Genome-wide association analysis identifies 13 new risk loci for schizophrenia (original) (raw)

References

  1. Saha, S., Chant, D. & McGrath, J. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch. Gen. Psychiatry 64, 1123–1131 (2007).
    Article PubMed Google Scholar
  2. World Health Organization. The Global Burden of Disease: 2004 Update (World Health Organization Press, Geneva, 2008).
  3. Knapp, M., Mangalore, R. & Simon, J. The global costs of schizophrenia. Schizophr. Bull. 30, 279–293 (2004).
    Article PubMed Google Scholar
  4. Lichtenstein, P. et al. Recurrence risks for schizophrenia in a Swedish national cohort. Psychol. Med. 36, 1417–1425 (2006).
    Article PubMed Google Scholar
  5. Lichtenstein, P. et al. Common genetic influences for schizophrenia and bipolar disorder: a population-based study of 2 million nuclear families. Lancet 373, 234–239 (2009).
    Article CAS PubMed Google Scholar
  6. Sullivan, P.F., Kendler, K.S. & Neale, M.C. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch. Gen. Psychiatry 60, 1187–1192 (2003).
    Article PubMed Google Scholar
  7. Lee, S.H. et al. Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nat. Genet. 44, 247–250 (2012).
    Article CAS PubMed PubMed Central Google Scholar
  8. Sullivan, P.F., Daly, M.J. & O'Donovan, M. Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat. Rev. Genet. 13, 537–551 (2012).
    Article CAS PubMed PubMed Central Google Scholar
  9. Ng, M.Y. et al. Meta-analysis of 32 genome-wide linkage studies of schizophrenia. Mol. Psychiatry 14, 774–785 (2009).
    Article CAS PubMed Google Scholar
  10. Girard, S.L. et al. Increased exonic de novo mutation rate in individuals with schizophrenia. Nat. Genet. 43, 860–863 (2011).
    Article CAS PubMed Google Scholar
  11. Xu, B. et al. De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nat. Genet. 44, 1365–1369 (2012).
    Article CAS PubMed PubMed Central Google Scholar
  12. Need, A.C. et al. Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia. Am. J. Hum. Genet. 91, 303–312 (2012).
    Article CAS PubMed PubMed Central Google Scholar
  13. Kim, Y., Zerwas, S., Trace, S.E. & Sullivan, P.F. Schizophrenia genetics: where next? Schizophr. Bull. 37, 456–463 (2011).
    Article PubMed PubMed Central Google Scholar
  14. International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009).
  15. Shi, J. et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460, 753–757 (2009).
    Article CAS PubMed PubMed Central Google Scholar
  16. Stefansson, H. et al. Common variants conferring risk of schizophrenia. Nature 460, 744–747 (2009).
    Article CAS PubMed PubMed Central Google Scholar
  17. Schizophrenia Psychiatric Genome-Wide Association Study Consortium. Genome-wide association study identifies five new schizophrenia loci. Nat. Genet. 43, 969–976 (2011).
  18. Wray, N.R. & Visscher, P.M. Narrowing the boundaries of the genetic architecture of schizophrenia. Schizophr. Bull. 36, 14–23 (2010).
    Article PubMed Google Scholar
  19. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).
    CAS PubMed Google Scholar
  20. Yang, J. et al. Genomic inflation factors under polygenic inheritance. Eur. J. Hum. Genet. 19, 807–812 (2011).
    Article PubMed PubMed Central Google Scholar
  21. de Bakker, P.I. et al. Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum. Mol. Genet. 17, R122–R128 (2008).
    Article CAS PubMed PubMed Central Google Scholar
  22. Pe'er, I., Yelensky, R., Altshuler, D. & Daly, M.J. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet. Epidemiol. 32, 381–385 (2008).
    Article PubMed Google Scholar
  23. Major Depressive Disorder Working Group of the PGC. A mega-analysis of genome-wide association studies for major depressive disorder. Mol. Psychiatry 18, 497–511 (2013).
  24. Hindorff, L.A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl. Acad. Sci. USA 106, 9362–9367 (2009).
    Article CAS PubMed PubMed Central Google Scholar
  25. Maurano, M.T. et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190–1195 (2012).
    Article CAS PubMed PubMed Central Google Scholar
  26. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).
  27. Psychiatric GWAS Consortium Bipolar Disorder Working Group. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat. Genet. 43, 977–983 (2011).
  28. Ferreira, M.A. et al. Collaborative genome-wide association analysis of 10,596 individuals supports a role for Ankyrin-G (ANK3) and the α-1C subunit of the L-type voltage-gated calcium channel (CACNA1C) in bipolar disorder. Nat. Genet. 40, 1056–1058 (2008).
    Article CAS PubMed PubMed Central Google Scholar
  29. Hamshere, M.L. et al. Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC. Mol. Psychiatry 18, 708–712 (2013).
    Article CAS PubMed Google Scholar
  30. Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381, 1371–1379 (2013).
  31. Cichon, S. et al. Genome-wide association study identifies genetic variation in neurocan as a susceptibility factor for bipolar disorder. Am. J. Hum. Genet. 88, 372–381 (2011).
    Article CAS PubMed PubMed Central Google Scholar
  32. Bidaud, I., Mezghrani, A., Swayne, L.A., Monteil, A. & Lory, P. Voltage-gated calcium channels in genetic diseases. Biochim. Biophys. Acta 1763, 1169–1174 (2006).
    Article CAS PubMed Google Scholar
  33. Bichet, D. et al. The I-II loop of the Ca2+ channel α1 subunit contains an endoplasmic reticulum retention signal antagonized by the β subunit. Neuron 25, 177–190 (2000).
    Article CAS PubMed Google Scholar
  34. Müller, C.S. et al. Quantitative proteomics of the Cav2 channel nano-environments in the mammalian brain. Proc. Natl. Acad. Sci. USA 107, 14950–14957 (2010).
    Article PubMed PubMed Central Google Scholar
  35. Woodside, B.L., Borroni, A.M., Hammonds, M.D. & Teyler, T.J. NMDA receptors and voltage-dependent calcium channels mediate different aspects of acquisition and retention of a spatial memory task. Neurobiol. Learn. Mem. 81, 105–114 (2004).
    Article CAS PubMed Google Scholar
  36. Moosmang, S. et al. Role of hippocampal Cav1.2 Ca2+ channels in NMDA receptor–independent synaptic plasticity and spatial memory. J. Neurosci. 25, 9883–9892 (2005).
    Article CAS PubMed PubMed Central Google Scholar
  37. White, J.A. et al. Conditional forebrain deletion of the L-type calcium channel Cav1.2 disrupts remote spatial memories in mice. Learn. Mem. 15, 1–5 (2008).
    Article CAS PubMed Google Scholar
  38. Mangoni, M.E. et al. Voltage-dependent calcium channels and cardiac pacemaker activity: from ionic currents to genes. Prog. Biophys. Mol. Biol. 90, 38–63 (2006).
    Article CAS PubMed Google Scholar
  39. Perrin, M.J. & Gollob, M.H. Genetics of cardiac electrical disease. Can. J. Cardiol. 29, 89–99 (2013).
    Article PubMed Google Scholar
  40. Splawski, I. et al. Cav1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119, 19–31 (2004).
    Article CAS PubMed Google Scholar
  41. Koponen, H. et al. Schizophrenia and sudden cardiac death: a review. Nord. J. Psychiatry 62, 342–345 (2008).
    Article PubMed Google Scholar
  42. Stöllberger, C., Huber, J.O. & Finsterer, J. Antipsychotic drugs and QT prolongation. Int. Clin. Psychopharmacol. 20, 243–251 (2005).
    Article PubMed Google Scholar
  43. McKusick, V.A. Mendelian Inheritance in Man and its online version, OMIM. Am. J. Hum. Genet. 80, 588–604 (2007).
    Article CAS PubMed PubMed Central Google Scholar
  44. Lewis, B.P., Burge, C.B. & Bartel, D.P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005).
    Article CAS PubMed Google Scholar
  45. Szulwach, K.E. et al. Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J. Cell Biol. 189, 127–141 (2010).
    Article CAS PubMed PubMed Central Google Scholar
  46. Smrt, R.D. et al. MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1. Stem Cells 28, 1060–1070 (2010).
    Article CAS PubMed PubMed Central Google Scholar
  47. Willemsen, M.H. et al. Chromosome 1p21.3 microdeletions comprising DPYD and MIR137 are associated with intellectual disability. J. Med. Genet. 48, 810–818 (2011).
    Article CAS PubMed Google Scholar
  48. Cabili, M.N. et al. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 25, 1915–1927 (2011).
    Article CAS PubMed PubMed Central Google Scholar
  49. Lee, P.H., O'Dushlaine, C., Thomas, B. & Purcell, S. InRich: interval-based enrichment analysis for genome-wide association studies. Bioinformatics 28, 1797–1799 (2012).
    Article CAS PubMed PubMed Central Google Scholar
  50. Majewski, J. & Pastinen, T. The study of eQTL variations by RNA-seq: from SNPs to phenotypes. Trends Genet. 27, 72–79 (2011).
    Article CAS PubMed Google Scholar
  51. Cookson, W., Liang, L., Abecasis, G., Moffatt, M. & Lathrop, M. Mapping complex disease traits with global gene expression. Nat. Rev. Genet. 10, 184–194 (2009).
    Article CAS PubMed PubMed Central Google Scholar
  52. Nicolae, D.L. et al. Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genet. 6, e1000888 (2010).
    Article PubMed PubMed Central CAS Google Scholar
  53. Stranger, B.E. et al. Patterns of cis regulatory variation in diverse human populations. PLoS Genet. 8, e1002639 (2012).
    CAS PubMed PubMed Central Google Scholar
  54. Grundberg, E. et al. Mapping _cis_- and _trans_-regulatory effects across multiple tissues in twins. Nat. Genet. 44, 1084–1089 (2012).
    Article CAS PubMed PubMed Central Google Scholar
  55. Lango Allen, H. et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467, 832–838 (2010).
    Article CAS PubMed PubMed Central Google Scholar
  56. Emilsson, V. et al. Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008).
    Article CAS PubMed Google Scholar
  57. de Jong, S. et al. Expression QTL analysis of top loci from GWAS meta-analysis highlights additional schizophrenia candidate genes. Eur. J. Hum. Genet. 20, 1004–1008 (2012).
    Article CAS PubMed PubMed Central Google Scholar
  58. Fransen, K. et al. Analysis of SNPs with an effect on gene expression identifies UBE2L3 and BCL3 as potential new risk genes for Crohn's disease. Hum. Mol. Genet. 19, 3482–3488 (2010).
    Article CAS PubMed Google Scholar
  59. Luo, R. et al. Genome-wide transcriptome profiling reveals the functional impact of rare de novo and recurrent CNVs in autism spectrum disorders. Am. J. Hum. Genet. 91, 38–55 (2012).
    Article CAS PubMed PubMed Central Google Scholar
  60. Speliotes, E.K. et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat. Genet. 42, 937–948 (2010).
    Article CAS PubMed PubMed Central Google Scholar
  61. Zeller, T. et al. Genetics and beyond—the transcriptome of human monocytes and disease susceptibility. PLoS ONE 5, e10693 (2010).
    Article PubMed PubMed Central CAS Google Scholar
  62. Gamazon, E.R., Huang, R.S., Cox, N.J. & Dolan, M.E. Chemotherapeutic drug susceptibility associated SNPs are enriched in expression quantitative trait loci. Proc. Natl. Acad. Sci. USA 107, 9287–9292 (2010).
    Article CAS PubMed PubMed Central Google Scholar
  63. Thurman, R.E. et al. The accessible chromatin landscape of the human genome. Nature 489, 75–82 (2012).
    Article CAS PubMed PubMed Central Google Scholar
  64. Degner, J.F. et al. DNase I sensitivity QTLs are a major determinant of human expression variation. Nature 482, 390–394 (2012).
    Article CAS PubMed PubMed Central Google Scholar
  65. Yang, J., Lee, S.H., Goddard, M.E. & Visscher, P.M. GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88, 76–82 (2011).
    CAS PubMed PubMed Central Google Scholar
  66. Saha, S., Chant, D., Welham, J. & McGrath, J. A systematic review of the prevalence of schizophrenia. PLoS Med. 2, e141 (2005).
    Article PubMed PubMed Central Google Scholar
  67. Stahl, E.A. et al. Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis. Nat. Genet. 44, 483–489 (2012).
    Article CAS PubMed PubMed Central Google Scholar
  68. Wray, N.R. & Gottesman, I.I. Using summary data from the Danish national registers to estimate heritabilities for schizophrenia, bipolar disorder, and major depressive disorder. Front. Genet. 3, 118 (2012).
    Article PubMed PubMed Central Google Scholar
  69. Lander, E.S. Initial impact of the sequencing of the human genome. Nature 470, 187–197 (2011).
    Article CAS PubMed Google Scholar
  70. Sullivan, P. Don't give up on GWAS. Mol. Psychiatry 17, 2–3 (2012).
    Article CAS PubMed Google Scholar
  71. Park, J.H. et al. Estimation of effect size distribution from genome-wide association studies and implications for future discoveries. Nat. Genet. 42, 570–575 (2010).
    Article CAS PubMed PubMed Central Google Scholar
  72. Stahl, E.A. et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat. Genet. 42, 508–514 (2010).
    CAS PubMed PubMed Central Google Scholar
  73. Betancur, C. Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 1380, 42–77 (2011).
    Article CAS PubMed Google Scholar
  74. Chiurazzi, P., Schwartz, C.E., Gecz, J. & Neri, G. XLMR genes: update 2007. Eur. J. Hum. Genet. 16, 422–434 (2008).
    Article CAS PubMed Google Scholar
  75. Inlow, J.K. & Restifo, L.L. Molecular and comparative genetics of mental retardation. Genetics 166, 835–881 (2004).
    Article CAS PubMed PubMed Central Google Scholar
  76. Bergen, S.E. et al. Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared to bipolar disorder. Mol. Psychiatry 17, 880–886 (2012).
    Article CAS PubMed PubMed Central Google Scholar
  77. Kristjansson, E., Allebeck, P. & Wistedt, B. Validity of the diagnosis of schizophrenia in a psychiatric inpatient register. Nord. Psykiatr. Tidsskr. 41, 229–234 (1987).
    Article Google Scholar
  78. Dalman, C., Broms, J., Cullberg, J. & Allebeck, P. Young cases of schizophrenia identified in a national inpatient register—are the diagnoses valid? Soc. Psychiatry Psychiatr. Epidemiol. 37, 527–531 (2002).
    Article PubMed Google Scholar
  79. World Health Organization. International Classification of Diseases (World Health Organization, Geneva, 1967).
  80. World Health Organization. International Classification of Diseases (World Health Organization, Geneva, 1978).
  81. World Health Organization. International Classification of Diseases (World Health Organization, Geneva, 1992).
  82. Hultman, C.M., Sparen, P., Takei, N., Murray, R.M. & Cnattingius, S. Prenatal and perinatal risk factors for schizophrenia, affective psychosis, and reactive psychosis of early onset: case-control study. Br. Med. J. 318, 421–426 (1999).
    Article CAS Google Scholar
  83. Zammit, S. et al. Investigating the association between cigarette smoking and schizophrenia in a cohort study. Am. J. Psychiatry 160, 2216–2221 (2003).
    Article PubMed Google Scholar
  84. Andersson, R.E., Olaison, G., Tysk, C. & Ekbom, A. Appendectomy and protection against ulcerative colitis. N. Engl. J. Med. 344, 808–814 (2001).
    Article CAS PubMed Google Scholar
  85. Hansson, L.E. et al. The risk of stomach cancer in patients with gastric or duodenal ulcer disease. N. Engl. J. Med. 335, 242–249 (1996).
    Article CAS PubMed Google Scholar
  86. Schwartz, S. & Susser, E. Genome-wide association studies: does only size matter? Am. J. Psychiatry 167, 741–744 (2010).
    Article PubMed Google Scholar
  87. Craddock, N. & Owen, M.J. The Kraepelinian dichotomy—going, going but still not gone. Br. J. Psychiatry 196, 92–95 (2010).
    Article PubMed PubMed Central Google Scholar
  88. Hartge, P. Participation in population studies. Epidemiology 17, 252–254 (2006).
    Article PubMed Google Scholar
  89. Morton, L.M., Cahill, J. & Hartge, P. Reporting participation in epidemiologic studies: a survey of practice. Am. J. Epidemiol. 163, 197–203 (2006).
    Article PubMed Google Scholar
  90. Bulik, C.M. et al. Patterns of remission, continuation and incidence of broadly defined eating disorders during early pregnancy in the Norwegian Mother and Child Cohort Study (MoBa). Psychol. Med. 37, 1109–1118 (2007).
    Article PubMed PubMed Central Google Scholar
  91. Purcell, S. et al. PLINK: a toolset for whole-genome association and population-based linkage analysis. Am. J. Hum. Genet. 81, 559–575 (2007).
    Article CAS PubMed PubMed Central Google Scholar
  92. Howie, B., Marchini, J. & Stephens, M. Genotype imputation with thousands of genomes. G3 1, 457–470 (2011).
    Article PubMed PubMed Central Google Scholar
  93. Delaneau, O., Marchini, J. & Zagury, J.F. A linear complexity phasing method for thousands of genomes. Nat. Methods 9, 179–181 (2012).
    Article CAS Google Scholar
  94. McGrath, J.J. Variations in the incidence of schizophrenia: data versus dogma. Schizophr. Bull. 32, 195–197 (2006).
    Article PubMed PubMed Central Google Scholar
  95. Lips, E.S. et al. Functional gene group analysis identifies synaptic gene groups as risk factor for schizophrenia. Mol. Psychiatry 17, 996–1006 (2012).
    Article CAS PubMed Google Scholar
  96. Irish Schizophrenia Genomics Consortium & Wellcome Trust Case Control Consortium. Genome-wide association study implicates HLA-C*01:02 as a risk factor at the MHC locus in schizophrenia. Biol. Psychiatry 72, 620–628 (2012).
  97. Psychosis Endophenotypes International Consortium & Wellcome Trust Case-Control Consortium 2. A genome-wide association analysis of a broad psychosis phenotype identifies three loci for further investigation. Biol. Psychiatry doi:10.1016/j.biopsych.2013.03.033 (17 July 2013).10.1016/j.biopsych.2013.03.033
  98. Levinson, D.F. et al. Genome-wide association study of multiplex schizophrenia pedigrees. Am. J. Psychiatry 169, 963–973 (2012).
    Article PubMed PubMed Central Google Scholar

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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.

Author information

Author notes

  1. Stephan Ripke, Colm O'Dushlaine and Ananth C Viswanathan: These authors contributed equally to this work.
  2. Nicholas W Wood, Christina M Hultman and Patrick F Sullivan: These authors jointly directed this work.

Authors and Affiliations

  1. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
    Stephan Ripke, Menachem Fromer, Brendan K Bulik-Sullivan, Benjamin M Neale & Shaun Purcell
  2. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
    Stephan Ripke, Colm O'Dushlaine, Kimberly Chambert, Jennifer L Moran, Menachem Fromer, Nick Sanchez, Benjamin M Neale, Edward Scolnick, Shaun Purcell & Steven A McCarroll
  3. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA
    Anna K Kähler, Ann L Collins, James J Crowley, Yunjung Kim, Stephanie Williams & Patrick F Sullivan
  4. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
    Anna K Kähler, Susanne Akterin, Sarah E Bergen, Patrik K E Magnusson, Christina M Hultman & Patrick F Sullivan
  5. Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
    Anna K Kähler
  6. Department of Psychiatry, Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, New York, USA
    Menachem Fromer, Eli A Stahl, Douglas Ruderfer, Jeremy M Silverman, Shaun Purcell & Pamela Sklar
  7. Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia
    Sang Hong Lee, Naomi R Wray, Bryan J Mowry & Deborah A Nertney
  8. Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina, USA
    Kai Xia & Patrick F Sullivan
  9. deCODE Genetics, Reykjavik, Iceland
    Francesco Bettella, Hreinn Stefansson, Stacy Steinberg & Kari Stefansson
  10. Aarhus University Hospital, Risskov, Denmark
    Anders D Borglum
  11. Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark
    Anders D Borglum
  12. Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus and Copenhagen, Denmark
    Anders D Borglum, Ole Mors & Preben B Mortensen
  13. Department of Psychiatry, Trinity College Dublin, Dublin, Ireland
    Paul Cormican, Michael Gill, Derek W Morris, Aiden P Corvin, Aiden P Corvin & Aiden P Corvin
  14. Medical Research Council (MRC) Centre for Psychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK
    Nick Craddock, Marian L Hamshere, Peter Holmans, Michael J Owen, Alexander L Richards, James T Walters, Michael C O'Donovan, Michael J Owen, Peter Holmans, Nadine Norton, Nigel M Williams & Michael C O'Donovan
  15. Department of Functional Genomics, Clinical Genetics, Center for Neurogenomics and Cognitive Research, VU University Amsterdam and VU Medical Center, Amsterdam, The Netherlands
    Christiaan de Leeuw, Danielle Posthuma & Matthijs Verhage
  16. Institute for Computing and Information Sciences, Radboud University, Nijmegen, The Netherlands
    Christiaan de Leeuw
  17. Department of Child and Adolescent Psychiatry, University Clinic of Psychiatry, Skopje, Republic of Macedonia
    Naser Durmishi
  18. Neuropsychiatric Genetics Research Group, Trinity College Dublin, Dublin, Ireland
    Michael Gill, Derek W Morris, Aiden P Corvin, Aiden P Corvin & Aiden P Corvin
  19. Mental Health Research Center, Russian Academy of Medical Sciences, Moscow, Russia
    Vera Golimbet
  20. Statens Serum Institut, Copenhagen, Denmark
    David M Hougaard
  21. Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA
    Kenneth S Kendler, Brien P Riley, Kenneth S Kendler & Brien P Riley
  22. Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA
    Kenneth S Kendler, Brien P Riley, Kenneth S Kendler, Brien P Riley, Robert Ribble & Brandon Wormley
  23. Institute of Psychiatry at King's College London, London, UK
    Kuang Lin, John Powell, Maria J Arranz, Elvira Bramon, David Collier, Conrad Iyegbe, Cathryn M Lewis, Kuang Lin, Robin M Murray, John Powell, Jim Van Os, Muriel Walshe, Elvira Bramon & Elvira Bramon
  24. Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark
    Ole Mors
  25. National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark
    Preben B Mortensen
  26. Centre for Public Health, Queen's University, Belfast, UK
    Francis A O'Neill & Francis A O'Neill
  27. University of Belgrade, Faculty of Medicine, Belgrade, Serbia
    Milica Pejovic Milovancevic
  28. Department of Child and Adolescent Psychiatry, Erasmus University Medical Centre, Rotterdam, The Netherlands
    Danielle Posthuma
  29. Department of Neuroscience, King's College London, London, UK
    John Powell & John Powell
  30. Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, USA
    Brien P Riley & Brien P Riley
  31. Department of Psychiatry, University of Halle, Halle, Germany
    Dan Rujescu & Dan Rujescu
  32. Department of Psychiatry, University of Munich, Munich, Germany
    Dan Rujescu & Dan Rujescu
  33. Department of Psychiatry, University of Iceland, Reykjavik, Iceland
    Engilbert Sigurdsson
  34. Department of Psychiatry, Tbilisi State Medical University, Tbilisi, Georgia
    Teimuraz Silagadze
  35. Center for Neurogenomics and Cognitive Research, VU University Amsterdam, Amsterdam, The Netherlands
    August B Smit
  36. Department of Molecular and Cellular Neuroscience, VU University Amsterdam, Amsterdam, The Netherlands
    August B Smit
  37. Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland
    Jaana Suvisaari
  38. Section of Psychiatry, University of Verona, Verona, Italy
    Sarah Tosato
  39. Institute of Cognitive Neuroscience, University College London, London, UK
    Elvira Bramon, Elvira Bramon & Elvira Bramon
  40. Mental Health Sciences Unit, University College London, London, UK
    Elvira Bramon, Elvira Bramon & Elvira Bramon
  41. Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
    Shaun Purcell
  42. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA
    Steven A McCarroll
  43. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, USA
    Douglas F Levinson & Madeline Alexander
  44. Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem and University of Chicago, Evanston, Illinois, USA
    Pablo V Gejman, Jubao Duan & Alan R Sanders
  45. Child and Adolescent Psychiatry, Pierre and Marie Curie Faculty of Medicine, Brain and Spinal Cord Institute, Paris, France
    Claudine Laurent
  46. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    Ann E Pulver & Gerald Nestadt
  47. Psychiatry and Psychotherapy Clinic, Friedrich-Alexander University, Erlangen-Nuremberg, Erlangen, Germany
    Sibylle G Schwab
  48. Department of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Western Australia, Australia
    Dieter B Wildenauer
  49. Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
    Frank Dudbridge
  50. Division of Cancer Epidemiology & Genetics, National Cancer Institute, Bethesda, Maryland, USA
    Jianxin Shi
  51. State Mental Hospital, Haar, Germany
    Margot Albus
  52. INSERM U1079, Faculté de Médecine, Rouen, France
    Dominique Campion
  53. Pierre and Marie Curie Faculty of Medicine, Institute for Intelligent Systems and Robotics, Paris, France
    David Cohen
  54. First Department of Psychiatry, University of Athens Medical School, Athens, Greece
    Dimitris Dikeos & George N Papadimitriou
  55. Department of Psychiatry, University of Regensburg, Regensburg, Germany
    Peter Eichhammer
  56. INSERM, Institut de Myologie, Hôpital Pitié Salpêtrière, Paris, France
    Stephanie Godard
  57. Illumina, Inc., La Jolla, California, USA
    Mark Hansen
  58. Department of Psychiatry, Hadassah–Hebrew University Medical Center, Jerusalem, Israel
    F Bernard Lerer
  59. Department of Biostatistics, Johns Hopkins University, Baltimore, Maryland, USA
    Kung-Yee Liang
  60. Department of Psychiatry, University of Bonn, Bonn, Germany
    Wolfgang Maier
  61. CNRS, Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, Hôpital Pitié Salpêtrière, Paris, France
    Jacques Mallet
  62. The Health Research Board, Dublin, Ireland
    Dermot Walsh
  63. Fundacio de Docencia i Recerca Mutua de Terrassa, Universitat de Barcelona, Barcelona, Spain
    Maria J Arranz
  64. Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands
    Steven Bakker & Rene S Kahn
  65. Child and Adolescent Psychiatry, University of Technology Dresden, Dresden, Germany
    Stephan Bender
  66. Section for Experimental Psychopathology, General Psychiatry, Heidelberg, Germany
    Stephan Bender & Matthias Weisbrod
  67. Discovery Neuroscience Research, Eli Lilly and Company, London, UK
    David Collier
  68. CIBERSAM (Centro Investigación Biomédica en Red Salud Mental), Madrid, Spain
    Benedicto Crespo-Facorro & Ignacio Mata
  69. University Hospital Marques de Valdecilla, Instituto de Formacion e Investigacion Marques de Valdecilla, University of Cantabria, Santander, Spain
    Benedicto Crespo-Facorro & Ignacio Mata
  70. Division of Psychiatry, University of Edinburgh, Edinburgh, UK
    Jeremy Hall, Stephen Lawrie & Andrew McIntosh
  71. Centre for Clinical Research in Neuropsychiatry, The University of Western Australia, Perth, Western Australia, Australia
    Assen Jablensky
  72. Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia
    Luba Kalaydjieva
  73. Western Australian Institute for Medical Research, The University of Western Australia, Perth, Western Australia, Australia
    Luba Kalaydjieva
  74. Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
    Don H Linszen
  75. Center for Neurobehavioral Genetics, University of California, Los Angeles, Los Angeles, California, USA
    Roel A Ophoff
  76. Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, EURON, Maastricht, The Netherlands
    Jim Van Os
  77. Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
    Durk Wiersma
  78. Department of Statistics, University of Oxford, Oxford, UK
    Peter Donnelly (Chair) & Peter Donnelly
  79. Wellcome Trust Centre for Human Genetics, Oxford, UK
    Peter Donnelly (Chair), Anna Rautanen, Chris C A Spencer, Gavin Band, Céline Bellenguez, Colin Freeman, Garrett Hellenthal, Eleni Giannoulatou, Matti Pirinen, Richard D Pearson, Amy Strange, Zhan Su, Damjan Vukcevic, Peter Donnelly & Chris C A Spencer
  80. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
    Ines Barroso (Deputy Chair), Panos Deloukas, Cordelia Langford, Sarah E Hunt, Sarah Edkins, Rhian Gwilliam, Hannah Blackburn, Suzannah J Bumpstead, Serge Dronov, Matthew Gillman, Emma Gray, Naomi Hammond, Alagurevathi Jayakumar, Owen T McCann, Jennifer Liddle, Simon C Potter, Radhi Ravindrarajah, Michelle Ricketts, Avazeh Tashakkori-Ghanbaria, Matthew J Waller, Paul Weston, Sara Widaa, Pamela Whittaker, Ines Barroso & Panos Deloukas
  81. Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge, UK
    Jenefer M Blackwell & Jenefer M Blackwell
  82. Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Subiaco, Western Australia, Australia
    Jenefer M Blackwell & Jenefer M Blackwell
  83. Diamantina Institute of Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia
    Matthew A Brown & Matthew A Brown
  84. Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK
    Juan P Casas
  85. Department of Epidemiology and Public Health, University College London, London, UK
    Juan P Casas
  86. Molecular and Physiological Sciences, The Wellcome Trust, London, UK
    Audrey Duncanson
  87. Peninsula School of Medicine and Dentistry, Plymouth University, Plymouth, UK
    Janusz Jankowski
  88. Clinical Neurosciences, St. George's University of London, London, UK
    Hugh S Markus
  89. Department of Medical and Molecular Genetics, School of Medicine, King's College London, Guy's Hospital, London, UK
    Christopher G Mathew, Richard C Trembath & Christopher G Mathew (Chair)
  90. Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, UK
    Colin N A Palmer
  91. Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK
    Robert Plomin
  92. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
    Stephen J Sawcer
  93. Institute of Ophthalmology, University College London, London, UK
    Ananth C Viswanathan
  94. National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital National Health Service Foundation Trust, London, UK
    Ananth C Viswanathan
  95. Department of Molecular Neuroscience, Institute of Neurology, London, UK
    Nicholas W Wood
  96. Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK
    Mark I McCarthy

Authors

  1. Stephan Ripke
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  2. Colm O'Dushlaine
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  3. Kimberly Chambert
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  4. Jennifer L Moran
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  5. Anna K Kähler
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  6. Susanne Akterin
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  7. Sarah E Bergen
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  8. Ann L Collins
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  9. James J Crowley
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  10. Menachem Fromer
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  11. Yunjung Kim
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  12. Sang Hong Lee
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  13. Patrik K E Magnusson
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  14. Nick Sanchez
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  15. Eli A Stahl
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  18. Kai Xia
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  19. Francesco Bettella
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  20. Anders D Borglum
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  44. Douglas Ruderfer
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  45. Dan Rujescu
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  46. Engilbert Sigurdsson
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  47. Teimuraz Silagadze
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  48. August B Smit
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  54. James T Walters
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  57. Michael C O'Donovan
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  58. Kari Stefansson
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  59. Edward Scolnick
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  60. Shaun Purcell
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  61. Steven A McCarroll
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  62. Pamela Sklar
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  64. Patrick F Sullivan
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Consortia

Multicenter Genetic Studies of Schizophrenia Consortium

Psychosis Endophenotypes International Consortium

Wellcome Trust Case Control Consortium 2

Contributions

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.

Corresponding author

Correspondence toPatrick F Sullivan.

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Competing interests

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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