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Response to Mitchell and Porteus

Molecular Psychiatry volume 15, pages 450–452 (2010)Cite this article

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We appreciate the opportunity to respond to the letter from Drs Mitchell and Porteus1 regarding our paper from the Psychiatric GWAS Consortium (PGC) describing a framework for interpreting genome-wide association studies (GWAS) for psychiatric disorders.2 The central assertion of the Mitchell and Porteus letter is that the causation of psychiatric disorders is mostly, perhaps entirely, under a multiple-rare variant model (MRV) as opposed to a common-disease/common-variant model (CDCV). Moreover, Mitchell and Porteus predict that any CDCV will explain only a very small fraction of the heritability of psychiatric disorders. Both points are inconsistent with the scientific evidence.

There have been multiple reports in high-profile journals in the past year describing the identification of previously unknown common genetic variants for autism, bipolar disorder and schizophrenia. Most of these findings have replicated in multiple samples with levels of significance that render false positives due to the play of chance unlikely (Table 1). Thus, the exclusivist MRV position advocated by Mitchell and Porteus is inconsistent with empirical data.

Table 1 Notable CDCV findings for three neuropsychiatric disorders
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Authors and Affiliations

  1. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

    P F Sullivan

  2. Department of Psychiatry, Northshore University Health System and Northwestern University, Evanston, IL, USA

    P V Gejman

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  1. P F Sullivan
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  2. P V Gejman
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Correspondence to P F Sullivan or P V Gejman.

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Sullivan, P., Gejman, P. Response to Mitchell and Porteus. Mol Psychiatry 15, 450–452 (2010). https://doi.org/10.1038/mp.2009.106

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