Abstract
Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300–10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.
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Acknowledgements
We are deeply grateful for the participation of all subjects contributing to this research and to the collection team that worked to recruit them: E. Flordal-Thelander, A.-B. Holmgren, M. Hallin, M. Lundin, A.-K. Sundberg, C. Pettersson, R. Satgunanthan-Dawoud, S. Hassellund, M. Rådstrom, B. Ohlander, L. Nyrén and I. Kizling. Funding support was provided by the NIMH (R01 MH077139 to P.F.S. and R01 MH095034 to P.S.), the Stanley Center for Psychiatric Research, the Sylvan Herman Foundation, the Friedman Brain Institute at the Mount Sinai School of Medicine, the Karolinska Institutet, Karolinska University Hospital, the Swedish Research Council, the Swedish County Council, the Söderström Königska Foundation and the Netherlands Scientific Organization (NWO 645-000-003). SGENE was supported by European Union grant HEALTH-F2-2009-223423 (project PsychCNVs). The study of the Aarhus sample was supported by grants from the Danish Strategic Research Council, H. Lundbeck A/S, the Faculty of Health Sciences at Aarhus University, the Lundbeck Foundation and the Stanley Research Foundation. The Wellcome Trust Case Control Consortium 2 project collection was funded by the Wellcome Trust (085475/B/08/Z and 085475/Z/08/Z). The funders had no role in study design, execution or analysis or in manuscript preparation.
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S.R., C.O., E.A.S., M.F., N.R.W., N.S., S.E.B., S.H.L., A.B.S., A.L.R., B.K.B.-S., B.M.N., C.d.L., D.P., D. Ruderfer, F.B., J.P., K.L., M.L.H., M.V., P.H., S.S., S.A.M., S.P. and P.F.S. conducted statistical analyses. A.D.B., D.M.H., D. Rujescu, E. Sigurdsson, J.S., M.P.M., N.D., O.M., P.B.M., S.T., T.S. and V.G. ascertained subjects. A.L.C., J.J.C., S.W., Y.K., K.X. and P.F.S. performed bioinformatics analyses. K.C., J.L.M. and S.A. managed the project. B.P.R., D.W.M., F.A.O., H.S., J.T.W., K.S.K., M.G., M.J.O., N.C., P.C., the Multicenter Genetic Studies of Schizophrenia, the Psychosis Endophenotypes International Consortium, the Wellcome Trust Case Control Consortium 2, A.P.C., E.B., K.S. and M.C.O. provided replication samples and genotypes. A.K.K. interfaced with Swedish national registers. The manuscript was written by P.K.E.M., S.A.M., S.P., P.S., C.M.H. and P.F.S. The study was designed by S.P., P.S., C.M.H. and P.F.S. Funding was obtained by E. Scolnick, P.S., C.M.H. and P.F.S.
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P.F.S. was on the scientific advisory board of Expression Analysis (Durham, North Carolina, USA). P.S. is on the Board of Directors of Catalytic, Inc. The other authors report no conflicts.
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Ripke, S., O'Dushlaine, C., Chambert, K. et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet 45, 1150–1159 (2013). https://doi.org/10.1038/ng.2742
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DOI: https://doi.org/10.1038/ng.2742
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