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The complement system: a gateway to gene–environment interactions in schizophrenia pathogenesis

Molecular Psychiatry volume 22, pages 1554–1561 (2017)Cite this article

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Abstract

The pathogenesis of schizophrenia is considered to be multi-factorial, with likely gene–environment interactions (GEI). Genetic and environmental risk factors are being identified with increasing frequency, yet their very number vastly increases the scope of possible GEI, making it difficult to identify them with certainty. Accumulating evidence suggests a dysregulated complement pathway among the pathogenic processes of schizophrenia. The complement pathway mediates innate and acquired immunity, and its activation drives the removal of damaged cells, autoantigens and environmentally derived antigens. Abnormalities in complement functions occur in many infectious and autoimmune disorders that have been linked to schizophrenia. Many older reports indicate altered serum complement activity in schizophrenia, though the data are inconclusive. Compellingly, recent genome-wide association studies suggest repeat polymorphisms incorporating the complement 4A (C4A) and 4B (C4B) genes as risk factors for schizophrenia. The C4A/C4B genetic associations have re-ignited interest not only in inflammation-related models for schizophrenia pathogenesis, but also in neurodevelopmental theories, because rodent models indicate a role for complement proteins in synaptic pruning and neurodevelopment. Thus, the complement system could be used as one of the ‘staging posts’ for a variety of focused studies of schizophrenia pathogenesis. They include GEI studies of the C4A/C4B repeat polymorphisms in relation to inflammation-related or infectious processes, animal model studies and tests of hypotheses linked to autoimmune diseases that can co-segregate with schizophrenia. If they can be replicated, such studies would vastly improve our understanding of pathogenic processes in schizophrenia through GEI analyses and open new avenues for therapy.

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Acknowledgements

This study was funded by grants from the Stanley Medical Research Institute to RHY and grant 07R-1712 to VLN. Additional support was provided by the National Institute of Health (MH63480, MH93246 and D43 TW009114 to VLN; MH101566 to KMP; MH94268 to RHY). We thank Mr Joel Wood for help with illustrations.

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Authors and Affiliations

  1. Department of Psychiatry, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA,

    V L Nimgaonkar, K M Prasad & K V Chowdari

  2. Department of Human Genetics, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA, USA

    V L Nimgaonkar

  3. Stanley Division of Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    E G Severance & R H Yolken

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  1. V L Nimgaonkar
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Correspondence to V L Nimgaonkar.

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Nimgaonkar, V., Prasad, K., Chowdari, K. et al. The complement system: a gateway to gene–environment interactions in schizophrenia pathogenesis. Mol Psychiatry 22, 1554–1561 (2017). https://doi.org/10.1038/mp.2017.151

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  • DOI: https://doi.org/10.1038/mp.2017.151

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