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DISC1 association, heterogeneity and interplay in schizophrenia and bipolar disorder

Molecular Psychiatry volume 14, pages 865–873 (2009)Cite this article

Abstract

Disrupted in schizophrenia 1 (DISC1) has been associated with risk of schizophrenia, schizoaffective disorder, bipolar disorder, major depression, autism and Asperger syndrome, but apart from in the original translocation family, true causal variants have yet to be confirmed. Here we report a harmonized association study for DISC1 in European cohorts of schizophrenia and bipolar disorder. We identify regions of significant association, demonstrate allele frequency heterogeneity and provide preliminary evidence for modifying interplay between variants. Whereas no associations survived permutation analysis in the combined data set, significant corrected associations were observed for bipolar disorder at rs1538979 in the Finnish cohorts (uncorrected P=0.00020; corrected P=0.016; odds ratio=2.73±95% confidence interval (CI) 1.42–5.27) and at rs821577 in the London cohort (uncorrected P=0.00070; corrected P=0.040; odds ratio=1.64±95% CI 1.23–2.19). The rs821577 single nucleotide polymorphism (SNP) showed evidence for increased risk within the combined European cohorts (odds ratio=1.27±95% CI 1.07–1.51), even though significant corrected association was not detected (uncorrected P=0.0058; corrected P=0.28). After conditioning the European data set on the two risk alleles, reanalysis revealed a third significant SNP association (uncorrected P=0.00050; corrected P=0.025). This SNP showed evidence for interplay, either increasing or decreasing risk, dependent upon the presence or absence of rs1538979 or rs821577. These findings provide further support for the role of DISC1 in psychiatric illness and demonstrate the presence of locus heterogeneity, with the effect that clinically relevant genetic variants may go undetected by standard analysis of combined cohorts.

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Acknowledgements

We thank Dr Simon Cooper for his help in preparing the figures. This work was funded in part by the UK Medical Research Council and the Chief Scientist Office, Scotland (WH, PT, DB, WM, DP), Research into Ageing, the Chief Scientist Office, Scotland and the UK Biotechnology and Biological Sciences Research Council (IJD, SEH) and the Center of Excellence of the Academy of Finland and Biocentrum Helsinki Foundation (LP). The research at University College London was funded by UK Medical Research Council Grant number G0500791. The UK UCL sample was collected with generous help from the UK Manic Depression Fellowship. Professor Arpo Aromaa is acknowledged for his role with the Finnish control cohort. WH is a long-term EMBO Research Fellow and he was also supported by the Finnish Cultural Foundation Piippa Stiina Immonen grant. AL is supported by an Academy of Finland post-doctoral fellowship. IJD is the recipient of a Royal Society-Wolfson Research Merit Award.

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Authors and Affiliations

  1. Medical Genetics Section, University of Edinburgh, Edinburgh, Scotland

    W Hennah, P Thomson & D Porteous

  2. Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland

    W Hennah, A Loukola, T Paunio, E Pylkkö, P Soronen & L Peltonen

  3. Department of Mental Health Science, Molecular Psychiatry Laboratory, Windeyer Institute of Medical Sciences, University College London, London, England

    A McQuillin, N Bass, A Anjorin, J Lawrence, M Robinson, S Thirumalai & H Gurling

  4. Finnish Genome Center, University of Helsinki, Helsinki, Finland

    A Loukola & A Palotie

  5. Division of Psychiatry, University of Edinburgh, Edinburgh, Scotland

    D Blackwood & W Muir

  6. Queen Mary College, University of London, London, England

    D Curtis

  7. City Mental Health Trust, Royal London Hospital, London, England

    D Curtis

  8. Department of Psychology, University of Edinburgh, Edinburgh, Scotland

    I J Deary & S E Harris

  9. Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland

    E T Isometsä, J Lönnqvist, T Partonen & J Suvisaari

  10. Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland

    E T Isometsä, J Lönnqvist & T Paunio

  11. Department of Psychiatry, Jorvi Hospital, Helsinki University Central Hospital, Espoo, Finland

    K Suominen

  12. Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland

    D St Clair

  13. Department of Medical Genetics, University of Helsinki, Helsinki, Finland

    L Peltonen

  14. The Broad Institute, Massachusetts Institute of Technology, Boston, MA, USA

    L Peltonen

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  1. W Hennah
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Correspondence to W Hennah.

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Hennah, W., Thomson, P., McQuillin, A. et al. DISC1 association, heterogeneity and interplay in schizophrenia and bipolar disorder. Mol Psychiatry 14, 865–873 (2009). https://doi.org/10.1038/mp.2008.22

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