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Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia

Molecular Psychiatry volume 19, pages 1017–1024 (2014)Cite this article

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Abstract

Bipolar disorder and schizophrenia are two often severe disorders with high heritabilities. Recent studies have demonstrated a large overlap of genetic risk loci between these disorders but diagnostic and molecular distinctions still remain. Here, we perform a combined genome-wide association study (GWAS) of 19 779 bipolar disorder (BP) and schizophrenia (SCZ) cases versus 19 423 controls, in addition to a direct comparison GWAS of 7129 SCZ cases versus 9252 BP cases. In our case–control analysis, we identify five previously identified regions reaching genome-wide significance (CACNA1C, IFI44L, MHC, TRANK1 and MAD1L1) and a novel locus near PIK3C2A. We create a polygenic risk score that is significantly different between BP and SCZ and show a significant correlation between a BP polygenic risk score and the clinical dimension of mania in SCZ patients. Our results indicate that first, combining diseases with similar genetic risk profiles improves power to detect shared risk loci and second, that future direct comparisons of BP and SCZ are likely to identify loci with significant differential effects. Identifying these loci should aid in the fundamental understanding of how these diseases differ biologically. These findings also indicate that combining clinical symptom dimensions and polygenic signatures could provide additional information that may someday be used clinically.

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Author information

Author notes

  1. D M Ruderfer, A H Fanous and S Ripke: These authors contributed equally to this work.

  2. , and: Individual members are listed in the Supplementary Appendix.

  3. P Sklar and K S Kendler: These authors contributed equally to this work.

Authors and Affiliations

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

    D M Ruderfer & P Sklar

  2. Washington DC VA Medical Center, Washington, DC, USA

    A H Fanous & R L Amdur

  3. Department of Psychiatry, Georgetown University School of Medicine, Washington, DC, USA

    A H Fanous

  4. Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

    A H Fanous & K S Kendler

  5. Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, USA, MA

    S Ripke

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

    S Ripke

  7. Molecular Psychiatry Laboratory, Mental Health Sciences Unit, University College London, London, England, UK

    A McQuillin

  8. Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem and University of Chicago, Evanston, IL, USA

    P V Gejman

  9. Department of Psychological Medicine and Neurology, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, Wales, UK

    M C O'Donovan, N Craddock & P Holmans

  10. Division of Mental Health and Addiction, NORMENT, KG Jebsen Centre for Psychosis Research, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    O A Andreassen & S Djurovic

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

    C M Hultman & M Landén

  12. Department of Psychiatry, University of California, San Diego, CA, USA

    J R Kelsoe

  13. Department of Psychiatry, Special Treatment and Evaluation Program (STEP), Veterans Affairs San Diego Healthcare System, San Diego, CA, USA

    J R Kelsoe

  14. Département de Psychiatrie, INSERM, U955,

    S Jamain & M Leboyer

  15. Université Paris Est, Faculté de Médecine, Assistance Publique–Hôpitaux de Paris (AP-HP), Creéteil, France

    S Jamain & M Leboyer

  16. Département de Psychiatrie, Hôpital H. Mondor–A. Chenevier, ENBREC group, Fondation Fondamental,

    S Jamain & M Leboyer

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

    M Landén

  18. Department of Psychiatry, WPIC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    V Nimgaonkar

  19. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    J Nurnberger

  20. Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Stanley Center for Psychiatric Research, Broad Institute, Boston, MA, USA

    J W Smoller

  21. Department of Psychiatry and Institute of Molecular Medicine, Neuropsychiatric Genetics Research Group, Trinity College Dublin, Dublin, Ireland

    A Corvin

  22. Department of Genetics, University of North Carolina at Chapel Hill, Raleigh, NC, USA

    P F Sullivan

  23. Biostatistics and Bioinformatics Unit, Cardiff University School of Medicine, Cardiff, UK

    P Holmans

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

    K S Kendler

Authors
  1. D M Ruderfer
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  2. A H Fanous
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  3. S Ripke
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  7. M C O'Donovan
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  8. O A Andreassen
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  9. S Djurovic
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  10. C M Hultman
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  11. J R Kelsoe
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  15. V Nimgaonkar
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  16. J Nurnberger
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  20. P F Sullivan
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  21. P Holmans
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  22. P Sklar
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  23. K S Kendler
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Consortia

Schizophrenia Working Group of the Psychiatric Genomics Consortium

Bipolar Disorder Working Group of the Psychiatric Genomics Consortium

Cross-Disorder Working Group of the Psychiatric Genomics Consortium

Corresponding authors

Correspondence to P Sklar or K S Kendler.

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The authors declare no conflict of interest.

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Ruderfer, D., Fanous, A., Ripke, S. et al. Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia. Mol Psychiatry 19, 1017–1024 (2014). https://doi.org/10.1038/mp.2013.138

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  • DOI: https://doi.org/10.1038/mp.2013.138

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