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Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC

Molecular Psychiatry volume 18, pages 708–712 (2013)Cite this article

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A Corrigendum to this article was published on 05 March 2013

Abstract

The Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC) highlighted 81 single-nucleotide polymorphisms (SNPs) with moderate evidence for association to schizophrenia. After follow-up in independent samples, seven loci attained genome-wide significance (GWS), but multi-locus tests suggested some SNPs that did not do so represented true associations. We tested 78 of the 81 SNPs in 2640 individuals with a clinical diagnosis of schizophrenia attending a clozapine clinic (CLOZUK), 2504 cases with a research diagnosis of bipolar disorder, and 2878 controls. In CLOZUK, we obtained significant replication to the PGC-associated allele for no fewer than 37 (47%) of the SNPs, including many prior GWS major histocompatibility complex (MHC) SNPs as well as 3/6 non-MHC SNPs for which we had data that were reported as GWS by the PGC. After combining the new schizophrenia data with those of the PGC, variants at three loci (ITIH3/4, CACNA1C and SDCCAG8) that had not previously been GWS in schizophrenia attained that level of support. In bipolar disorder, we also obtained significant evidence for association for 21% of the alleles that had been associated with schizophrenia in the PGC. Our study independently confirms association to three loci previously reported to be GWS in schizophrenia, and identifies the first GWS evidence in schizophrenia for a further three loci. Given the number of independent replications and the power of our sample, we estimate 98% (confidence interval (CI) 78–100%) of the original set of 78 SNPs represent true associations. We also provide strong evidence for overlap in genetic risk between schizophrenia and bipolar disorder.

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Acknowledgements

We thank the participants in this study and Novartis for their guidance and co-operation in obtaining CLOZUK. We also thank staff at The Doctor's Laboratory, in particular Lisa Levett and Andrew Levett, for help and advice regarding sample acquisition. We acknowledge Kiran Mantripragada, Lesley Bates, Catherine Bresner and Lucinda Hopkins for laboratory sample management, and Dobril Ivanov for computing support. Sample collection and analysis was supported by the following grants: Medical Research Council (MRC) Centre (G0800509) and Program Grant (G0801418), the Wellcome Trust (WT; 078901), the European Community's Seventh Framework Programme (HEALTH-F2-2010-241909 (Project EU-GEI)), the Stanley Medical Research Institute via the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, and by CONTE NIMH (5P50MH066392-09). Genotyping was supported by the WT under WTCCC+ (Bipolar and controls) and WTCCC2. We thank the WTCCC2 project funded by WT (083948/Z/07/Z) for making available the control data. We acknowledge use of the British 1958 Birth Cohort DNA collection, funded by the MRC (G0000934) and the WT (068545/Z/0), the UK Blood Services collection of Common Controls (UKBS-CC collection), funded by the WT (076113/C/04/Z) and by NIHR programme grant to NHSBT (RP-PG-0310-1002).

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Authors and Affiliations

  1. MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Heath Park, Cardiff, UK

    M L Hamshere, J T R Walters, R Smith, A L Richards, E Green, D Grozeva, I Jones, L Forty, K Gordon-Smith, P Holmans, N Craddock, M J Owen & M C O'Donovan

  2. Department of Psychiatry, School of Clinical and Experimental Medicine, University of Birmingham, National Centre for Mental Health, Birmingham, UK

    L Jones & K Gordon-Smith

  3. Department of Psychiatry and Human Genetics, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

    B Riley & K S Kendler

  4. Department of Psychiatry, Queens University, Belfast, Ireland

    T O'Neill

  5. Stanley Centre for Psychiatric Research at the Broad Institute of MIT and Harvard, Cambridge, MA, USA

    P Sklar, S Purcell & J Kranz

  6. Mount Sinai School of Medicine, New York, NY, USA

    P Sklar, S Purcell & J Kranz

  7. Neuropsychiatric Genetics Research Group, Trinity College Dublin, Dublin, Ireland

    D Morris, M Gill & A Corvin

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  1. M L Hamshere
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  2. J T R Walters
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  3. R Smith
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  4. A L Richards
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  7. I Jones
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  8. L Forty
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  9. L Jones
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  10. K Gordon-Smith
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  11. B Riley
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  12. T O'Neill
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  13. K S Kendler
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  14. P Sklar
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  15. S Purcell
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  16. J Kranz
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  17. D Morris
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  18. M Gill
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  19. P Holmans
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  22. M J Owen
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Consortia

The Schizophrenia Psychiatric Genome-wide Association Study Consortium (PGC), Wellcome Trust Case Control Consortium+ (WTCCC+), Wellcome Trust Case Control Consortium 2 (WTCCC2)

Corresponding authors

Correspondence to M J Owen or M C O'Donovan.

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The authors declare no conflict of interest.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website

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Hamshere, M., Walters, J., Smith, R. et al. Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC. Mol Psychiatry 18, 708–712 (2013). https://doi.org/10.1038/mp.2012.67

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