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An environmental analysis of genes associated with schizophrenia: hypoxia and vascular factors as interacting elements in the neurodevelopmental model

Molecular Psychiatry volume 17, pages 1194–1205 (2012)Cite this article

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Abstract

Investigating and understanding gene–environment interaction (G × E) in a neurodevelopmentally and biologically plausible manner is a major challenge for schizophrenia research. Hypoxia during neurodevelopment is one of several environmental factors related to the risk of schizophrenia, and links between schizophrenia candidate genes and hypoxia regulation or vascular expression have been proposed. Given the availability of a wealth of complex genetic information on schizophrenia in the literature without knowledge on the connections to environmental factors, we now systematically collected genes from candidate studies (using SzGene), genome-wide association studies (GWAS) and copy number variation (CNV) analyses, and then applied four criteria to test for a (theoretical) link to ischemia–hypoxia and/or vascular factors. In all, 55% of the schizophrenia candidate genes (n=42 genes) met the criteria for a link to ischemia–hypoxia and/or vascular factors. Genes associated with schizophrenia showed a significant, threefold enrichment among genes that were derived from microarray studies of the ischemia–hypoxia response (IHR) in the brain. Thus, the finding of a considerable match between genes associated with the risk of schizophrenia and IHR and/or vascular factors is reproducible. An additional survey of genes identified by GWAS and CNV analyses suggested novel genes that match the criteria. Findings for interactions between specific variants of genes proposed to be IHR and/or vascular factors with obstetric complications in patients with schizophrenia have been reported in the literature. Therefore, the extended gene set defined here may form a reasonable and evidence-based starting point for hypothesis-based testing of G × E interactions in clinical genetic and translational neuroscience studies.

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Acknowledgements

RS-K is supported by CES COM of FAU, FL, USA. Research of JvO and BPFR on schizophrenia is funded by the European Community's Seventh Framework Programme under Grant agreement no. HEALTH-F2-2009-241909 (Project EU-GEI). BPFR is the recipient of a Veni Award (NWO, Veni, 916.11.086).

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Authors and Affiliations

  1. Integrated Medical Science Department, CE Schmidt College of Medicine, Florida Atlantic University (FAU), Boca Raton, FL, USA

    R Schmidt-Kastner

  2. Department of Psychiatry and Psychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, European Graduate School of Neuroscience, South Limburg Mental Health Research and Teaching Network, Maastricht, The Netherlands

    J van Os, G Esquivel, H W M Steinbusch & B P F Rutten

  3. Department of Psychosis Studies, King's College London, King's Health Partners, Institute of Psychiatry, London, UK

    J van Os

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  1. R Schmidt-Kastner
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Correspondence to R Schmidt-Kastner.

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Schmidt-Kastner, R., van Os, J., Esquivel, G. et al. An environmental analysis of genes associated with schizophrenia: hypoxia and vascular factors as interacting elements in the neurodevelopmental model. Mol Psychiatry 17, 1194–1205 (2012). https://doi.org/10.1038/mp.2011.183

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