Association between TCF4 and schizophrenia does not exert its effect by common nonsynonymous variation or by influencing cis-acting regulation of mRNA expression in adult human brain

Authors

  • Hywel J. Williams,

    1. MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
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  • Valentina Moskvina,

    1. MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
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  • Rhodri L. Smith,

    1. MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
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  • Sarah Dwyer,

    1. MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
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  • Giancarlo Russo,

    1. MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
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  • Michael J. Owen,

    1. MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
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  • Michael C. O'Donovan

    Corresponding author
    1. MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
    • MRC Centre for Neuropsychiatric Genetics and Genomics, Henry Wellcome Building, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
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  • How to Cite this Article: Williams HJ, Moskvina V, Smith RL, Dwyer S, Russo G, Owen MJ, O'Donovan MC. 2011. Association Between TCF4 and Schizophrenia Does Not Exert its Effect by Common Nonsynonymous Variation or by Influencing cis-Acting Regulation of mRNA Expression in Adult Human Brain. Am J Med Genet Part B 156:781–784.

Abstract

Large collaborative Genome-wide Association studies of schizophrenia have identified genes and genomic regions that are associated with the disorder at highly stringent levels of statistical significance. Among these, transcription factor 4 (TCF4) is one of the best supported although the associated SNP (rs9960767) is located within intron 3 and has no obvious function. Seeking the mechanism at TCF responsible for the association, we examined TCF4 for coding variants, and for cis regulated variation in TCF4 gene expression correlated with the associated SNP using an assay to detect differential allelic expression. Using data from the 1000 genomes project, we were unable to identify any nonsynonymous coding variants at the locus. Allele specific expression analysis using human post mortem brain samples revealed no evidence for cis-regulated mRNA expression related to genotype at the schizophrenia associated SNP. We conclude that association between schizophrenia and TCF4 is not mediated by a relatively common non-synonymous variant, or by a variant that alters mRNA expression as measured in adult human brain. It remains possible that the risk allele at this locus exerts effects on expression exclusively in a developmental context, in cell types or brain regions not adequately represented in our analysis, or through post-transcriptional effects, for example in the abundance of the protein or its sub-cellular distribution. © 2011 Wiley-Liss, Inc.

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