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Expanding the range of ZNF804A variants conferring risk of psychosis

Abstract

A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10−8) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10−7, and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10−8. In this study, using 5164 schizophrenia cases and 20 709 controls, we replicated the association with schizophrenia (odds ratio OR=1.08, P=0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N=609, OR=1.09, P=0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]—common and with low relative risk—may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39 481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P=0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P=0.0016 for association with the larger set of psychiatric disorders).

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Acknowledgements

We thank the subjects, their families and the recruitment center staff. This work was supported by the European Union (LSHM-CT-2006-037761 (Project SGENE), PIAP-GA-2008-218251 (Project PsychGene) and HEALTH-F2-2009-223423 (Project PsychCNVs)), the National Genomic Network (NGFN-2) of the German Federal Ministry of Education and Research (BMBF), the National Institute of Mental Health (R01 MH078075), the Center of Excellence for Complex Disease Genetics of the Academy of Finland (Grants 213506, 129680) and the Biocentrum Helsinki Foundation and Research Program for Molecular Medicine, Faculty of Medicine, University of Helsinki.

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Correspondence to K Stefansson.

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Some of the authors, including Kari Stefansson (CEO of deCODE Genetics) and Augustine Kong (VP Statistics of deCODE Genetics), are shareholders in deCODE Genetics.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website

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Appendix

Appendix

Members of Genetic Risk and Outcome in Psychosis (GROUP) are as follows:

René S Kahn, MD, PhD; Wiepke Cahn, MD PhD; Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Postbus 85060, Utrecht, The Netherlands.

Don H Linszen, MD, PhD; Lieuwe de Haan, MD PhD; Academic Medical Centre University of Amsterdam, Department of Psychiatry, Amsterdam, NL326 Groot-Amsterdam, The Netherlands.

Jim van Os, MD, PhD; Lydia Krabbendam, MD PhD; Inez Myin-Germeys, MD PhD; Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, 6229 HX Maastricht, The Netherlands.

Durk Wiersma, MD, PhD; Richard Bruggeman, MD PhD; University Medical Center Groningen, Department of Psychiatry, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.

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Steinberg, S., Mors, O., Børglum, A. et al. Expanding the range of ZNF804A variants conferring risk of psychosis. Mol Psychiatry 16, 59–66 (2011). https://doi.org/10.1038/mp.2009.149

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