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The emerging molecular architecture of schizophrenia, polygenic risk scores and the clinical implications for GxE research


Schizophrenia is a devastating mental disorder. The level of risk in the general population is sustained by the persistence of social, environmental and biological factors, as well as their interactions. Socio-environmental risk factors for schizophrenia are well established and robust. The same can belatedly be said of genetic risk factors for the disorder. Recent progress in schizophrenia genetics is primarily fuelled by genome-wide association, which is able to leverage substantial proportions of additional explained variance previously classified as ‘missing’. Here, we provide an outline of the emerging genetic landscape of schizophrenia and demonstrate how this knowledge can be turned into a simple empirical measure of genetic risk, known as a polygenic risk score. We highlight the statistical framework used to assess the clinical potential of the new score and finally, draw relevance to and discuss the clinical implications for the study of gene–environment interaction.

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CI is funded by the National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and (Institute of Psychiatry) King’s College London. AB and DC are funded by the European Community Seventh Framework Programme Grant on European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI).

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The authors declare no conflict of interest.

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Correspondence to Conrad Iyegbe.

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Iyegbe, C., Campbell, D., Butler, A. et al. The emerging molecular architecture of schizophrenia, polygenic risk scores and the clinical implications for GxE research. Soc Psychiatry Psychiatr Epidemiol 49, 169–182 (2014). https://doi.org/10.1007/s00127-014-0823-2

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  • Polygenic risk score
  • Schizophrenia
  • Gene–environment interaction
  • Prediction
  • GWAS