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Genome-wide association study identifies five new schizophrenia loci

Abstract

We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10−11) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10−9), ANK3 (rs10994359, P = 2.5 × 10−8) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10−9).

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Figure 1: Manhattan plot for stages 1 and 2.
Figure 2: Regional association plots for five new schizophrenia loci.

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Acknowledgements

We thank the study participants and the research staff at the many study sites. Over 40 US National Institutes of Health grants and similar numbers of government grants from other countries, along with substantial private and foundation support, enabled this work. We greatly appreciate the sustained efforts of T. Lehner (National Institute of Mental Health) on behalf of the Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium (PGC). Detailed acknowledgments, including grant support, are listed in the Supplementary Note.

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Contributions

The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium (PGC): overall coordination: P.V.G. Coordination of statistical analyses: M.J.D. Coordination of phenotypic analyses: K.S.K. Statistical analyses: S.R., M.J.D., P.A.H., D.-Y.L., S.P., F.D., B.M.N., L.R., P.M.V., D.P., D.M.R. Manuscript preparation: P.V.G. (primary), M.J.D. (primary), A.R.S. (primary), S.R. (primary), M.C.O. (primary), K.S.K., D.F.L., P.S., P.A.H., P.F.S. (primary), D.-Y.L., J.D., R.A.O., O.A.A., E. Scolnick. Phenotypic analyses: K.S.K., A.F., A.C., R.L.A. Stage 1 GWAS sample 1–Cardiff, UK: M.C.O., N.C., P.A.H., M. Hamshere, H.J.W., V. Moskvina, S. Dwyer, L.G., S.Z., M.J.O. Stage 1 GWAS sample 2–Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE): P.F.S., D.-Y.L., E.v.d.O., Y.K., T.S.S., J.A.L. Stage 1 GWAS sample 3–International Schizophrenia Consortium (ISC)–Aberdeen: D.St.C. Stage 1 GWAS sample 4–ISC–Cardiff: G.K.K., M.C.O., P.A.H., L.G., I.N., H.J.W., D.T., V. Milanova, M.J.O. Stage 1 GWAS sample 5–ISC–Dublin: D.W.M., C.T.O., E.K., E.M.Q., M.G., A.C. Stage 1 GWAS sample 6–ISC–Edinburgh: D.H.R.B., K.A.M., B.P., P. Malloy, A.W.M., A. McIntosh. Stage 1 GWAS sample 7–ISC–London: A. McQuillin, K.C., S. Datta, J.P., S. Thirumalai, V.P., R.K., J. Lawrence, D.Q., N.B., H.G. Stage 1 GWAS sample 8–ISC–Portugal: M.T.P., C.N.P., A.F. Stage 1 GWAS sample 9–ISC–SW1–Sweden, stage 1 GWAS sample 10–ISC–SW2–Sweden, stage 2 replication follow-up sample 16–SW3–Sweden, stage 2 replication follow-up sample 17–SW4–Sweden: C.M.H., P.L., S.E.B., S.P., E. Scolnick, P.S., P.F.S. Stage 1 GWAS sample 11–Molecular Genetics of Schizophrenia (MGS): J. Shi, D.F.L., J.D., A.R.S., M.C.K., B.J.M., A.O., F.A., C.R.C., J.M.S., N.G.B., W.FB., D.W.B., K.S.K., R.F., P.V.G. Stage 1 GWAS sample 12–Schizophrenia Genetics Consortium (SGENE)–Bonn: S.C., M. Rietschel, M.M.N., W.M., T.G.S., M. Mattheisen. Stage 1 GWAS sample 13–SGENE–Copenhagen, stage 2 replication follow-up sample 5–SGENE–Copenhagen: T.H., A.I., K.D.J., L.D., G.J., H.B.R., B.G., J.N., S. Timm, L.O., A.G.W., A.F.-J., J.H.T., T.W. Stage 1 GWAS sample 14–SGENE–Munich, stage 2 replication follow-up sample 12–SGENE–Munich, stage 2 replication follow-up sample 13–SGENE–Munich: I.G., A.M.H., H.K., M.F., B.K., P. Muglia, D.R. Stage 1 GWAS sample 15–SGENE–Thematic Organized Psychoses Research 3 (TOP3): S. Djurovic, M. Mattingsdal, I.A., I.M., O.A.A. Stage 1 GWAS sample 16–SGENE–UCLA: R.A.O., R.M.C., N.B.F., R.S.K., D.H.L., J.v.O., D. Wiersma, R.B., W.C., L.d.H., L.K., I.M.-G., E. Strengman. Stage 1 GWAS sample 1–Zucker Hillside A.K.M., T.L.Stage 2 replication follow-up sample –multicenter pedigree P.A.H., B.P.R., A.E.P., M.J.O., D.B.W., P.V.G., B.J.M., C.L., K.S.K., G.N., N.M.W., S.G.S., A.R.S., M. Hansen, D.A.N., J.M., B.W., V.K.L., M.C.O., J.D., M. Albus, M. Alexander, S.G., R.R., K.-Y.L., N.N., W.M., G.P., D. Walsh, M.J., F.A.O., F.B.L., D. Dikeos, J.M.S., D.F.L.Stage 2 replication follow-up sample –SGEN–Aarhus A.D.B., D. Demontis, P.B.M., D.M.H., T.FØ., O.M.Stage 2 replication follow-up sample –SGEN–Aarhus O.M., M.N., A.D.B.Stage 2 replication follow-up sample –SGEN–Belgium R.v.W., G.K., M.D.H., J.V.Stage 2 replication follow-up sample –SGEN–Iceland H.S., S.S., E. Sigurdsson, H.P., K.S.Stage 2 replication follow-up sample –SGEN–England D.A.C.Stage 2 replication follow-up sample –SGEN–Helsinki, stage 2 replication follow-up sample 1–SGEN–Kuusamo L.P., O.P.H.P., J. Suvisaari, J. önnqvist.Stage 2 replication follow-up sample –SGEN–Hungary I.B., J.M.R.Stage 2 replication follow-up sample 1–SGEN–Italy M. Ruggeri, S. Tosato.Stage 2 replication follow-up sample 1–SGEN–Russia V.G.Stage 2 replication follow-up sample 1–SGEN–Sweden E.G.J., I.A., L.T.Stage 2 replication follow-up sample 1–University of Queensland B.J.M., M.A.B., P.A.D., J.J.M., D.E.M.Stage 2 replication follow-up sample 1–Australian Schizophrenia Research Bank B.J.M., V.J.C., R.J.S., S.V.C., F.A.H., A.V.J., C.M.L., P.T.M., C.P., U.S.Stage 2 replication follow-up sample 1–Irish Schizophrenia Genomics Consortium (ISGC) A.C., D.W.M., P.C., B.S.M., C.T.O., G.D., F.A.O., M.G., K.S.K., B.P.R., ISGC (see the Acknowledgments in theSupplementary Not for additional contributors not listed above).Stage 2 replication follow-up sample 1–Wellcome Trust Case Control Consortium 2 (WTCCC2) P.D. (Chair of Management Committee; Data and Analysis Group), C.C.A.S. (Data and Analysis Group; Publications Committee), A.S. (Data and Analysis Group), WTCCC2 (see Acknowledgments in theSupplementary Not for additional contributors not listed above). All authors contributed to the current version of the paper

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Correspondence to Pablo V Gejman.

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Competing interests

Eli Lilly funded portions of the genotyping for CATIE and TOP. P.F.S. received research funding from Eli Lilly in connection with CATIE. T.S.S. received research funding from Eli Lilly and consulting fees from Janssen Pharmaceutica, GlaxoSmithKline and Bristol-Myers Squibb. J.A.L. received research funding from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Janssen Pharmaceutica and Pfizer and consulting and educational fees from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Novartis, Pfizer and Solvay. D.St.C. received research funding from GlaxoSmithKline and Generation Scotland, Genetics Health Initiative. F.A. received funds from Pfizer, Organon and the Foundation for the National Institutes of Health. D.W.B. has received research support from Shire and Forest, has been on the speakers' bureau for Pfizer and has received consulting honoraria from Forest and Jazz. T.W. has received consulting and lecture fees from H. Lundbeck A/S. O.A.A. has received Speaker's honorarium from AstraZeneca, Janssen, Bristol-Myers Squibb and GlaxoSmithKline. I.M. has received a Speaker's honorarium from Janssen and AstraZeneca. A.K.M. has received consulting fees or honoraria from Eli Lilly & Company, Janssen Pharmaceutica, Merck, Bristol-Meyers Squibb, Pfizer, PGxHealth (a division of Clinical Data, Inc.), Roche Diagnostics and Vanda Pharmaceuticals and has received research support from Eli Lilly & Company. T.L. has received consulting fees or honoraria from Merck, Eli Lilly & Company, Golden Helix, Inc., InforMed Insights and PGxHealth (a division of Clinical Data, Inc.). I.B. has been an advisory board member, consultant and lecturer for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, EGIS, Janssen, H. Lundbeck A/S, Novartis, Pfizer, Richter and Schering-Plough and received a grant for an investigator-initiated study from H. Lundbeck A/S. J.J.M. has received consulting and speaker's fees from Johnson & Johnson, Schering-Plough and Eli Lilly. C.P. has received grant support from Janssen-Cilag, Eli Lilly, Hospira (Mayne) and AstraZeneca, provided consultancy to Janssen-Cilag, Eli Lilly, Hospira (Mayne), AstraZeneca, Pfizer and Schering-Plough and has undertaken investigator-initiated studies supported by Eli Lilly, Hospira, Janssen Cilag and AstraZeneca. The Denmark-Aarhus group (The GEMS Stud with principal investigators A.D.B., O.M. and P.B.M.) received research funding from H. Lundbeck A/S. E.G.J. has served as an unpaid consultant for Eli Lilly.

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The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci. Nat Genet 43, 969–976 (2011). https://doi.org/10.1038/ng.940

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