Abstract
A recent genome-wide association study (GWAS) reported evidence for association between rs1344706 within ZNF804A (encoding zinc-finger protein 804A) and schizophrenia (P=1.61 × 10−7), and stronger evidence when the phenotype was broadened to include bipolar disorder (P=9.96 × 10−9). In this study we provide additional evidence for association through meta-analysis of a larger data set (schizophrenia/schizoaffective disorder N=18 945, schizophrenia plus bipolar disorder N=21 274 and controls N=38 675). 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 (P=2.5 × 10−11, odds ratio (OR) 1.10, 95% confidence interval 1.07–1.14) and schizophrenia and bipolar disorder combined (P=4.1 × 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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Cardno AG, Gottesman II II . Twin studies of schizophrenia: from bow-and arrow concordances to star wars Mx and functional genomics (review). Am J Med Genet 2000; 97: 12–17.
Sullivan PF, Kendler KS, Neale MC . Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 2003; 60: 1187–1192.
Williams HJ, Owen MJ, O’Donovan MC . Schizophrenia genetics: new insights from new approaches. Br Med Bull 2009; 91: 61–74.
O’Donovan MC, Craddock N, Norton N, Williams H, Peirce T, Moskvina V et al. Identification of novel schizophrenia loci by genome-wide association and follow-up. Nat Genet 2008; 40: 1053–1055.
The International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009; 460: 748–752.
Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D et al. Common variants conferring risk of schizophrenia. Nature 2009; 460: 744–747.
Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe’er I et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 2009; 460: 753–757.
Dudbridge F, Gusnanto A . Estimation of significance thresholds for genomewide association scans. Genet Epidemiol 2008; 32: 227–234.
Craddock N, O’Donovan MC, Owen MJ . Psychosis genetics: modeling the relationship between schizophrenia, bipolar disorder, and mixed (or ‘schizoaffective’) psychoses. Schizophr Bull 2009; 35: 482–490.
Riley B, Thiselton D, Maher BS, Bigdeli T, Wormley B, McMichael GO et al. Replication of association between schizophrenia and ZNF804A in the Irish case–control study of schizophrenia sample. Mol Psychiatry 2010; 15: 29–37.
Steinberg S, Mors O, Gustafsson O, Werge T, Mortensen PB, Andreassen OA et al. Expanding the range of ZNF804A variants conferring risk of psychosis. Mol Psychiatry 2010. e-pub ahead of print 5 January 2010; doi:10.1038/mp.2009.149.
O’Donovan MC, Craddock NJ, Owen MJ . Genetics of psychosis; insights from views across the genome. Hum Genet 2009; 126: 3–12.
Stranger BE, Nica AC, Forrest MS, Dimas A, Bird CP, Beazley C et al. Population genomics of human gene expression. Nat Genet 2007; 39: 1217–1224.
Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.
WTCCC. Genome-wide association study of 14 000 cases of seven common diseases and 3000 shared controls. Nature 2007; 447: 661–678.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.
Browning BL, Browning SR . A unified approach to genotype imputation and haplotype phase inference for large data sets of trios and unrelated individuals. Am J Hum Genet 2009; 84: 210–223.
Li H, Ruan J, Durbin R . Mapping short DNA sequencing reads and calling variants using mapping quality scores. Genome Res 2008; 18: 1851–1858.
Bray NJ, Preece A, Williams NM, Moskvina V, Buckland P, Owen MJ et al. Haplotypes at the dystrobrevin binding protein 1 (DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1 expression. Hum Mol Genet 2005; 14: 1947–1954.
Lencz T, Morgan TV, Athanasiou M, Dain B, Reed CR, Kane JM et al. Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia. Mol Psychiatry 2007; 12: 572–580.
The International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 2008; 455: 237–241.
Talkowski ME, Kirov G, Bamne M, Georgieva L, Torres G, Mansour H et al. A network of dopaminergic gene variations implicated as risk factors for schizophrenia. Hum Mol Genet 2008; 17: 747–758.
Need AC, Ge D, Weale ME, Maia J, Feng S, Heinzen EL et al. A genome-wide investigation of SNPs and CNVs in schizophrenia. PLoS Genet 2009; 5: e1000373.
Sullivan PF, Lin D, Tzeng JY, van den Oord E, Perkins D, Stroup TS et al. Genomewide association for schizophrenia in the CATIE study: results of stage 1. Mol Psychiatry 2008; 13: 570–584.
Moskvina V, O’Donovan MC . Detailed analysis of the relative power of direct and indirect association studies and the implications for their interpretation. Hum Hered 2007; 64: 63–73.
Dimas AS, Deutsch S, Stranger BE, Montgomery SB, Borel C, Attar-Cohen H et al. Common regulatory variation impacts gene expression in a cell type-dependent manner. Science 2009; 325: 1246–1250.
Ferreira MA, O’Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 2008; 40: 1056–1058.
Green EK, Grozeva D, Jones I, Jones L, Kirov G, Caesar S et al. The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia. Mol Psychiatry 2009. e-pub ahead of print 21 July 2009; doi:10.1038/mp.2009.49.
Gamsjaeger R, Liew CK, Loughlin FE, Crossley M, Mackay JP . Sticky fingers: zinc-fingers as protein-recognition motifs. Trends Biochem Sci 2007; 32: 63–70.
Esslinger C, Walter H, Kirsch P, Erk S, Schnell K, Arnold C et al. Neural mechanisms of a genome-wide supported psychosis variant. Science 2009; 324: 605.
Walters JTR, Corvin A, Owen MJ, Williams H, Dragovic M, Quinn EM et al. The psychosis susceptibility gene ZNF804A is associated with less impaired cognitive performance in schizophrenia. Arch Gen Psychiatry (in press).
Acknowledgements
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.
Author information
Authors and Affiliations
Consortia
Corresponding authors
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Molecular Psychiatry website
Supplementary information
Appendix
Appendix
The following authors are included under:
Molecular Genetics of Schizophrenia Collaboration
PV Gejman (Evanston Northwestern Healthcare and Northwestern University, IL, USA), AR Sanders (Evanston Northwestern Healthcare and Northwestern University, IL, USA), J Duan (Evanston Northwestern Healthcare and Northwestern University, IL, USA), DF Levinson (Stanford University, CA, USA), NG Buccola (Louisiana State University Health Sciences Center, LA, USA), BJ Mowry (Queensland Centre for Mental Health Research, and Queensland Institute for Medical Research, Queensland, Australia), R Freedman (University of Colorado Denver, Colorado, USA), F Amin (Atlanta Veterans Affairs Medical Center and Emory University, Atlanta, USA), DW Black (University of Iowa Carver College of Medicine, IA, USA), JM Silverman (Mount Sinai School of Medicine, New York, USA), WJ Byerley (University of California at San Francisco, California, USA), CR Cloninger (Washington University, Missouri, USA).
SGENE-plus
H Stefansson (deCODE genetics, Reykjavik, Iceland), S Steinberg (deCODE genetics, Reykjavik, Iceland), E Strengman (Universiteitsweg, Utrecht, The Netherlands), T Hansen (Copenhagen University Hospital, Roskilde, Denmark), HB Rasmussen(Copenhagen University Hospital, Roskilde, Denmark), O Gustafsson (University of Oslo, Oslo, Norway), S Djurovic (University of Oslo, Oslo, Norway), I Giegling (Ludwig-Maximilians-University, Munich, Germany), M Nyegaard (Aarhus University, Arhus C, Denmark), OP Pietiläinen (Institute of Molecular Medicine, Helsinki, Finland and Wellcome Trust Sanger Institute, Cambridge UK), A Tuulio-Henriksson (National Public Health Institute, Helsinki, Finland), E Sigurdsson (National University Hospital, Reykjavik, Iceland), H Petursson (National University Hospital, Reykjavik, Iceland), B Glenthøj (Copenhagen University Hospital, Glostrup, Denmark), G Jürgens (Bispebjerg University Hospital, Copenhagen, Denmark), I Melle (University of Oslo, Oslo, Norway), M Rietschel (University of Heidelberg, Mannheim, Germany), AD Børglum (Aarhus University Hospital, Risskov, Denmark), A Ingason (deCODE genetics, Reykjavik, Iceland), U Thorsteinsdottir (deCODE genetics, Reykjavik, Iceland), A Kong (deCODE genetics, Reykjavik, Iceland), P Muglia (GlaxoSmithKline R&D, Verona, Italy), LA Kiemeney (Radboud University, Nijmegen, The Netherlands), B Franke (Radbound University, Nijmegen, The Netherlands), M Ruggeri (University of Verona, Verona, Italy), S Tosato (University of Verona, Verona, Italy), TE Thorgeirsson (deCODE genetics, Reykjavik, Iceland), O Mors (Aarhus University Hospital, Risskov, Denmark), PB Mortensen (Aarhus University, Aarhus, Denmark), I Bitter (Semmelweis University, Budapest, Hungary), EG Jönsson (Karolinska Institutet and Hospital, Stockholm, Sweden), S Cichon (University of Bonn, Bonn, Germany), MM Nöthen (University of Bonn, Bonn, Germany), OA Andreassen (University of Oslo, Oslo, Norway), V Golimbet (Russian Academy of Medical Sciences, Moscow, Russia), T Li (Institute of Psychiatry, London, UK), T Werge (Copenhagen University Hospital, Roskilde, Denmark), RA Ophoff (UCLA, Los Angeles, USA and University Medical Center Utrecht, Utrecht, The Netherlands), D St Clair (University of Aberdeen, Aberdeen, UK), DA Collier (Institute of Psychiatry, London, UK), L Peltonen (Institute of Molecular Medicine, Helsinki, Finland and Wellcome Trust Sanger Institute, Cambridge, UK), D Rujescu (Ludwig-Maximilians-University, Munich, Germany) and K Stefansson (deCODE genetics, Reykjavik, Iceland).
Genetic Risk and Outcome in Psychosis (GROUP)
RS Kahn (Rudolf Magnus Institute of Neuroscience, Utrecht, The Netherlands), DH Linszen (Academic Medical Centre University of Amsterdam, Amsterdam, The Netherlands), J van Os (Maastricht University Medical Centre, Maastricht, The Netherlands), D Wiersma (University of Groningen, Groningen, The Netherlands), R Bruggeman (University of Groningen, Groningen, The Netherlands), W Cahn (Rudolf Magnus Institute of Neuroscience, Utrecht, The Netherlands), L de Haan (Academic Medical Centre University of Amsterdam, Amsterdam, The Netherlands), L Krabbendam (Maastricht University Medical Centre, Maastricht, The Netherlands) and Inez Myin-Germeys (Maastricht University Medical Centre, Maastricht, The Netherlands).
International Schizophrenia Consortium (ISC)
Michael C O’Donovan (Cardiff University, Cardiff, UK), George K Kirov (Cardiff University, Cardiff, UK), Nick J Craddock (Cardiff University, Cardiff, UK), Peter A Holmans (Cardiff University, Cardiff, UK), Nigel M Williams (Cardiff University, Cardiff, UK), Lyudmila Georgieva (Cardiff University, Cardiff, UK), Ivan Nikolov (Cardiff University, Cardiff, UK), N Norton (Cardiff University, Cardiff, UK), H Williams (Cardiff University, Cardiff, UK), Draga Toncheva (University Hospital Maichin Dom, Sofia, Bulgaria), Vihra Milanova (Alexander University Hospital, Sofia, Bulgaria), Michael J Owen (Cardiff University, Cardiff, UK), Christina M Hultman (Karolinska Institutet, Stockholm, Sweden and Uppsala University, Uppsala, Sweden), Paul Lichtenstein (Karolinska Institutet, Stockholm, Sweden), Patrick Sullivan (University of North Carolina at Chapel Hill, NC, USA), Derek W Morris (Trinity College Dublin, Dublin, Ireland), Colm T O’Dushlaine (Trinity College Dublin, Dublin, Ireland), Elaine Kenny (Trinity College Dublin, Dublin, Ireland), Emma M Quinn (Trinity College Dublin, Dublin, Ireland), Michael Gill (Trinity College Dublin, Dublin, Ireland), Aiden Corvin (Trinity College Dublin, Dublin, Ireland), Andrew McQuillin (University College London, London, UK), Khalid Choudhury (University College London, London, UK), Susmita Datta (University College London, London, UK), Jonathan Pimm (University College London, London, UK), Srinivasa Thirumalai (West Berkshire NHS Trust, Reading, UK), Vinay Puri (University College London, London, UK), Robert Krasucki (University College London, London, UK), Jacob Lawrence (University College London, London, UK), Digby Quested (University of Oxford, Oxford, UK), Nicholas Bass (University College London, London, UK), Hugh Gurling (University College London, London, UK), Caroline Crombie (University of Aberdeen, Aberdeen, UK), Gillian Fraser (University of Aberdeen, Aberdeen, UK), Soh Leh Kuan (University of Aberdeen, Aberdeen, UK), Nicholas Walker (Ravenscraig Hospital, Greenock, UK), David St Clair (University of Aberdeen, Aberdeen, UK), Douglas HR Blackwood (University of Edinburgh, Edinburgh, UK), Walter J Muir (University of Edinburgh, Edinburgh, UK), Kevin A McGhee (University of Edinburgh, Edinburgh, UK), Ben Pickard (University of Edinburgh, Edinburgh, UK), Pat Malloy (University of Edinburgh, Edinburgh, UK), Alan W Maclean (University of Edinburgh, Edinburgh, UK), Margaret Van Beck (University of Edinburgh, Edinburgh, UK), Naomi R Wray (Queensland Institute of Medical Research, Queensland, Australia), Stuart Macgregor (Queensland Institute of Medical Research, Queensland, Australia), Peter M. Visscher (Queensland Institute of Medical Research, Queensland, Australia), Michele T Pato (University of Southern California, California, USA), Helena Medeiros (University of Southern California, California, USA), Frank Middleton (Upstate Medical University, New York, USA), Celia Carvalho (University of Southern California, California, USA), Christopher Morley (Upstate Medical University, New York, USA), Ayman Fanous (University of Southern California, California, USA and Washington VA Medical Center, Washington, USA and Georgetown University School of Medicine, Washington DC, USA and Virginia Commonwealth University, Virginia, USA), David Conti (University of Southern California, California, USA), James A. Knowles (University of Southern California, California, USA), Carlos Paz Ferreira (Department of Psychiatry, Azores, Portugal), Antonio Macedo (University of Coimbra, Coimbra, Portugal), M Helena Azevedo (University of Coimbra, Coimbra, Portugal), Carlos N Pato (University of Southern California, California, USA); Massachusetts General Hospital Jennifer L Stone (Massachusetts General Hospital, Massachusetts, USA and The Broad Institute of Harvard and MIT, Massachusetts, USA), Douglas M Ruderfer (Massachusetts General Hospital, Massachusetts, USA and The Broad Institute of Harvard and MIT, Massachusetts, USA), Andrew N Kirby (Massachusetts General Hospital, Massachusetts, USA and The Broad Institute of Harvard and MIT, Massachusetts, USA), Manuel AR Ferreira (Massachusetts General Hospital, Massachusetts, USA and The Broad Institute of Harvard and MIT, Massachusetts, USA), Mark J Daly (Massachusetts General Hospital, Massachusetts, USA and The Broad Institute of Harvard and MIT, Massachusetts, USA), Shaun M Purcell (Massachusetts General Hospital, Massachusetts, USA and The Broad Institute of Harvard and MIT, Massachusetts, USA), Jennifer L Stone (Massachusetts General Hospital, Massachusetts, USA and The Broad Institute of Harvard and MIT, Massachusetts, USA), Kimberly Chambert (The Broad Institute of Harvard and MIT, Massachusetts, USA), Douglas M Ruderfer (Massachusetts General Hospital, Massachusetts, USA and The Broad Institute of Harvard and MIT, Massachusetts, USA), Finny Kuruvilla (The Broad Institute of Harvard and MIT, Massachusetts, USA), Stacey B Gabriel (The Broad Institute of Harvard and MIT, Massachusetts, USA), Kristin Ardlie (The Broad Institute of Harvard and MIT, Massachusetts, USA), Jennifer L Moran (The Broad Institute of Harvard and MIT, Massachusetts, USA), Edward M Scolnick (The Broad Institute of Harvard and MIT, Massachusetts, USA), Pamela Sklar (Massachusetts General Hospital, Massachusetts, USA and The Broad Institute of Harvard and MIT, Massachusetts, USA).
Rights and permissions
About this article
Cite this article
Williams, H., Norton, N., Dwyer, S. et al. Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder. Mol Psychiatry 16, 429–441 (2011). https://doi.org/10.1038/mp.2010.36
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/mp.2010.36
Keywords
This article is cited by
-
A functional neuroimaging association study on the interplay between two schizophrenia genome-wide associated genes (CACNA1C and ZNF804A)
European Archives of Psychiatry and Clinical Neuroscience (2022)
-
Schizophrenia risk ZNF804A interacts with its associated proteins to modulate dendritic morphology and synaptic development
Molecular Brain (2021)
-
ZFP804A mutant mice display sex-dependent schizophrenia-like behaviors
Molecular Psychiatry (2021)
-
Hyperfunctioning of the right posterior superior temporal sulcus in response to neutral facial expressions presents an endophenotype of schizophrenia
Neuropsychopharmacology (2020)
-
Family-based association study of ZNF804A polymorphisms and autism in a Han Chinese population
BMC Psychiatry (2019)