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. Riley; K. 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

doi:10.1038/mp.2010.36

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

Research output: Contribution to journal › Article › peer-review

212 Scopus citations

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 language	English (US)
Pages (from-to)	429-441
Number of pages	13
Journal	Molecular psychiatry
Volume	16
Issue number	4
DOIs	https://doi.org/10.1038/mp.2010.36
State	Published - Apr 2011
Externally published	Yes

Keywords

ZNF804A
association
bipolar disorder
meta-analysis
schizophrenia

ASJC Scopus subject areas

Molecular Biology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

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10.1038/mp.2010.36

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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

Williams, HJ, Norton, N, Dwyer, S, Moskvina, V, Nikolov, I, Carroll, L, Georgieva, L, Williams, NM, Morris, DW, Quinn, EM, Giegling, I, Ikeda, M, Wood, J, Lencz, T, Hultman, C, Lichtenstein, P, Thiselton, D, Maher, BS, Malhotra, AK, Riley, B, Kendler, KS, Gill, M, Sullivan, P, Sklar, P, Purcell, S, Nimgaonkar, VL, Kirov, G, Holmans, P, Corvin, A, Rujescu, D, Craddock, N, Owen, MJ & O'Donovan, MC 2011, 'Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder', Molecular psychiatry, vol. 16, no. 4, pp. 429-441. https://doi.org/10.1038/mp.2010.36

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

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.",

keywords = "ZNF804A, association, bipolar disorder, meta-analysis, schizophrenia",

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

note = "Funding Information: We thank all the families who contributed to the sample collections we used. We also thank The MRC London Neurodegenerative Diseases Brain Bank, UK; The Stanley Medical Research Institute Brain Bank, USA; and The Karolinska Institute, Sweden, that supplied the post-mortem brain tissue. This study makes use of control data generated by the Wellcome Trust Case/Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. The UK research was supported by grants from the MRC, the Wellcome Trust and by a NIMH (USA) CONTE: 2 P50 MH066392-05A1.",

year = "2011",

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doi = "10.1038/mp.2010.36",

language = "English (US)",

volume = "16",

pages = "429--441",

journal = "Molecular psychiatry",

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T1 - Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder

AU - Williams, H. J.

AU - Norton, N.

AU - Dwyer, S.

AU - Moskvina, V.

AU - Nikolov, I.

AU - Carroll, L.

AU - Georgieva, L.

AU - Williams, N. M.

AU - Morris, D. W.

AU - Quinn, E. M.

AU - Giegling, I.

AU - Ikeda, M.

AU - Wood, J.

AU - Lencz, T.

AU - Hultman, C.

AU - Lichtenstein, P.

AU - Thiselton, D.

AU - Maher, B. S.

AU - Malhotra, A. K.

AU - Riley, B.

AU - Kendler, K. S.

AU - Gill, M.

AU - Sullivan, P.

AU - Sklar, P.

AU - Purcell, S.

AU - Nimgaonkar, V. L.

AU - Kirov, G.

AU - Holmans, P.

AU - Corvin, A.

AU - Rujescu, D.

AU - Craddock, N.

AU - Owen, M. J.

AU - O'Donovan, M. C.

N1 - Funding Information: We thank all the families who contributed to the sample collections we used. We also thank The MRC London Neurodegenerative Diseases Brain Bank, UK; The Stanley Medical Research Institute Brain Bank, USA; and The Karolinska Institute, Sweden, that supplied the post-mortem brain tissue. This study makes use of control data generated by the Wellcome Trust Case/Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. The UK research was supported by grants from the MRC, the Wellcome Trust and by a NIMH (USA) CONTE: 2 P50 MH066392-05A1.

PY - 2011/4

Y1 - 2011/4

N2 - 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.

AB - 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.

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KW - bipolar disorder

KW - meta-analysis

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

Abstract

Keywords

ASJC Scopus subject areas

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