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Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection

Nature Geneticsvolume 50pages381389 (2018) | Download Citation

Abstract

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.

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Acknowledgements

General. This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement 279227 (CRESTAR Consortium). The work at Cardiff University was funded by the Medical Research Council (MRC) Centre (MR/L010305/1), a program grant (G0800509) and a project grant (MR/L011794/1) and by the European Community’s Seventh Framework Programme HEALTH-F2-2010-241909 (project EU-GEI). U.D. received funding from the German Research Foundation (DFG, grant FOR2107 DA1151/5-1; SFB-TRR58, project C09) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17). E.M.B. and N.R.W. received salary funding from the National Health and Medical Research Council (NHMRC; 1078901, 105363). E. Santiago and A.C. received funding from the Agencia Estatal de Investigación (AEI; CGL2016-75904-C2-1-P), Xunta de Galicia (ED431C 2016-037) and Fondo Europeo de Desarrollo Regional (FEDER). The iPSYCH and GEMS2 teams acknowledge funding from the Lundbeck Foundation (grants R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, an advanced grant from the European Research Council (project 294838), the Danish Strategic Research Council and grants from Aarhus University to the iSEQ and CIRRAU centers.

Case data. We thank the participants and clinicians who took part in the CardiffCOGS study. For the CLOZUK2 sample, we thank Leyden Delta for supporting the sample collection, anonymization and data preparation (particularly M. Helthuis, J. Jansen, K. Jollie and A. Colson), Magna Laboratories, UK (A. Walker) and, for CLOZUK1, Novartis and the Doctor’s Laboratory staff for their guidance and cooperation. We acknowledge L. Bates, C. Bresner and L. Hopkins, at Cardiff University, for laboratory sample management. We acknowledge W. Lawrence and M. Einon, at Cardiff University, for support with the use and setup of computational infrastructures.

Control data. A full list of the investigators who contributed to the generation of the Wellcome Trust Case Control Consortium (WTCCC) data is available from its website. Funding for the project was provided by the Wellcome Trust under award 076113. The UK10K project was funded by Wellcome Trust award WT091310. Venous blood collection for the 1958 Birth Cohort (NCDS) was funded by UK MRC grant G0000934, peripheral blood lymphocyte preparation was funded by the Juvenile Diabetes Research Foundation (JDRF) and the Wellcome Trust, and cell line production, DNA extraction and processing were funded by Wellcome Trust grant 06854/Z/02/Z. Genotyping was supported by the Wellcome Trust (083270) and the European Union (ENGAGE: HEALTH-F4-2007-201413). The UK Blood Services Common Controls (UKBS-CC collection) was funded by the Wellcome Trust (076113/C/04/Z) and by a National Institute for Health Research (NIHR) programme grant to the NHS Blood and Transplant authority (NHSBT; RP-PG-0310-1002). NHSBT also made possible the recruitment of the Cardiff Controls, from participants who provided informed consent. Generation Scotland (GS) received core funding from the Chief Scientist Office of the Scottish government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland, and was funded by the MRC and Wellcome Trust (grant 10436/Z/14/Z). The Type 1 Diabetes Genetics Consortium (T1DGC; EGA dataset EGAS00000000038) is a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), the National Human Genome Research Institute (NHGRI), the National Institute of Child Health and Human Development (NICHD) and JDRF. The People of the British Isles project (POBI) is supported by the Wellcome Trust (088262/Z/09/Z). TwinsUK is funded by the Wellcome Trust, MRC, European Union, NIHR-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. Funding for the QIMR samples was provided by the Australian NHMRC (241944, 339462, 389875, 389891, 389892, 389927, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613608, 613674, 619667), the Australian Research Council (FT0991360, FT0991022), the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254) and the US National Institutes of Health (NIH; AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951) and the Center for Inherited Disease Research (Baltimore, MD, USA). TEDS is supported by a program grant from the MRC (G0901245-G0500079), with additional support from the NIH (HD044454, HD059215). In the GERAD1 Consortium, Cardiff University was supported by the Wellcome Trust, the MRC, Alzheimer’s Research UK (ARUK) and the Welsh government. King’s College London acknowledges support from the MRC. The University of Belfast acknowledges support from ARUK, the Alzheimer’s Society, Ulster Garden Villages, the Northern Ireland R&D Office and the Royal College of Physicians/Dunhill Medical Trust. Washington University was funded by NIH grants, the Barnes Jewish Foundation, and the Charles and Joanne Knight Alzheimer’s Research Initiative. The Bonn group was supported by the German Federal Ministry of Education and Research (BMBF), Competence Network Dementia and Competence Network Degenerative Dementia and by the Alfried Krupp von Bohlen und Halbach-Stiftung.

Author information

Affiliations

  1. MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK

    • Antonio F. Pardiñas
    • , Peter Holmans
    • , Andrew J. Pocklington
    • , Valentina Escott-Price
    • , Noa Carrera
    • , Sophie E. Legge
    • , Sophie Bishop
    • , Darren Cameron
    • , Marian L. Hamshere
    • , Jun Han
    • , Leon Hubbard
    • , Amy Lynham
    • , Kiran Mantripragada
    • , Elliott Rees
    • , Valentina Escott-Price
    • , Peter Holmans
    • , Michael O’Donovan
    • , Michael Owen
    • , Sophie E. Legge
    • , Michael C. O’Donovan
    • , Michael J. Owen
    • , Antonio F. Pardiñas
    • , James T. R. Walters
    • , George Kirov
    • , Michael J. Owen
    • , Michael C. O’Donovan
    •  & James T. R. Walters
  2. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

    • Stephan Ripke
  3. Department of Psychiatry and Psychotherapy, Charité, Campus Mitte, Berlin, Germany

    • Stephan Ripke
  4. Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    • James H. MacCabe
    • , Fiona Gaughran
    •  & James MacCabe
  5. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    • Steven A. McCarroll
  6. Discipline of Psychiatry, University of Adelaide, Adelaide, South Australia, Australia

    • Bernhard T. Baune
  7. MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    • Gerome Breen
    • , Thalia C. Eley
    • , Robert Plomin
    • , Gerome Breen
    • , David A. Collier
    • , Danai Dima
    • , Cathryn Lewis
    • , Jonathan Mill
    • , Evangelos Vassos
    • , Moira Verbelen
    •  & David A. Collier
  8. NIHR Biomedical Research Centre for Mental Health, Maudsley Hospital and Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    • Gerome Breen
    •  & Gerome Breen
  9. Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia

    • Enda M. Byrne
    •  & Naomi R. Wray
  10. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia

    • Enda M. Byrne
    •  & Naomi R. Wray
  11. Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany

    • Udo Dannlowski
  12. Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

    • Caroline Hayward
    •  & David J. Porteous
  13. School of Psychology, University of Queensland, Brisbane, Queensland, Australia

    • Nicholas G. Martin
  14. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

    • Nicholas G. Martin
  15. Division of Psychiatry, University of Edinburgh, Edinburgh, UK

    • Andrew M. McIntosh
  16. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK

    • Andrew M. McIntosh
  17. Departamento de Bioquímica, Genética e Inmunología. Facultad de Biología, Universidad de Vigo, Vigo, Spain

    • Armando Caballero
  18. Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    • Daniel H. Geschwind
    •  & Hyejung Won
  19. Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Laura M. Huckins
    • , Douglas M. Ruderfer
    • , Pamela Sklar
    •  & Eli A. Stahl
  20. Departamento de Biología Funcional. Facultad de Biología, Universidad de Oviedo, Oviedo, Spain

    • Enrique Santiago
  21. iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark

    • Esben Agerbo
    • , Thomas D. Als
    • , Marie Bækvad-Hansen
    • , Preben Bo Mortensen
    • , Carsten Bøcker Pedersen
    • , Anders D. Børglum
    • , Jonas Bybjerg-Grauholm
    • , Marianne Giørtz Pedersen
    • , Jakob Grove
    • , David M. Hougaard
    • , Manuel Mattheisen
    • , Ole Mors
    • , Merete Nordentoft
    • , Christine Søholm Hansen
    • , Thomas Werge
    • , Esben Agerbo
    • , Jakob Grove
    • , Ole Mors
    • , Preben Bo Mortensen
    • , Carsten B. Pedersen
    •  & Thomas Werge
  22. National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark

    • Esben Agerbo
    • , Preben Bo Mortensen
    • , Carsten Bøcker Pedersen
    • , Marianne Giørtz Pedersen
    • , Esben Agerbo
    • , Preben Bo Mortensen
    •  & Carsten B. Pedersen
  23. iSEQ, Center for Integrative Sequencing, Aarhus University, Aarhus, Denmark

    • Thomas D. Als
    • , Preben Bo Mortensen
    • , Anders D. Børglum
    • , Jakob Grove
    • , Manuel Mattheisen
    • , Jakob Grove
    •  & Preben Bo Mortensen
  24. Department of Biomedicine–Human Genetics, Aarhus University, Aarhus, Denmark

    • Thomas D. Als
    • , Anders D. Børglum
    • , Jakob Grove
    • , Manuel Mattheisen
    •  & Jakob Grove
  25. Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    • Ole A. Andreassen
  26. NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway

    • Ole A. Andreassen
  27. Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark

    • Marie Bækvad-Hansen
    • , Jonas Bybjerg-Grauholm
    • , David M. Hougaard
    •  & Christine Søholm Hansen
  28. NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway

    • Srdjan Djurovic
  29. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway

    • Srdjan Djurovic
  30. Department of Child and Adolescent Psychiatry, University Clinic of Psychiatry, Skopje, Macedonia

    • Naser Durmishi
  31. Department of Clinical Genetics, Mental Health Research Center, Moscow, Russia

    • Vera Golimbet
  32. Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark

    • Jakob Grove
    •  & Jakob Grove
  33. Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway

    • Espen Molden
    •  & Ole Köhler
  34. Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark

    • Ole Mors
    •  & Ole Mors
  35. Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark

    • Merete Nordentoft
    •  & Holger J. Sørensen
  36. Department of Psychiatry, School of Medicine, University of Belgrade, Belgrade, Serbia

    • Milica Pejovic-Milovancevic
  37. Department of Psychiatry, National University Hospital, Reykjavik, Iceland

    • Engilbert Sigurdsson
  38. Department of Psychiatry and Drug Addiction, Tbilisi State Medical University (TSMU), Tbilisi, Georgia

    • Teimuraz Silagadze
  39. deCODE Genetics, Reykjavik, Iceland

    • Kari Stefansson
    • , Hreinn Stefansson
    • , Stacy Steinberg
    •  & Hreinn Stefansson
  40. Section of Psychiatry, Department of Public Health and Community Medicine, University of Verona, Verona, Italy

    • Sarah Tosato
  41. Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark

    • Thomas Werge
    •  & Thomas Werge
  42. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    • Thomas Werge
    •  & Thomas Werge
  43. Discovery Neuroscience Research, Eli Lilly and Company, Lilly Research Laboratories, Windlesham, UK

    • David A. Collier
    •  & David A. Collier
  44. Department of Psychiatry, University of Halle, Halle, Germany

    • Ina Giegling
    • , Annette M. Hartmann
    • , Bettina Konte
    • , Dan Rujescu
    •  & Dan Rujescu
  45. Department of Psychiatry, University of Munich, Munich, Germany

    • Dan Rujescu
    •  & Dan Rujescu
  46. MRC Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK

    • Denise Harold
    • , Rebecca Sims
    • , Amy Gerrish
    • , Jade Chapman
    • , Richard Abraham
    • , Paul Hollingworth
    • , Jaspreet Pahwa
    • , Nicola Denning
    • , Charlene Thomas
    • , Sarah Taylor
    •  & Julie Williams
  47. Neuropsychiatric Genetics Group, Department of Psychiatry, Trinity Centre for Health Sciences, St James’s Hospital, Dublin, Ireland

    • Denise Harold
  48. Institute of Psychiatry, Department of Neuroscience, King’s College London, London, UK

    • John Powell
    • , Petroula Proitsi
    • , Michelle Lupton
    •  & Simon Lovestone
  49. Department of Psychiatry, University of Oxford, Oxford, UK

    • Simon Lovestone
  50. Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University, Belfast, UK

    • Peter Passmore
    • , David Craig
    • , Bernadette McGuinness
    • , Janet Johnston
    •  & Stephen Todd
  51. Department of Psychiatry, University of Bonn, Bonn, Germany

    • Wolfgang Maier
    • , Frank Jessen
    • , Reiner Heun
    • , Britta Schurmann
    •  & Alfredo Ramirez
  52. Institute for Molecular Psychiatry, University of Bonn, Bonn, Germany

    • Britta Schurmann
  53. Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany

    • Tim Becker
    • , Christine Herold
    • , André Lacour
    •  & Dmitriy Drichel
  54. Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany

    • Markus Nothen
    •  & Markus M. Nöthen
  55. Departments of Psychiatry, Neurology and Genetics, Washington University School of Medicine, St. Louis, MO, USA

    • Alison Goate
    • , Carlos Cruchaga
    • , Petra Nowotny
    • , John C. Morris
    •  & Kevin Mayo
  56. Centre for Economics of Mental and Physical Health, Health Service and Population Research Department, Institute of Psychiatry, King’s College London, London, UK

    • Evanthia Achilla
    • , Ramon Sabes-Figuera
    •  & Paul McCrone
  57. Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada

    • Cathy L. Barr
  58. National Centre for Register-Based Research, Department of Economics and Business, School of Business and Social Sciences, Aarhus University, Aarhus, Denmark

    • Theresa Wimberly Böttger
    • , Christiane Gasse
    • , Henriette Thisted Horsdal
    •  & Sandra M. Meier
  59. Department of Community Mental Health, Mental Health Organization North–Holland North, Heerhugowaard, the Netherlands

    • Dan Cohen
  60. Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    • Sarah Curran
  61. Brighton and Sussex Medical School, University of Sussex, Brighton, UK

    • Sarah Curran
  62. University of Exeter Medical School, RILD, University of Exeter, Exeter, UK

    • Emma Dempster
    • , Eilis Hannon
    •  & Jonathan Mill
  63. Toxicology Unit, Department of Clinical Biochemistry, King’s College Hospital NHS Foundation Trust, London, UK

    • Robert J. Flanagan
  64. Clinical Neurosciences Studies Center, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Sophia Frangou
  65. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany

    • Josef Frank
    • , Maren Lang
    • , Marcella Rietschel
    •  & Jana Strohmaier
  66. Centre for Integrated Register-based Research, CIRRAU, Aarhus University, Aarhus, Denmark

    • Christiane Gasse
    •  & Henrik Støvring
  67. Concentris Research Management, Fürstenfeldbruck, Germany

    • Barbara Heißerer
    •  & Ameli Schwalber
  68. Leyden Delta, Nijmegen, the Netherlands

    • Marinka Helthuis
    •  & Karel Jollie
  69. Department of Psychiatry, Landspitali University Hospital, Reykjavik, Iceland

    • Oddur Ingimarsson
    •  & Engilbert Sigurdsson
  70. Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    • James L. Kennedy
  71. Division of Psychiatry Research, Zucker Hillside Hospital, Northwell Health System, Glen Oaks, NY, USA

    • Anil K. Malhotra
  72. Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    • Benjamin Spencer
  73. Center for Psychiatric Genomics, Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

    • Patrick Sullivan
  74. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    • Patrick Sullivan

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Consortia

  1. GERAD1 Consortium:

  1. CRESTAR Consortium:

  1. GERAD1 Consortium

    1. CRESTAR Consortium

      1. GERAD1 Consortium

        1. CRESTAR Consortium

          Contributions

          A.F.P. curated and processed genetic data, performed statistical analyses, contributed to the interpretation of results and participated in the primary drafting of the manuscript. P.H., A.J.P., V.E.-P., A.C. and E. Santiago performed statistical analyses, contributed to the interpretation of results and participated in the primary drafting of the manuscript. S.R. curated and processed genetic data and participated in the primary drafting of the manuscript. N.C. and M.L.H. contributed to the interpretation of results and participated in the primary drafting of the manuscript. S.E.L., S.B. and A.L. participated in the recruitment of participants for the study and curated and managed their phenotypic information. D.C., J.H., L.H., E.R. and G.K. contributed and curated data used in the statistical analyses. K.M. managed the laboratory and genotyping procedures at Cardiff University. J.H.M., D.A.C. and D.R. supervised the recruitment of the participants for the study. S.A.M. managed the genotyping of samples for the study. N.R.W. contributed genotypes of control samples and participated in the primary drafting of the manuscript. Control data were obtained from the GERAD1 Consortium; as such, the investigators within the GERAD1 Consortium contributed to the design and implementation of GERAD1 and/or provided control data but did not participate in analysis or writing of this report. D.H.G., L.M.H., D.M.R., P.S., E.A.S. and H.W. performed statistical analyses and contributed to the interpretation of results. M.J.O. and M.C.O’D. conceived and supervised the project, contributed to the interpretation of results and participated in the primary drafting of the manuscript. J.T.R.W. conceived and supervised the project, led the recruitment of the participants and sample acquisition for the study, performed statistical analysis, contributed to the interpretation of results and participated in the primary drafting of the manuscript. All other authors contributed genotypes of control samples or summary statistics of replication samples. All authors had the opportunity to review and comment on the manuscript, and all approved the final manuscript.

          Competing interests

          D.A.C. is a full-time employee and stockholder of Eli Lilly and Company. The remaining authors declare no conflicts of interest.

          Corresponding authors

          Correspondence to Michael J. Owen or Michael C. O’Donovan or James T. R. Walters.

          Supplementary information

          1. Supplementary Text and Figures

            Supplementary Figures 1–8 and Supplementary Note

          2. Life Sciences Reporting Summary

          3. Supplementary Tables

            Supplementary Tables 1–15

          4. Supplementary Data

            Gene sets that survive conditional analysis

          About this article

          Publication history

          Received

          Accepted

          Published

          DOI

          https://doi.org/10.1038/s41588-018-0059-2

          Further reading