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GWAS for psychiatric disease: is the framework built on a solid foundation?

Molecular Psychiatry volume 14, pages 740–741 (2009)Cite this article

In setting out their framework for interpreting genome-wide association studies of psychiatric disorders,1 the Psychiatric GWAS Consortium Steering Committee considers all possible outcomes ranging from the most favorable (‘psychiatric’ equivalents to association between fat mass and obesity associated (FTO) variants and body mass index), through to the least, that the common disease/common variants (CDCV) hypothesis predicated by the GWAS-study design is flawed. This laudable and transparent synopsis of what may or may not emerge from costly GWAS mega-analyses raises conceptual and practical issues that bear comment.

The CDCV model of psychiatric disease is founded on the multifactorial threshold model of risk for disease2 and assumes that disease arises from the co-inheritance of multiple risk variants, each of small individual effect. To explain the population prevalence, such variants must themselves be common and should therefore be detectable by GWAS.3 This model assumes that liability is normally distributed in the population. To explain how a discontinuous trait such as a psychiatric diagnosis can emerge from such a distribution, a threshold of liability (of unspecified origin) is invoked, with those individuals above being at high and those below at low risk of the disease. This statistical sleight of hand allows the powerful statistics of normal distributions to be applied, but how strong is this conceptual foundation?

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Authors and Affiliations

  1. Smurfit Institute of Genetics, Trinity College, Dublin, Ireland

    K J Mitchell

  2. Medical Genetics Section, Institute of Genetics and Molecular Medicine, University of Edinburgh Molecular Medicine Centre, Edinburgh, UK

    D J Porteous

Authors
  1. K J Mitchell
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  2. D J Porteous
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Correspondence to K J Mitchell or D J Porteous.

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Mitchell, K., Porteous, D. GWAS for psychiatric disease: is the framework built on a solid foundation?. Mol Psychiatry 14, 740–741 (2009). https://doi.org/10.1038/mp.2009.17

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