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Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples

Molecular Psychiatry volume 15, pages 463–472 (2010)Cite this article

Abstract

Several studies have reported structural brain abnormalities, decreased myelination and oligodendrocyte dysfunction in schizophrenia. In the central nervous system, glia-derived de novo synthesized cholesterol is essential for both myelination and synaptogenesis. Previously, we demonstrated in glial cell lines that antipsychotic drugs induce the expression of genes involved in cholesterol and fatty acids biosynthesis through activation of the sterol regulatory element binding protein (SREBP) transcription factors, encoded by the sterol regulatory element binding transcription factor 1 (SREBF1) and sterol regulatory element binding transcription factor 2 (SREBF2) genes. Considering the importance of these factors in the lipid biosynthesis and their possible involvement in antipsychotic drug effects, we hypothesized that genetic variants of SREBF1 and/or SREBF2 could affect schizophrenia susceptibility. We therefore conducted a HapMap-based association study in a large German sample, and identified association between schizophrenia and five markers in SREBF1 and five markers in SREBF2. Follow-up studies in two independent samples of Danish and Norwegian origin (part of the Scandinavian collaboration of psychiatric etiology study, SCOPE) replicated the association for the five SREBF1 markers and for two markers in SREBF2. A combined analysis of all samples resulted in highly significant genotypic P-values of 9 × 10−4 for SREBF1 (rs11868035, odd ration (OR)=1.26, 95% confidence interval (CI) (1.09–1.45)) and 4 × 10−5 for SREBF2 (rs1057217, OR=1.39, 95% CI (1.19–1.63)). This finding strengthens the hypothesis that SREBP-controlled cholesterol biosynthesis is involved in the etiology of schizophrenia.

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Acknowledgements

This study is based on an initial microarray-based gene expression analysis on antipsychotic drug action, using the infrastructure provided by the Norwegian Microarray Consortium FUGE technology platform (www.microarray.no), funded by the FUGE program of the Research Council of Norway. The study was supported by grants from the Research Council of Norway (incl. FUGE grant nos. 151904 and 183327, and Psykisk Helse grant no. 175345), Helse Vest RHF and Dr Einar Martens Fund. MMN, SC received support for their work from the Alfried Krupp von Bohlen und Halbach-Stiftung. CV was supported through a Marie Curie grant as part of the Research Training Netweork ‘EUTwins’ to MMN, SC, IN, HS (EU, FP6). The Norwegian TOP study was supported by Research Council of Norway (grants nos. 167153/V50 and 163070/V50) and the Eastern Norway Health Authority. We are indebted to the patients for their participation in this study.

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Author notes

  1. S Le Hellard, T W Mühleisen, S Cichon and V M Steen: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Medicine, Bergen Mental Health Research Center, University of Bergen, Bergen, Norway

    S Le Hellard, J Fernø, M B Raeder & V M Steen

  2. Dr Einar Martens’ Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Helse Bergen HF, Bergen, Norway

    S Le Hellard, J Fernø, M B Raeder & V M Steen

  3. Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany

    T W Mühleisen, Z Ouriaghi, M Mattheisen, C Vasilescu, F F Brockschmidt, M M Nöthen & S Cichon

  4. Department of Medical Genetics, Ullevål University Hospital, Kirkeveien 166, Oslo, Norway

    S Djurovic

  5. The TOP Study Group, Institute of Psychiatry, University of Oslo, Oslo, Norway

    S Djurovic, I Melle & O A Andreassen

  6. Research Institute of Biological Psychiatry, Sct. Hans Hospital, Boserupvej 2, Roskilde, Denmark

    T Hansen & T Werge

  7. Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany

    J Strohmaier, A Georgi & M Rietschel

  8. Department of Psychiatry, Ullevål University Hospital, Kirkeveien 166, Oslo, Norway

    I Melle & O A Andreassen

  9. Department of Psychiatry and Psychotherapy, Friedrich-Schiller-University of Jena, Philosophenweg 3, Jena, Germany

    I Nenadic & H Sauer

  10. Insitute of Human Genetics, University of Bonn, Wilhelmstr 31, Bonn, Germany

    M M Nöthen & S Cichon

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  1. S Le Hellard
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  2. T W Mühleisen
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Correspondence to S Le Hellard.

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Le Hellard, S., Mühleisen, T., Djurovic, S. et al. Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples. Mol Psychiatry 15, 463–472 (2010). https://doi.org/10.1038/mp.2008.110

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