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Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder

Molecular Psychiatry volume 17, pages 880–886 (2012)Cite this article

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Abstract

Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable psychiatric disorders with overlapping susceptibility loci and symptomatology. We conducted a genome-wide association study (GWAS) of these disorders in a large Swedish sample. We report a new and independent case–control analysis of 1507 SCZ cases, 836 BD cases and 2093 controls. No single-nucleotide polymorphisms (SNPs) achieved significance in these new samples; however, combining new and previously reported SCZ samples (2111 SCZ and 2535 controls) revealed a genome-wide significant association in the major histocompatibility complex (MHC) region (rs886424, P=4.54 × 10−8). Imputation using multiple reference panels and meta-analysis with the Psychiatric Genomics Consortium SCZ results underscored the broad, significant association in the MHC region in the full SCZ sample. We evaluated the role of copy number variants (CNVs) in these subjects. As in prior reports, deletions were enriched in SCZ, but not BD cases compared with controls. Singleton deletions were more frequent in both case groups compared with controls (SCZ: P=0.003, BD: P=0.013), whereas the largest CNVs (>500 kb) were significantly enriched only in SCZ cases (P=0.0035). Two CNVs with previously reported SCZ associations were also overrepresented in this SCZ sample: 16p11.2 duplications (P=0.0035) and 22q11 deletions (P=0.03). These results reinforce prior reports of significant MHC and CNV associations in SCZ, but not BD.

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Acknowledgements

We are deeply grateful for the participation of all subjects contributing to this research, and to the collection team that worked to recruit them: Emma Flordal-Thelander, Ann-Britt Holmgren, Marie Hallin, Marie Lundin, Ann-Kristin Sundberg, Christina Pettersson, Radja Satgunanthan-Dawoud, Sonja Hassellund, Malin Rådstrom, Birgitta Ohlander, Leila Nyrén, Isabelle Kizling, Louise Frisén, Inger Röhmer, Catharina Lavebratt, Malin Kärn, Martina Wennberg and Agneta Carswärd-Kjellin. We would also like to thank Professor Martin Schalling for facilitating collection of many subjects with BD. Funding support was provided by the Stanley Center for Psychiatric Research, Broad Institute from a grant from Stanley Medical Research Institute, NIMH MH077139 (PFS), the Karolinska Institutet, Karolinska University Hospital, the Swedish Research Council, ALF grant from Swedish County Council and Söderström Königska Foundation.

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Author notes

  1. C M Hultman, S M Purcell, P Sklar and P F Sullivan: These authors contributed equally to this work.

Authors and Affiliations

  1. Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

    S E Bergen, C T O'Dushlaine, P H Lee, D M Ruderfer, S M Purcell & P Sklar

  2. Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA

    S E Bergen, C T O'Dushlaine, S Ripke, P H Lee, D M Ruderfer, J L Moran, K D Chambert, R E Handsaker, S McCarroll, E M Scolnick, S M Purcell & P Sklar

  3. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

    C T O'Dushlaine, S Ripke, P H Lee, D M Ruderfer & S M Purcell

  4. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    S Akterin, M Landen, P K E Magnusson, P Lichtenstein & C M Hultman

  5. Department of Genetics, Harvard Medical School, Boston, MA, USA

    R E Handsaker & S McCarroll

  6. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

    L Backlund & U Ösby

  7. Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

    M Landen

  8. Division of Psychiatric Genomics, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA

    S M Purcell & P Sklar

  9. Departments of Genetics, Psychiatry and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    P F Sullivan

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  1. S E Bergen
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  2. C T O'Dushlaine
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Correspondence to S E Bergen.

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Bergen, S., O'Dushlaine, C., Ripke, S. et al. Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder. Mol Psychiatry 17, 880–886 (2012). https://doi.org/10.1038/mp.2012.73

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