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Regional gene expression signatures are associated with sex-specific functional connectivity changes in depression

Author

Listed:
  • Aleksandr Talishinsky

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Jonathan Downar

    (University Health Network
    University of Toronto)

  • Petra E. Vértes

    (University of Cambridge)

  • Jakob Seidlitz

    (Children’s Hospital of Philadelphia
    University of Pennsylvania)

  • Katharine Dunlop

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Charles J. Lynch

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Heather Whalley

    (University of Edinburgh)

  • Andrew McIntosh

    (University of Edinburgh)

  • Fidel Vila-Rodriguez

    (University of British Columbia)

  • Zafiris J. Daskalakis

    (University of California)

  • Daniel M. Blumberger

    (University of Toronto
    Centre for Addiction and Mental Health)

  • Conor Liston

    (Weill Cornell Medicine
    Weill Cornell Medicine)

Abstract

The neural substrates of depression may differ in men and women, but the underlying mechanisms are incompletely understood. Here, we show that depression is associated with sex-specific patterns of abnormal functional connectivity in the default mode network and in five regions of interest with sexually dimorphic transcriptional effects. Regional differences in gene expression in two independent datasets explained the neuroanatomical distribution of abnormal connectivity. These gene sets varied by sex and were strongly enriched for genes implicated in depression, synapse function, immune signaling, and neurodevelopment. In an independent sample, we confirmed the prediction that individual differences in default mode network connectivity are explained by inferred brain expression levels for six depression-related genes, including PCDH8, a brain-specific protocadherin integral membrane protein implicated in activity-related synaptic reorganization. Together, our results delineate both shared and sex-specific changes in the organization of depression-related functional networks, with implications for biomarker development and fMRI-guided therapeutic neuromodulation.

Suggested Citation

  • Aleksandr Talishinsky & Jonathan Downar & Petra E. Vértes & Jakob Seidlitz & Katharine Dunlop & Charles J. Lynch & Heather Whalley & Andrew McIntosh & Fidel Vila-Rodriguez & Zafiris J. Daskalakis & Da, 2022. "Regional gene expression signatures are associated with sex-specific functional connectivity changes in depression," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32617-1
    DOI: 10.1038/s41467-022-32617-1
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    as
    1. Michael J. Hawrylycz & Ed S. Lein & Angela L. Guillozet-Bongaarts & Elaine H. Shen & Lydia Ng & Jeremy A. Miller & Louie N. van de Lagemaat & Kimberly A. Smith & Amanda Ebbert & Zackery L. Riley & Chr, 2012. "An anatomically comprehensive atlas of the adult human brain transcriptome," Nature, Nature, vol. 489(7416), pages 391-399, September.
    2. Jakob Seidlitz & Ajay Nadig & Siyuan Liu & Richard A. I. Bethlehem & Petra E. Vértes & Sarah E. Morgan & František Váša & Rafael Romero-Garcia & François M. Lalonde & Liv S. Clasen & Jonathan D. Blume, 2020. "Transcriptomic and cellular decoding of regional brain vulnerability to neurogenetic disorders," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    3. Daniel J Smith & Barbara I Nicholl & Breda Cullen & Daniel Martin & Zia Ul-Haq & Jonathan Evans & Jason M R Gill & Beverly Roberts & John Gallacher & Daniel Mackay & Matthew Hotopf & Ian Deary & Nick , 2013. "Prevalence and Characteristics of Probable Major Depression and Bipolar Disorder within UK Biobank: Cross-Sectional Study of 172,751 Participants," PLOS ONE, Public Library of Science, vol. 8(11), pages 1-7, November.
    4. David M. Howard & Mark J. Adams & Masoud Shirali & Toni-Kim Clarke & Riccardo E. Marioni & Gail Davies & Jonathan R. I. Coleman & Clara Alloza & Xueyi Shen & Miruna C. Barbu & Eleanor M. Wigmore & Jud, 2018. "Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    5. Cedric Huchuan Xia & Zongming Ma & Rastko Ciric & Shi Gu & Richard F. Betzel & Antonia N. Kaczkurkin & Monica E. Calkins & Philip A. Cook & Angel García de la Garza & Simon N. Vandekar & Zaixu Cui & T, 2018. "Linked dimensions of psychopathology and connectivity in functional brain networks," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    6. Jeremy A. Miller & Song-Lin Ding & Susan M. Sunkin & Kimberly A. Smith & Lydia Ng & Aaron Szafer & Amanda Ebbert & Zackery L. Riley & Joshua J. Royall & Kaylynn Aiona & James M. Arnold & Crissa Bennet, 2014. "Transcriptional landscape of the prenatal human brain," Nature, Nature, vol. 508(7495), pages 199-206, April.
    7. Clare Bycroft & Colin Freeman & Desislava Petkova & Gavin Band & Lloyd T. Elliott & Kevin Sharp & Allan Motyer & Damjan Vukcevic & Olivier Delaneau & Jared O’Connell & Adrian Cortes & Samantha Welsh &, 2018. "The UK Biobank resource with deep phenotyping and genomic data," Nature, Nature, vol. 562(7726), pages 203-209, October.
    8. Matthew F. Glasser & Timothy S. Coalson & Emma C. Robinson & Carl D. Hacker & John Harwell & Essa Yacoub & Kamil Ugurbil & Jesper Andersson & Christian F. Beckmann & Mark Jenkinson & Stephen M. Smith , 2016. "A multi-modal parcellation of human cerebral cortex," Nature, Nature, vol. 536(7615), pages 171-178, August.
    9. Nolan Kamitaki & Aswin Sekar & Robert E. Handsaker & Heather Rivera & Katherine Tooley & David L. Morris & Kimberly E. Taylor & Christopher W. Whelan & Philip Tombleson & Loes M. Olde Loohuis & Michae, 2020. "Complement genes contribute sex-biased vulnerability in diverse disorders," Nature, Nature, vol. 582(7813), pages 577-581, June.
    10. Aswin Sekar & Allison R. Bialas & Heather de Rivera & Avery Davis & Timothy R. Hammond & Nolan Kamitaki & Katherine Tooley & Jessy Presumey & Matthew Baum & Vanessa Van Doren & Giulio Genovese & Samue, 2016. "Schizophrenia risk from complex variation of complement component 4," Nature, Nature, vol. 530(7589), pages 177-183, February.
    11. David M. Howard & Mark J. Adams & Masoud Shirali & Toni-Kim Clarke & Riccardo E. Marioni & Gail Davies & Jonathan R. I. Coleman & Clara Alloza & Xueyi Shen & Miruna C. Barbu & Eleanor M. Wigmore & Jud, 2018. "Addendum: Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways," Nature Communications, Nature, vol. 9(1), pages 1-3, December.
    12. Jakob Seidlitz & Ajay Nadig & Siyuan Liu & Richard A. I. Bethlehem & Petra E. Vértes & Sarah E. Morgan & František Váša & Rafael Romero-Garcia & François M. Lalonde & Liv S. Clasen & Jonathan D. Blume, 2020. "Author Correction: Transcriptomic and cellular decoding of regional brain vulnerability to neurogenetic disorders," Nature Communications, Nature, vol. 11(1), pages 1-6, December.
    13. John D. Storey, 2002. "A direct approach to false discovery rates," Journal of the Royal Statistical Society Series B, Royal Statistical Society, vol. 64(3), pages 479-498, August.
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