Rokicki & Alexey A. Shadrin & Zillur Rahman & Olav B. Smeland & Piotr P. Jaholkowski & Nadine Parker & Pravesh Parekh & Kevin S. O’Connell & Torbjørn Elvsås, 2024. "The genetic landscape of basal ganglia and implications for common brain disorders," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    18. Jialiang S. Wang & Tushar Kamath & Courtney M. Mazur & Fatemeh Mirzamohammadi & Daniel Rotter & Hironori Hojo & Christian D. Castro & Nicha Tokavanich & Rushi Patel & Nicolas Govea & Tetsuya Enishi & , 2021. "Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    19. Jasjot Singh & Hadeer Elhabashy & Pathma Muthukottiappan & Markus Stepath & Martin Eisenacher & Oliver Kohlbacher & Volkmar Gieselmann & Dominic Winter, 2022. "Cross-linking of the endolysosomal system reveals potential flotillin structures and cargo," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    20. Yuping Chen & Jo-Hsi Huang & Connie Phong & James E. Ferrell, 2024. "Viscosity-dependent control of protein synthesis and degradation," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31436-8. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.