Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder

H. J. Williams, N. Norton, S. Dwyer, V. Moskvina, I. Nikolov, L. Carroll, L. Georgieva, N. M. Williams, D. W. Morris, E. M. Quinn, I. Giegling, M. Ikeda, J. Wood, T. Lencz, C. Hultman, P. Lichtenstein, D. Thiselton, B. S. Maher, A. K. Malhotra, B. RileyK. S. Kendler, M. Gill, P. Sullivan, P. Sklar, S. Purcell, V. L. Nimgaonkar, G. Kirov, P. Holmans, A. Corvin, D. Rujescu, N. Craddock, M. J. Owen, M. C. O'Donovan

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Abstract

A recent genome-wide association study (GWAS) reported evidence for association between rs1344706 within ZNF804A (encoding zinc-finger protein 804A) and schizophrenia (P1.61 × 10-7), and stronger evidence when the phenotype was broadened to include bipolar disorder (P9.96 × 10 -9). In this study we provide additional evidence for association through meta-analysis of a larger data set (schizophrenia/schizoaffective disorder N18 945, schizophrenia plus bipolar disorder N21 274 and controls N38 675). We also sought to better localize the association signal using a combination of de novo polymorphism discovery in exons, pooled de novo polymorphism discovery spanning the genomic sequence of the locus and high-density linkage disequilibrium (LD) mapping. The meta-analysis provided evidence for association between rs1344706 that surpasses widely accepted benchmarks of significance by several orders of magnitude for both schizophrenia (P2.5 × 10-11, odds ratio (OR) 1.10, 95% confidence interval 1.07-1.14) and schizophrenia and bipolar disorder combined (P4.1 × 10 -13, OR 1.11, 95% confidence interval 1.07-1.14). After de novo polymorphism discovery and detailed association analysis, rs1344706 remained the most strongly associated marker in the gene. The allelic association at the ZNF804A locus is now one of the most compelling in schizophrenia to date, and supports the accumulating data suggesting overlapping genetic risk between schizophrenia and bipolar disorder.

Original languageEnglish
Pages (from-to)429-441
Number of pages13
JournalMolecular Psychiatry
Volume16
Issue number4
DOIs
Publication statusPublished - 04-2011

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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    Williams, H. J., Norton, N., Dwyer, S., Moskvina, V., Nikolov, I., Carroll, L., Georgieva, L., Williams, N. M., Morris, D. W., Quinn, E. M., Giegling, I., Ikeda, M., Wood, J., Lencz, T., Hultman, C., Lichtenstein, P., Thiselton, D., Maher, B. S., Malhotra, A. K., ... O'Donovan, M. C. (2011). Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder. Molecular Psychiatry, 16(4), 429-441. https://doi.org/10.1038/mp.2010.36