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Cerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia

Author

Listed:
  • Jessica Gracias

    (Karolinska Institutet)

  • Funda Orhan

    (Karolinska Institutet)

  • Elin Hörbeck

    (University of Gothenburg
    Sahlgrenska University Hospital)

  • Jessica Holmén-Larsson

    (University of Gothenburg)

  • Neda Khanlarkani

    (Karolinska Institutet)

  • Susmita Malwade

    (Karolinska Institutet)

  • Sravan K. Goparaju

    (Karolinska Institutet)

  • Lilly Schwieler

    (Karolinska Institutet)

  • İlknur Ş. Demirel

    (Karolinska Institutet)

  • Ting Fu

    (Massachusetts General Hospital)

  • Helena Fatourus-Bergman

    (Karolinska Institutet
    Region Stockholm)

  • Aurimantas Pelanis

    (Sahlgrenska University Hospital)

  • Carleton P. Goold

    (Novartis Institutes of BioMedical Research)

  • Anneli Goulding

    (Sahlgrenska University Hospital
    University of Gothenburg)

  • Kristina Annerbrink

    (Sahlgrenska University Hospital)

  • Anniella Isgren

    (University of Gothenburg
    Sahlgrenska University Hospital)

  • Timea Sparding

    (University of Gothenburg)

  • Martin Schalling

    (Karolinska University Hospital)

  • Viviana A. Carcamo Yañez

    (NMI Natural and Medical Sciences Institute at the University of Tübingen)

  • Jens C. Göpfert

    (NMI Natural and Medical Sciences Institute at the University of Tübingen)

  • Johanna Nilsson

    (University of Gothenburg)

  • Ann Brinkmalm

    (University of Gothenburg)

  • Kaj Blennow

    (University of Gothenburg
    Sahlgrenska University Hospital)

  • Henrik Zetterberg

    (University of Gothenburg
    Sahlgrenska University Hospital
    UCL Institute of Neurology, Queen Square
    UK Dementia Research Institute at UCL)

  • Göran Engberg

    (Karolinska Institutet)

  • Fredrik Piehl

    (Karolinska Institutet)

  • Steven D. Sheridan

    (Massachusetts General Hospital)

  • Roy H. Perlis

    (Massachusetts General Hospital)

  • Simon Cervenka

    (Karolinska Institutet
    Region Stockholm
    Uppsala University)

  • Sophie Erhardt

    (Karolinska Institutet)

  • Mikael Landen

    (University of Gothenburg
    Karolinska Institutet)

  • Carl M. Sellgren

    (Karolinska Institutet
    Region Stockholm)

Abstract

Postsynaptic density is reduced in schizophrenia, and risk variants increasing complement component 4A (C4A) gene expression are linked to excessive synapse elimination. In two independent cohorts, we show that cerebrospinal fluid (CSF) C4A concentration is elevated in patients with first-episode psychosis (FEP) who develop schizophrenia (FEP-SCZ: median 0.41 fmol/ul [CI = 0.34–0.45], FEP-non-SCZ: median 0.29 fmol/ul [CI = 0.22–0.35], healthy controls: median 0.28 [CI = 0.24–0.33]). We show that the CSF elevation of C4A in FEP-SCZ exceeds what can be expected from genetic risk variance in the C4 locus, and in patient-derived cellular models we identify a mechanism dependent on the disease-associated cytokines interleukin (IL)−1beta and IL-6 to selectively increase neuronal C4A mRNA expression. In patient-derived CSF, we confirm that IL-1beta correlates with C4A controlled for genetically predicted C4A RNA expression (r = 0.39; CI: 0.01–0.68). These results suggest a role of C4A in early schizophrenia pathophysiology.

Suggested Citation

  • Jessica Gracias & Funda Orhan & Elin Hörbeck & Jessica Holmén-Larsson & Neda Khanlarkani & Susmita Malwade & Sravan K. Goparaju & Lilly Schwieler & İlknur Ş. Demirel & Ting Fu & Helena Fatourus-Bergma, 2022. "Cerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33797-6
    DOI: 10.1038/s41467-022-33797-6
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    References listed on IDEAS

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    1. 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.
    2. Fan Zuo & Priyadarshini Panda & Michele Kotiuga & Jiarui Li & Mingu Kang & Claudio Mazzoli & Hua Zhou & Andi Barbour & Stuart Wilkins & Badri Narayanan & Mathew Cherukara & Zhen Zhang & Subramanian K., 2017. "Habituation based synaptic plasticity and organismic learning in a quantum perovskite," Nature Communications, Nature, vol. 8(1), pages 1-7, December.
    3. 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.
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