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Testable Hypotheses Relating Complement Pathways to Elevated Risk for Schizophrenia

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Immuno-Psychiatry

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Abstract

Schizophrenia (SZ) is a common, potentially debilitating disorder. Over 70% of risk for SZ at the population level is attributable to genetic factors. Large-scale genome-wide association studies (GWAS) have revealed risk attributable to over 170 genomic loci, with varied effect sizes. Statistically, the most significant risk locus maps to the major histocompatibility complex (MHC) region on chromosome 6 (odds ratio ~1.28). One of the associated MHC loci involved the complement C4 gene. There is population-wide variation in C4 gene copy number, and SZ risk rises with the number of C4 genes that an individual’s genome encodes. C4 is a component of an immunologic defense mechanism that predates antibody-based adaptive immunity. In mammals, complement proteins also participate in neurodevelopment. Based on rodent model studies, it has been proposed that the C4-related risk for SZ could be explained by aberrant synaptic pruning—a developmental process also implicated in SZ risk. We review the synaptic pruning hypothesis and propose additional mechanisms to explain the C4-SZ link, including disruption in classical immunologic processes and changes in human endogenous retroviral sequences associated with C4. The evidence supporting these hypotheses is discussed, and empirical investigations are proposed.

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Authors and Affiliations

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

    Lora McClain, Matthew Demers, Wenxiao Zheng, Maribeth Wesesky, Joel Wood, Leonardo D’Aiuto, Konsale Prasad & Vishwajit Nimgaonkar

  2. Veterans Affairs, Pittsburgh Health System, Pittsburgh, PA, USA

    Lora McClain, Konsale Prasad & Vishwajit Nimgaonkar

  3. Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA

    Konsale Prasad

  4. Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA

    Vishwajit Nimgaonkar

  5. Department of Psychiatry, Western Psychiatric Hospital, Pittsburgh, PA, USA

    Vishwajit Nimgaonkar

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  1. Lora McClain
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Editors and Affiliations

  1. Deakin University, IMPACT - The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, VIC, Australia

    Michael Berk

  2. University Paris Est Créteil (UPEC), Inserm, IMRB (Translational NeuroPsychiatry lab), AP-HP, DMU IMPACT, AP-HP, Fondation FondaMental, Créteil, France

    Marion Leboyer

  3. UMC Groningen, Groningen, The Netherlands

    Iris E. Sommer

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McClain, L. et al. (2021). Testable Hypotheses Relating Complement Pathways to Elevated Risk for Schizophrenia. In: Berk, M., Leboyer, M., Sommer, I.E. (eds) Immuno-Psychiatry. Springer, Cham. https://doi.org/10.1007/978-3-030-71229-7_11

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