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

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-Bergman, Aurimantas Pelanis, Carleton P. Goold, Anneli Goulding, Kristina Annerbrink, Anniella Isgren, Timea Sparding, Martin Schalling, Viviana A. Carcamo Yañez, Jens C. Göpfert, Johanna Nilsson, Ann Brinkmalm, Kaj Blennow, Henrik Zetterberg, Göran Engberg, Fredrik Piehl, Steven D. Sheridan, Roy H. Perlis, Simon Cervenka, Sophie Erhardt, Mikael Landen and Carl M. Sellgren ()
Additional contact information
Jessica Gracias: Karolinska Institutet
Funda Orhan: Karolinska Institutet
Elin Hörbeck: University of Gothenburg
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
Aurimantas Pelanis: Sahlgrenska University Hospital
Carleton P. Goold: Novartis Institutes of BioMedical Research
Anneli Goulding: Sahlgrenska University Hospital
Kristina Annerbrink: Sahlgrenska University Hospital
Anniella Isgren: University of Gothenburg
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
Henrik Zetterberg: University of Gothenburg
Göran Engberg: Karolinska Institutet
Fredrik Piehl: Karolinska Institutet
Steven D. Sheridan: Massachusetts General Hospital
Roy H. Perlis: Massachusetts General Hospital
Simon Cervenka: Karolinska Institutet
Sophie Erhardt: Karolinska Institutet
Mikael Landen: University of Gothenburg
Carl M. Sellgren: Karolinska Institutet

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33797-6

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