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Strong genetic evidence for a selective influence of GABAA receptors on a component of the bipolar disorder phenotype

Molecular Psychiatry volume 15, pages 146–153 (2010)Cite this article

A Corrigendum to this article was published on 14 September 2010

Abstract

Despite compelling evidence for a major genetic contribution to risk of bipolar mood disorder, conclusive evidence implicating specific genes or pathophysiological systems has proved elusive. In part this is likely to be related to the unknown validity of current phenotype definitions and consequent aetiological heterogeneity of samples. In the recent Wellcome Trust Case Control Consortium genome-wide association analysis of bipolar disorder (1868 cases, 2938 controls) one of the most strongly associated polymorphisms lay within the gene encoding the GABAA receptor β1 subunit, GABRB1. Aiming to increase biological homogeneity, we sought the diagnostic subset that showed the strongest signal at this polymorphism and used this to test for independent evidence of association with other members of the GABAA receptor gene family. The index signal was significantly enriched in the 279 cases meeting Research Diagnostic Criteria for schizoaffective disorder, bipolar type (P=3.8 × 10−6). Independently, these cases showed strong evidence that variation in GABAA receptor genes influences risk for this phenotype (independent system-wide P=6.6 × 10−5) with association signals also at GABRA4, GABRB3, GABRA5 and GABRR1. Our findings have the potential to inform understanding of presentation, pathogenesis and nosology of bipolar disorders. Our method of phenotype refinement may be useful in studies of other complex psychiatric and non-psychiatric disorders.

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Acknowledgements

We are indebted to all individuals who have participated in our research. Funding for recruitment and phenotype assessment has been provided by the Wellcome Trust and the Medical Research Council. We are grateful to Dr Shaun Purcell for advice and support in the use of the PLINK analysis software. The genotype analyses were funded by the Wellcome Trust and undertaken within the context of the Wellcome Trust Case Control Consortium (WTCCC). The members of the WTCCC are listed in online supplementary information.

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Authors and Affiliations

  1. Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff, UK

    N Craddock, I R Jones, G Kirov, E K Green, D Grozeva, V Moskvina, I Nikolov, M L Hamshere, K Gordon-Smith, C Fraser, E Russell, N Norton, P A Holmans, M J Owen & M C O'Donovan

  2. Department of Psychiatry, Division of Neuroscience, Birmingham University, Birmingham, UK

    L Jones, S Caesar & K Gordon-Smith

  3. Biostatistics and Bioinformatics Unit, Henry Wellcome Building, School of Medicine, Cardiff University, Cardiff, UK

    V Moskvina, I Nikolov & P A Holmans

  4. Department of Statistics,

    M L Hamshere, D Vukcevic & P Donnelly

  5. , University of Oxford, Oxford, UK

    M L Hamshere, D Vukcevic & P Donnelly

  6. University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, UK

    G Breen & D St Clair

  7. SGDP, The Institute of Psychiatry, King's College London, De Crespigny Park Denmark Hill, London, UK

    G Breen, D A Collier, A Farmer & P McGuffin

  8. School of Neurology, Neurobiology and Psychiatry, Royal Victoria Infirmary, Newcastle upon Tyne, UK

    A H Young & I N Ferrier

  9. UBC Institute of Mental Health, Vancouver, BC, Canada

    A H Young

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  1. N Craddock
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  2. L Jones
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Wellcome Trust Case Control Consortium (WTCCC)

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Correspondence to N Craddock.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Craddock, N., Jones, L., Jones, I. et al. Strong genetic evidence for a selective influence of GABAA receptors on a component of the bipolar disorder phenotype. Mol Psychiatry 15, 146–153 (2010). https://doi.org/10.1038/mp.2008.66

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