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The emerging spectrum of allelic variation in schizophrenia: current evidence and strategies for the identification and functional characterization of common and rare variants

Molecular Psychiatry volume 18, pages 38–52 (2013)Cite this article

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Abstract

After decades of halting progress, recent large genome-wide association studies (GWAS) are finally shining light on the genetic architecture of schizophrenia. The picture emerging is one of sobering complexity, involving large numbers of risk alleles across the entire allelic spectrum. The aims of this article are to summarize the key genetic findings to date and to compare and contrast methods for identifying additional risk alleles, including GWAS, targeted genotyping and sequencing. A further aim is to consider the challenges and opportunities involved in determining the functional basis of genetic associations, for instance using functional genomics, cellular models, animal models and imaging genetics. We conclude that diverse approaches will be required to identify and functionally characterize the full spectrum of risk variants for schizophrenia. These efforts should adhere to the stringent standards of statistical association developed for GWAS and are likely to entail very large sample sizes. Nonetheless, now more than any previous time, there are reasons for optimism and the ultimate goal of personalized interventions and therapeutics, although still distant, no longer seems unattainable.

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Acknowledgements

This work was supported in part by Australian National Health and Medical Research Council Grants 631406, 631671 and by Queensland Health. We thank the anonymous referees for their helpful comments and Dee McGrath for help with the figures.

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  1. Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia

    B J Mowry & J Gratten

  2. Queensland Centre for Mental Health Research, Wacol, Brisbane, Queensland, Australia,

    B J Mowry

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Mowry, B., Gratten, J. The emerging spectrum of allelic variation in schizophrenia: current evidence and strategies for the identification and functional characterization of common and rare variants. Mol Psychiatry 18, 38–52 (2013). https://doi.org/10.1038/mp.2012.34

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