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.
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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.
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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).
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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
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DOI: https://doi.org/10.1038/mp.2010.36
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