Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-33797-6
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Funding
- Swedish Research Council
- One Mind Foundation
- Marianne and Marcus Wallenberg Foundation
- Erling-Persson Family Foundation
- Swedish Brain Foundation
- Swedish Society for Medical Research
- Swedish Research Council [2017-00915]
- Alzheimer Drug Discovery Foundation (ADDF), USA [RDAPB-201809-2016615]
- Swedish Alzheimer Foundation [AF-742881]
- Hjarnfonden, Sweden [FO2017-0243]
- Swedish government
- ALF agreement [ALFGBG-715986]
- European Union Joint Program for Neurodegenerative Disorders [JPND2019-466-236]
- National Institute of Health (NIH), USA [1R01AG068398-01]
- Alzheimer's Association 2021 Zenith Award [ZEN-21848495]
- European Research Council
- Swedish Federal Government
- State Ministry of Baden-Wuerttemberg for Economic Affairs, Labour and Tourism
- Swedish Foundation for Strategic Research
- Swedish National Infrastructure for Biological Mass Spectrometry (BioMS)
- County Councils
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This study found elevated levels of C4A in individuals with schizophrenia and suggested a role of C4A in early schizophrenia pathophysiology.
Schizophrenia risk has been associated with the complement component 4 (C4) genes. Here the authors show that C4A is elevated in individuals with schizophrenia. 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.
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