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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Nat Genet. Author manuscript; available in PMC Oct 1, 2012.
Published in final edited form as:
PMCID: PMC3303194
NIHMSID: NIHMS360727

Genome-wide association study identifies five new schizophrenia loci

The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium1

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).

In stage 1, we conducted a mega-analysis combining genome-wide assocation study (GWAS) data from 17 separate studies (with a total of 9,394 cases and 12,462 controls; Table 1 and Supplementary Tables 1,2). We imputed allelic dosages for 1,252,901 autosomal SNPs (Table 1, Supplementary Table 3 and Supplementary Note) using HapMap3 as the reference panel1. We tested for association using logistic regression of imputed dosages with sample identifiers and three principal components as covariates to minimize inflation in significance testing caused by population stratification. The quantile-quantile plot (Supplementary Fig. 1) deviated from the null distribution with a population stratification inflation factor of λ = 1.23. However, λ1000, a metric that standardizes the degree of inflation by sample size, was only 1.02, similar to that observed in other GWAS meta-analyses2,3. This deviation persisted despite comprehensive quality control and inclusion of up to 20 principal components (Supplementary Fig. 1). Thus, we interpret this deviation as indicative of a large number of weakly associated SNPs consistent with polygenic inheritance4. We also examined 298 ancestry-informative markers (AIMs) that reflect European-ancestry population substructure5. Unadjusted analyses showed greater inflation in the test statistics than we saw for all markers (AIMs λ = 2.26 compared to all markers λ = 1.56). After inclusion of principal components, the distributions of the test statistics did not differ between AIMs (λ = 1.18) and all markers (λ = 1.23), a result inconsistent with population stratification explaining the residual deviation seen in Supplementary Figure 1. Moreover, the results of a meta-analysis using summary results generated using study specific principal components (Supplementary Note) were highly correlated with those from the mega-analysis (Pearson correlation = 0.94, with a similar λ = 1.20; Supplementary Fig. 2). Of the ten SNPs in Table 2, four increased and six decreased in significance, suggesting that the most extreme values did not result from systematic inflation artifacts. Therefore, our primary analysis used unadjusted P values (nevertheless, see Table 2 for stage 1 P values adjusted for λ (ref. 6).

Table 1
Study design and samples
Table 2
Top genome-wide association results for schizophrenia

In stage 1 (Table 2, Supplementary Table 4 and Supplementary Figs. 3 and 4), 136 associations reached genome-wide significance (P < 5 × 10−8)7. The majority of these associations (N = 129) mapped to 5.5 Mb in the extended major histocompatibility complex (MHC, 6p21.32-p22.1), a region of high linkage disequilibrium (LD) previously implicated in schizophrenia in a subset of the samples used here4,8,9. The other stage 1 regions included new regions (10q24.33 and 8q21.3) and previously reported regions (18q21.2 at TCF4 (encoding transcription factor 4) and 11q24.2 (ref. 8)). The signal at 11q24.2 is ~0.85 Mb from NRGN (encoding neurogranin) and is uncorrelated with the previously associated variant near this gene8.

In Table 2 and Supplementary Table 4, we denote regions of association by the most significant marker. Associated SNPs with r2 ≥ 0.2 in HapMap3 (CEU+TSI populations) were not considered independent. However, we noticed instances where multiple SNPs within 250 kb of each other yielded evidence for association (P < 10−5) despite weak LD (r2 < 0.2) between them. For regions with P < 10−6, we performed a conditional analysis using as covariates the dosages of the strongest associated SNP, principal components 1–4 and 6 and study indicator. We observed multiple statistically independent signals at the MHC. Although a number of SNPs within the MHC were potentially independent per HapMap r2 values, only rs9272105 withstood formal conditional analysis, showing P = 1.8 × 10−6 conditional on association to the best SNP, rs2021722 (stage 1 P = 4.3 × 10−11, inter-SNP distance = 2.4 Mb, r2 = 0.01 in HapMap). Excluding the MHC region, we identified six regions with at least one SNP associated at P < 10−5 and a second SNP with a conditionally independent P < 10−3 (Supplementary Table 5). We performed 100 simulations after permuting case-control status randomly within each study. In contrast to the six regions in the real dataset, we never observed more than a single region with co-localized statistically independent signals in any simulated genome-wide scan, indicating our observation is highly unlikely to have occurred by chance.

Noteworthy co-localizing independent signals occurred at three regions (Supplementary Table 5): one region with a genome-wide significant association at 10q24.32-q24.33 (Table 2), a second region that nearly met this threshold at MAD1L1 (encoding mitotic arrest deficient-like 1; rs10226475, P = 5.06 × 10−8; Supplementary Table 4) and a third region at CACNA1C (encoding calcium channel, voltage-dependent, L type, α 1C subunit), the latter of which has previously been associated with bipolar disorder10 and other psychiatric phenotypes including schizophrenia11. The conditionally independent signal at CACNA1C was more significant than any observation made in 100 permutations of the entire experiment (both conditional P < 10−5) and supports CACNA1C in schizophrenia after genome-wide correction (P < 0.01), even without considering these prior reports.

In stage 2, we evaluated in 29,839 independent subjects (8,442 cases and 21,397 controls) the most significant SNPs (N = 81) in each LD region where at least one SNP had surpassed P < 2 × 10−5 (Supplementary Table 6) in the mega-analysis. Of 22 SNPs from the MHC, 5 surpassed the genome-wide significant threshold in stages 1 and 2 combined (minimum P = 2.2 × 10−12 at rs2021722; Supplementary Table 6). Excluding the MHC region, a sign test for consistency between stages 1 and 2 was highly significant (P < 10−6), with the same direction of effect as observed stage 1 also being observed in stage 2 for 49 of 59 SNPs. A Fisher’s combined test revealed the distribution of stage 2 P values was unlikely to have occurred by chance (P < 10−15). We also performed a transmission analysis using the family based Multicenter Pedigree replication sample in conjunction with a GWAS of 622 parent-offspring schizophrenia trios from Bulgaria12, and the stage 1 associated allele was over-transmitted to cases for 44 of the 59 SNPs (one-sided P = 1.0 × 10−4). Thus, the stage 2 replication results are highly consistent with the stage 1 discovery results.

In the combined dataset (stages 1 and 2), five new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two previously reported (6p21.32-p22.1 and 18q21.2) loci met genome-wide significance (Figs. 1,,2,2, Table 2, Supplementary Tables 6,7 and Supplementary Fig. 4). After adjusting for λ (ref. 6), four loci (1p21.3, 6p21.32-p22.1, 10q24.32-q24.33 and 18q21.2) remained significant at P ≤ 5 × 10−8. For the primary analyses (unadjusted for λ), the strongest new association was at 1p21.3 (rs1625579; P = 1.6 × 10−11), which is over 100 kb from any RefSeq protein-coding gene but is within intron 3 of AK094607, which contains the primary transcript for MIR137 (ref. 13). The next best locus, 10q24.32 (Supplementary Table 5 and Supplementary Fig. 5), has independent associations 130 kb apart at rs7914558 (P = 1.8 × 10−9) and rs11191580 (P = 1.1 × 10−8), implicating a 0.5-Mb region containing multiple genes (Supplementary Fig. 5). The third best locus, rs7004633 (P = 2.8 × 10−8) on 8q21.3, is 400 kb from the nearest gene (MMP16, encoding matrix metallopeptidase 16). The fourth best locus, rs10503253 (P = 4.4 × 10−8) at 8p23.2, is in an intron of CSMD1 (encoding CUB and Sushi multiple domains 1). Finally, rs17662626 (P = 4.7 × 10−8) at 2q32.3 is intergenic, mapping 300 kb from a non-coding RNA, PCGEM1 (prostate-specific transcript 1)14.

Figure 1
Manhattan plot for stages 1 and 2. Standard −log10 P plot of the study results. For the stage 1 results, 16 regions with one or more SNP achieving P < 10−6 are highlighted in color and labeled with the name of the nearest gene. ...
Figure 2
Regional association plots for five new schizophrenia loci. Regional P value plots for each of the five new schizophrenia loci: 1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33. Each plot shows the most associated SNP (key SNP) and its genomic region ...

MIR137 has been implicated in regulating adult neurogenesis15,16 and neuronal maturation17, mechanisms through which variation at this locus could contribute to brain development abnormalities in schizophrenia. Of relevance, two independent schizophrenia imaging studies found MIR137 to be one of three microRNAs with targets significantly enriched for association18. In stage 1, SNPs in or near 301 high-confidence predicted MIR137 targets (with a TargetScan19 probability of conserved targeting ≥0.9) were enriched for association compared with genes matched for size and marker density: 17 predicted MIR137 targets (Supplementary Table 8) had at least one SNP with P < 10−4, which is more than twice as many as the control gene sets (P < 0.01). Excluding the MHC and MIR137, of the nine loci with genome-wide significant support either in stage 1 or in the combined set (six loci, 2q32.3, 8p23.2, 8q21.3, 10q24.32-q24.33, 11q24.2 and 18q21.2; Table 2 and Supplementary Tables 6,7) or in a joint analysis with bipolar disorder (three genes, CACNA1C, ANK3 and ITIH3-ITIH4, described below), four genes (TCF4, CACNA1C, CSMD1 and C10orf26) have predicted MIR137 target sites according to analyses using three different prediction programs (TargetScan19, PicTar20 and miRanda21). In vitro overexpression and locked nucleic acid–mediated knockdown of MIR137 in neuronal cell line N2a leads to changes in expression levels of TCF4 protein, strongly supporting the prediction that TCF4 is a target of MIR137 (L.-H. Tsai, personal communication). Our observations suggest MIR137-mediated dysregulation as a new etiologic mechanism in schizophrenia.

The International Schizophrenia Consortium (ISC) reported evidence for a polygenic contribution to schizophrenia4. An independent family based study confirmed these results, greatly minimizing the possibility of population stratification artifact12. We reevaluated the polygenic model, dividing stage 1 samples into independent training and testing sets (Supplementary Note). The training set had 15,429 subjects (over twice the size of the ISC training set), and the testing set consisted of 6,428 individuals independent of the ISC report. The proportion of variance (Nagelkerke’s r2) explained in the testing set increased from 3% in the ISC to around 6% here (Supplementary Table 9 and Supplementary Fig. 6). This estimate is much lower than the true total variation in liability that is tagged by all SNPs because SNP effects are estimated with error3,4,2225. The polygenic model appears to explain a substantial fraction of the heritability of schizophrenia4, as has been shown for other complex traits3,2628. Some of these additional risk loci are likely contained near the most highly significant results of our stage 1 analysis. Supporting this hypothesis, of the top loci that did not reach genome-wide significance in the combined stage 1 and 2 analysis, a sign test (P < 10−4) and a Fisher’s combined test (P < 10−5) both showed an excess of same-direction allelic association (41 of 51 non-MHC SNPs) in the discovery and replication datasets.

Clinical, epidemiological and genetic findings suggest shared risk factors between bipolar disorder and schizophrenia29. In stage 1, three genes with strong support had prior genome-wide significant associations with bipolar disorder: CACNA1C, the region containing ITIH3-ITIH4 (encoding inter-α (globulin) inhibitors H3 and H4) and ANK3 (encoding ankyrin 3, node of Ranvier (ankyrin G))10,11,30 (Supplementary Table 10). We performed a joint analysis with the Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium (PGC) for bipolar disorder applying identical analytical methods. After removing duplicate subjects, we analyzed 16,374 cases with schizophrenia, schizoaffective disorder or bipolar disorder and 14,044 controls. Support for shared susceptibility was strengthened (Supplementary Table 11) at 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), each of which reached genome-wide significance. A coding variant in ITIH4 (p.Pro698Thr; rs4687657) is in perfect LD with the most associated SNP. Although we included all subjects from an earlier report10, the increased support found with additional independent cases (N = 11,987) and controls (N = 7,835) provides further evidence for shared risk effects of schizophrenia and bipolar disorder.

The risk variants implicated here confer small risks (odds ratios ~1.10), but the polygenic analysis shows many more susceptibility variants with effects for which our sample is underpowered (Supplementary Table 12). At every stage where samples were added, we found an increase in the number of genome-wide significant loci and enhancement of signals at CACNA1C, ANK3 and ITIH3-ITIH4 when schizophrenia and bipolar disorder were jointly analyzed. Thus, gains in power offset any penalty for increased heterogeneity.

In summary, we report seven genome-wide significant schizophrenia associations (five of which are new) in a two-stage analysis of 51,695 individuals. We also report loci that confer susceptibility to both bipolar disorder and schizophrenia. The association near MIR137, associations in multiple predicted MIR137 targets and the known role of MIR137 in neuronal maturation and function together suggest an intriguing new insight into the pathogenesis of schizophrenia.

METHODS

Methods and any associated references are available in the online version of the paper at http://www.nature.com/naturegenetics/.

Supplementary Material

Supplementary Note

Online Methods

Acknowledgments

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

Stephan Ripke1, Alan R Sanders2,3, Kenneth S Kendler46, Douglas F Levinson7, Pamela Sklar1,8, Peter A Holmans9,10, Dan-Yu Lin11, Jubao Duan2,3, Roel A Ophoff1215, Ole A Andreassen16,17, Edward Scolnick18, Sven Cichon1921, David St. Clair22, Aiden Corvin23, Hugh Gurling24, Thomas Werge25, Dan Rujescu26, Douglas H R Blackwood27, Carlos N Pato28, Anil K Malhotra2931, Shaun Purcell18, Frank Dudbridge32, Benjamin M Neale18, Lizzy Rossin1, Peter M Visscher33, Danielle Posthuma34,35, Douglas M Ruderfer1, Ayman Fanous5,36,37, Hreinn Stefansson38, Stacy Steinberg38, Bryan J Mowry39,40, Vera Golimbet41, Marc De Hert42, Erik G Jönsson43, István Bitter44, Olli P H Pietiläinen45,46, David A Collier47, Sarah Tosato48, Ingrid Agartz16,49, Margot Albus50, Madeline Alexander7, Richard L Amdur36,37, Farooq Amin51,52, Nicholas Bass24, Sarah E Bergen1, Donald W Black53, Anders D Børglum54,55, Matthew A Brown56, Richard Bruggeman57, Nancy G Buccola58, William F Byerley59,60, Wiepke Cahn61, Rita M Cantor14,15, Vaughan J Carr62, Stanley V Catts63, Khalid Choudhury24, C Robert Cloninger64, Paul Cormican23, Nicholas Craddock9,10, Patrick A Danoy56, Susmita Datta24, Lieuwe de Haan65, Ditte Demontis54, Dimitris Dikeos66, Srdjan Djurovic16,67, Peter Donnelly68,69, Gary Donohoe23, Linh Duong25, Sarah Dwyer9,10, Anders Fink-Jensen70, Robert Freedman71, Nelson B Freimer14, Marion Friedl26, Lyudmila Georgieva9,10, Ina Giegling26, Michael Gill23, Birte Glenthøj72, Stephanie Godard73, Marian Hamshere9,10, Mark Hansen74, Thomas Hansen25, Annette M Hartmann26, Frans A Henskens75, David M Hougaard76, Christina M Hultman77, Andrés Ingason25, Assen V Jablensky78, Klaus D Jakobsen25, Maurice Jay79,132, Gesche Jürgens80, René S Kahn61, Matthew C Keller81, Gunter Kenis82, Elaine Kenny23, Yunjung Kim83, George K Kirov9,10, Heike Konnerth26, Bettina Konte26, Lydia Krabbendam84, Robert Krasucki24, Virginia K Lasseter85,132, Claudine Laurent79, Jacob Lawrence24, Todd Lencz2931, F Bernard Lerer86, Kung-Yee Liang87, Paul Lichtenstein77, Jeffrey A Lieberman88, Don H Linszen65, Jouko Lönnqvist89, Carmel M Loughland90, Alan W Maclean27, Brion S Maher46, Wolfgang Maier91, Jacques Mallet92, Pat Malloy27, Manuel Mattheisen19,21,93, Morten Mattingsdal16,94, Kevin A McGhee27, John J McGrath39,40, Andrew McIntosh27, Duncan E McLean95, Andrew McQuillin24, Ingrid Melle16,17, Patricia T Michie96,97, Vihra Milanova98, Derek W Morris23, Ole Mors55, Preben B Mortensen99, Valentina Moskvina9,10, Pierandrea Muglia100,101, Inez Myin-Germeys84, Deborah A Nertney39,40, Gerald Nestadt85, Jimmi Nielsen102, Ivan Nikolov9,10, Merete Nordentoft103, Nadine Norton9,10, Markus M Nöthen19,21, Colm T O’Dushlaine23, Ann Olincy71, Line Olsen25, F Anthony O’Neill104, Torben F Ørntoft105,106, Michael J Owen9,10, Christos Pantelis107, George Papadimitriou66, Michele T Pato28, Leena Peltonen45,46,108,132, Hannes Petursson109, Ben Pickard110, Jonathan Pimm24, Ann E Pulver85, Vinay Puri24, Digby Quested111, Emma M Quinn23, Henrik B Rasmussen25, János M Réthelyi44, Robert Ribble46, Marcella Rietschel91,112, Brien P Riley46, Mirella Ruggeri48, Ulrich Schall97,113, Thomas G Schulze112,114, Sibylle G Schwab115117, Rodney J Scott118, Jianxin Shi119, Engilbert Sigurdsson109,120, Jeremy M Silverman8,121, Chris C A Spencer68, Kari Stefansson38, Amy Strange68, Eric Strengman12,13, T Scott Stroup88, Jaana Suvisaari89, Lars Terenius43, Srinivasa Thirumalai122, Johan H Thygesen25, Sally Timm123, Draga Toncheva124, Edwin van den Oord125, Jim van Os84, Ruud van Winkel42,82, Jan Veldink126, Dermot Walsh127, August G Wang128, Durk Wiersma57, Dieter B Wildenauer115,129, Hywel J Williams9,10, Nigel M Williams9,10, Brandon Wormley46, Stan Zammit9,10, Patrick F Sullivan77,83,130,131, Michael C O’Donovan9,10, Mark J Daly1 & Pablo V Gejman2,3

Footnotes

Note: Supplementary information is available on the Nature Genetics website.

AUTHOR 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 17–Zucker Hillside: A.K.M., T.L. Stage 2 replication follow-up sample 1–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 2–SGENE–Aarhus: A.D.B., D. Demontis, P.B.M., D.M.H., T.F.Ø., O.M. Stage 2 replication follow-up sample 3–SGENE–Aarhus: O.M., M.N., A.D.B. Stage 2 replication follow-up sample 4–SGENE–Belgium: R.v.W., G.K., M.D.H., J.V. Stage 2 replication follow-up sample 6–SGENE–Iceland: H.S., S.S., E. Sigurdsson, H.P., K.S. Stage 2 replication follow-up sample 7–SGENE–England: D.A.C. Stage 2 replication follow-up sample 8–SGENE–Helsinki, stage 2 replication follow-up sample 11–SGENE–Kuusamo: L.P., O.P.H.P., J. Suvisaari, J. Lönnqvist. Stage 2 replication follow-up sample 9–SGENE–Hungary: I.B., J.M.R. Stage 2 replication follow-up sample 10–SGENE–Italy: M. Ruggeri, S. Tosato. Stage 2 replication follow-up sample 14–SGENE–Russia: V.G. Stage 2 replication follow-up sample 15–SGENE–Sweden: E.G.J., I.A., L.T. Stage 2 replication follow-up sample 18–University of Queensland: B.J.M., M.A.B., P.A.D., J.J.M., D.E.M. Stage 2 replication follow-up sample 18–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 19–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 the Supplementary Note for additional contributors not listed above). Stage 2 replication follow-up sample 19–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 the Supplementary Note for additional contributors not listed above). All authors contributed to the current version of the paper.

COMPETING FINANCIAL INTERESTS

The authors declare competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/naturegenetics/.

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1Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

2Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, Illinois, USA.

3Department of Psychiatry and Behavioral Sciences, University of Chicago, Chicago, Illinois, USA.

4Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.

5Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.

6Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.

7Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, USA.

8Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA.

9Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK.

10Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.

11Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA.

12Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.

13Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.

14University of California at Los Angeles (UCLA) Center for Neurobehavioral Genetics, University of California at Los Angeles, Los Angeles, California, USA.

15Department of Human Genetics, University of California at Los Angeles, Los Angeles, California, USA.

16Psychiatry Section, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

17Department of Psychiatry, Oslo University Hospital, Oslo, Norway.

18Broad Institute, Cambridge, Massachusetts, USA.

19Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.

20Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany.

21Institute of Human Genetics, University of Bonn, Bonn, Germany.

22Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK.

23Neuropsychiatric Genetics Research Group, Trinity College Dublin, Dublin, Ireland.

24Molecular Psychiatry Laboratory, Research Department of Mental Health Sciences, University College London Medical School, Windeyer Institute of Medical Sciences, London, UK.

25Institute of Biological Psychiatry, Mental Health Center (MHC) Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark.

26Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany.

27Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.

28Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

29Department of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of the North Shore-Long Island Jewish Health System, Glen Oaks, New York, USA.

30Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, New York, USA.

31Department of Psychiatry and Behavioral Science, Albert Einstein College of Medicine of Yeshiva University, New York, New York, USA.

32Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.

33Queensland Statistical Genetics Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia.

34Vrije Universiteit (VU), Center for Neurogenomics and Cognitive Research (CNCR), Department of Functional Genomics, Amsterdam, The Netherlands.

35VU Medical Centre, Department of Medical Genomics, Amsterdam, The Netherlands.

36Washington Veteran’s Affairs Medical Center, Washington, DC, USA.

37Department of Psychiatry, Georgetown University School of Medicine, Washington, DC, USA.

38deCODE Genetics, Reykjavik, Iceland.

39Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.

40Queensland Centre for Mental Health Research, University of Queensland, Brisbane, Queensland, Australia.

41Mental Health Research Center, Russian Academy of Medical Sciences, Moscow, Russia.

42University Psychiatric Centre, Catholic University Leuven, Kortenberg, Belgium.

43Department of Clinical Neuroscience, Human Brain Informatics (HUBIN) Project, Karolinska Institutet and Hospital, Stockholm, Sweden.

44Semmelweis University, Department of Psychiatry and Psychotherapy, Budapest, Hungary.

45Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

46Department of Medical Genetics, University of Helsinki, Helsinki, Finland.

47Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College, London, UK.

48Section of Psychiatry and Clinical Psychology, University of Verona, Verona, Italy.

49Department of Research, Diakonhjemmet Hospital, Oslo, Norway.

50State Mental Hospital, Haar, Germany.

51Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia, USA.

52Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, Atlanta, Georgia, USA.

53Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.

54Institute of Human Genetics, University of Aarhus, Aarhus, Denmark.

55Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark.

56University of Queensland Diamantina Institute, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia.

57University Medical Center Groningen, Department of Psychiatry, University of Groningen, Groningen, The Netherlands.

58School of Nursing, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.

59Department of Psychiatry, University of California at San Francisco, San Francisco, California, USA.

60NCIRE (Northern California Institute for Research and Education), San Francisco, California, USA.

61Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.

62School of Psychiatry, University of New South Wales and Schizophrenia Research Institute, Sydney, New South Wales, Australia.

63Department of Psychiatry, University of Queensland, Royal Brisbane Hospital, Brisbane, Australia.

64Department of Psychiatry, Washington University, St. Louis, Missouri, USA.

65Academic Medical Centre, University of Amsterdam, Department of Psychiatry, Amsterdam, The Netherlands.

66Department of Psychiatry, University of Athens Medical School, Athens, Greece.

67Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.

68Wellcome Trust Centre for Human Genetics, Oxford, UK.

69Department of Statistics, University of Oxford, Oxford, UK.

70Mental Health Center Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark.

71Department of Psychiatry, University of Colorado Denver, Aurora, Colorado, USA.

72Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Mental Health Center Glostrup, Copenhagen University Hospital, Glostrup, Denmark.

73INSERM, Institut de Myologie, Hôpital de la Pitié-Salpêtrière, Paris, France.

74Illumina, Inc., La Jolla, California, USA.

75School of Electrical Engineering and Computing Science, University of Newcastle, Newcastle, New South Wales, Australia.

76Section of Neonatal Screening and Hormones, Department of Clinical Chemistry and Immunology, The State Serum Institute, Copenhagen, Denmark.

77Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

78Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth, Western Australia, Australia.

79Department of Child and Adolescent Psychiatry, Pierre and Marie Curie Faculty of Medicine, Paris, France.

80Department of Clinical Pharmacology, Bispebjerg University Hospital, Copenhagen, Denmark.

81Department of Psychology, University of Colorado, Boulder, Boulder, Colorado, USA.

82Department of Psychiatry and Psychology, School of Mental Health and Neuroscience, European Graduate School of Neuroscience (EURON), South Limburg Mental Health Research and Teaching Network (SEARCH), Maastricht University Medical Centre, Maastricht, The Netherlands.

83Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

84Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, Maastricht, The Netherlands.

85Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

86Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

87Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.

88Department of Psychiatry, Columbia University, New York, New York, USA.

89Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.

90Schizophrenia Research Institute, Sydney and Centre for Brain and Mental Health Research, University of Newcastle, Newcastle, New South Wales, Australia.

91Department of Psychiatry, University of Bonn, Bonn, Germany.

92Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, Centre National de la Recherche Scientifique, Hôpital de la Pitié Salpêtrière, Paris, France.

93Institute of Medical Biometry, Informatics and Epidemiology (IMBIE), University of Bonn, Bonn, Germany.

94Department of Research, Sørlandet Hospital, Kristiansand, Norway.

95Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, Queensland, Australia.

96Functional NeuroImaging Laboratory, School of Psychology, University of Newcastle, Sydney, New South Wales, Australia.

97Schizophrenia Research Institute, Sydney, New South Wales, Australia.

98Department of Psychiatry, First Psychiatric Clinic, Alexander University Hospital, Sofia, Bulgaria.

99National Centre for Register-Based Research, University of Aarhus, Aarhus, Denmark.

100Department of Psychiatry, University of Toronto, Toronto, Canada.

101NeuroSearch A/S, Ballerup, Denmark.

102Unit for Psychiatric Research, Aalborg Psychiatric Hospital, Aalborg, Denmark.

103Psychiatric Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark.

104Department of Psychiatry, Queens University, Belfast, Ireland.

105ARoS Applied Biotechnology A/S, Skejby, Denmark.

106Department of Molecular Medicine, Aarhus University Hospital, Skejby, Denmark.

107Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Melbourne, Victoria, Australia.

108Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

109Department of Psychiatry, National University Hospital, Reykjavik, Iceland.

110Strathclyde Institute of Pharmacy and Biomedical Sciences, The John Arbuthnott Building, University of Strathclyde, Glasgow, UK.

111Department of Psychiatry, University of Oxford, Warneford Hospital, Headington, Oxford, UK.

112Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.

113Priority Centre for Brain and Mental Health Research, University of Newcastle, Sydney, New South Wales, Australia.

114Department of Psychiatry and Psychotherapy, Georg-August-University, Göttingen, Germany.

115School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Western Australia, Australia.

116Department of Psychiatry, University of Erlangen-Nuremberg, Erlangen, Germany.

117Centre for Medical Research, Western Australian Institute for Medical Research, University of Western Australia, Perth, Western Australia, Australia.

118Centre for Information Based Medicine, University of Newcastle, Hunter Medical Research Institute, Newcastle and Schizophrenia Research Institute, Sydney, New South Wales, Australia.

119Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

120Department of Psychiatry, University of Iceland, Reykjavik, Iceland.

121Department of Psychiatry, Veterans Affairs Medical Center, New York, New York, USA.

122West Berkshire National Health Service (NHS) Trust, Reading, UK.

123Mental Health Center Frederiksberg, Copenhagen University Hospital, Copenhagen, Denmark.

124Department of Medical Genetics, University Hospital Maichin Dom, Sofia, Bulgaria.

125Department of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, USA.

126Rudolf Magnus Institute of Neuroscience, Department of Neurology, Universitair Medisch Centrum (UMC) Utrecht, Utrecht, The Netherlands.

127The Health Research Board, Dublin, Ireland.

128Mental Health Center Amager, Copenhagen University Hospital, Copenhagen, Denmark.

129Centre for Clinical Research in Neuropsychiatry, Graylands Hospital, Mt Claremont, Western Australia, Australia.

130Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

131Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

132Deceased. Correspondence should be addressed to P.V.G. (moc.liamg@namjegp).

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