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Replication of association between schizophrenia and ZNF804A in the Irish Case–Control Study of Schizophrenia sample

Molecular Psychiatry volume 15, pages 29–37 (2010)Cite this article

Abstract

A recent genome-wide association study reported association between schizophrenia and the ZNF804A gene on chromosome 2q32.1. We attempted to replicate these findings in our Irish Case–Control Study of Schizophrenia (ICCSS) sample (N=1021 cases, 626 controls). Following consultation with the original investigators, we genotyped three of the most promising single-nucleotide polymorphisms (SNPs) from the Cardiff study. We replicate association with rs1344706 (trend test one-tailed P=0.0113 with the previously associated A allele) in ZNF804A. We detect no evidence of association with rs6490121 in NOS1 (one-tailed P=0.21), and only a trend with rs9922369 in RGRIP1L (one-tailed P=0.0515). On the basis of these results, we completed genotyping of 11 additional linkage disequilibrium-tagging SNPs in ZNF804A. Of 12 SNPs genotyped, 11 pass quality control criteria and 4 are nominally associated, with our most significant evidence of association at rs7597593 (P=0.0013) followed by rs1344706. We observe no evidence of differential association in ZNF804A on the basis of family history or sex of case. The associated SNP rs1344706 lies in ∼30 bp of conserved mammalian sequence, and the associated A allele is predicted to maintain binding sites for the brain-expressed transcription factors MYT1l and POU3F1/OCT-6. In controls, expression is significantly increased from the A allele of rs1344706 compared with the C allele. Expression is increased in schizophrenic cases compared with controls, but this difference does not achieve statistical significance. This study replicates the original reported association of ZNF804A with schizophrenia and suggests that there is a consistent link between the A allele of rs1344706, increased expression of ZNF804A and risk for schizophrenia.

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Acknowledgements

This work was supported by the National Institute of Mental Health Grant R01-MH41953 to KSK/BR. AF was supported by a Department of Veterans Affairs Merit Review award. We thank X Chen for genotyping macros and sex determination data and the Northern Ireland Blood Transfusion Services for their invaluable assistance in control sampling.

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Authors and Affiliations

  1. Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA

    B Riley, D Thiselton, B S Maher, B Wormley, G O McMichael, A H Fanous, V Vladimirov & K S Kendler

  2. Department of Human Genetics, Virginia Commonwealth University, Richmond, VA, USA

    B Riley, B S Maher, T Bigdeli, A H Fanous & K S Kendler

  3. Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

    B Riley, D Thiselton, B S Maher, T Bigdeli, B Wormley, G O McMichael, V Vladimirov & K S Kendler

  4. Department of Psychiatry, Georgetown University School of Medicine, Washington, DC, USA

    A H Fanous

  5. Mental Health Service Line, Washington VA Medical Center, Washington, DC, USA

    A H Fanous

  6. Department of Psychiatry, Queens University, Belfast, UK

    F A O'Neill

  7. The Health Research Board, Dublin, Ireland

    D Walsh

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  1. B Riley
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Riley, B., Thiselton, D., Maher, B. et al. Replication of association between schizophrenia and ZNF804A in the Irish Case–Control Study of Schizophrenia sample. Mol Psychiatry 15, 29–37 (2010). https://doi.org/10.1038/mp.2009.109

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