Genome-wide association studies suggest limited immune gene enrichment in schizophrenia compared to 5 autoimmune diseases

Pouget, Jennie G. and Gonçalves, Vanessa F. and Spain, Sarah L. and Finucane, Hilary K. and Raychaudhuri, Soumya and Kennedy, James L. and Knight, Jo (2016) Genome-wide association studies suggest limited immune gene enrichment in schizophrenia compared to 5 autoimmune diseases. Schizophrenia Bulletin, 42 (5). pp. 1176-1184. ISSN 0586-7614

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There has been intense debate over the immunological basis of schizophrenia, and the potential utility of adjunct immunotherapies. The major histocompatibility complex is consistently the most powerful region of association in genome-wide association studies (GWASs) of schizophrenia and has been interpreted as strong genetic evidence supporting the immune hypothesis. However, global pathway analyses provide inconsistent evidence of immune involvement in schizophrenia, and it remains unclear whether genetic data support an immune etiology per se. Here we empirically test the hypothesis that variation in immune genes contributes to schizophrenia. We show that there is no enrichment of immune loci outside of the MHC region in the largest genetic study of schizophrenia conducted to date, in contrast to 5 diseases of known immune origin. Among 108 regions of the genome previously associated with schizophrenia, we identify 6 immune candidates (DPP4, HSPD1, EGR1, CLU, ESAM, NFATC3) encoding proteins with alternative, nonimmune roles in the brain. While our findings do not refute evidence that has accumulated in support of the immune hypothesis, they suggest that genetically mediated alterations in immune function may not play a major role in schizophrenia susceptibility. Instead, there may be a role for pleiotropic effects of a small number of immune genes that also regulate brain development and plasticity. Whether immune alterations drive schizophrenia progression is an important question to be addressed by future research, especially in light of the growing interest in applying immunotherapies in schizophrenia.

Item Type:
Journal Article
Journal or Publication Title:
Schizophrenia Bulletin
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© The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (, which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact
Uncontrolled Keywords:
?? schizophreniageneticimmuneinflammationautoimmuneinflammatorypsychiatry and mental health ??
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Deposited On:
13 Jun 2016 09:04
Last Modified:
31 Dec 2023 00:42