Abstract

By performing a meta-analysis of rare coding variants in whole-exome sequences from 4,133 schizophrenia cases and 9,274 controls, de novo mutations in 1,077 family trios, and copy number variants from 6,882 cases and 11,255 controls, we show that individuals with schizophrenia carry a significant burden of rare, damaging variants in 3,488 genes previously identified as having a near-complete depletion of loss-of-function variants. In patients with schizophrenia who also have intellectual disability, this burden is concentrated in risk genes associated with neurodevelopmental disorders. After excluding known risk genes for neurodevelopmental disorders, a significant rare variant burden persists in other genes intolerant of loss-of-function variants; although this effect is notably stronger in patients with both schizophrenia and intellectual disability, it is also seen in patients with schizophrenia who do not have intellectual disability. Together, our results show that rare, damaging variants contribute to the risk of schizophrenia both with and without intellectual disability and support an overlap of genetic risk between schizophrenia and other neurodevelopmental disorders.

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Acknowledgements

We gratefully thank all participants in these studies. We thank T. Touloupoulou, M. Picchioni, C. Nosarti, F. Gaughran, and O. Howes for contributing clinical data used in this study. The UK10K project was funded by Wellcome Trust grant WT091310. The INTERVAL sequencing studies are funded by Wellcome Trust grant WT098051. T.S. is supported by the Williams College Dr. Herchel Smith Fellowship. A.P. is supported by Academy of Finland grants 251704 and 286500, NIMH grant U01MH105666, and the Sigrid Juselius Foundation. The work at Cardiff University was funded by Medical Research Council (MRC) Centre (G0801418) and Program (G0800509) grants. P.F.S. gratefully acknowledges support from the Swedish Research Council (Vetenskapsrådet, award D0886501). Creation of the Sweden schizophrenia study data was supported by NIMH grant R01 MH077139 and the Stanley Center of the Broad Institute. Participants in INTERVAL were recruited with the active collaboration of NHS Blood and Transplant England, which has supported fieldwork and other elements of the trial. DNA extraction and genotyping were funded by the National Institute of Health Research (NIHR), the NIHR BioResource, and the NIHR Cambridge Biomedical Research Centre. The academic coordinating center for INTERVAL was supported by core funding from the following: the NIHR Blood and Transplant Research Unit in Donor Health and Genomics, the UK MRC (G0800270), and the British Heart Foundation (SP/09/002). For the CNV analysis, we would like to acknowledge the contribution of data from outside sources: (i) Genetic Architecture of Smoking and Smoking Cessation accessed through dbGaP (study accession phs000404.v1.p1). Funding support for genotyping, which was performed at the Center for Inherited Disease Research (CIDR), was provided by 1 X01 HG005274-01. CIDR is fully funded through a federal contract from the National Institutes of Health to the Johns Hopkins University, contract number HHSN268200782096C. Assistance with genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies (GENEVA) Coordinating Center (U01 HG004446). Funding support for collection of data sets and samples was provided by the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the University of Wisconsin Transdisciplinary Tobacco Use Research Center (P50 DA019706 and P50 CA084724). (ii) High-Density SNP Association Analysis of Melanoma: Case–Control and Outcomes Investigation (dbGaP study accession phs000187.v1.p1). Research support to collect data and develop an application to support this project was provided by 3P50CA093459, 5P50CA097007, 5R01ES011740, and 5R01CA133996. (iii) Genetic Epidemiology of Refractive Error in the KORA Study (dbGaP study accession phs000303.v1.p1). Principal investigators: D. Stambolian (University of Pennsylvania) and H.E. Wichmann (Institut für Humangenetik, Helmholtz Zentrum München; National Eye Institute, National Institutes of Health). Funding was provided by R01 EY020483 from the National Institutes of Health. (iv) WTCCC2 study. Samples were downloaded from EGA (http://www.ebi.ac.uk/ega/) and include samples from the National Blood Donors Cohort (EGAD00000000024) and samples from the 1958 British Birth Cohort (EGAD00000000022). Funding for these projects was provided by the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z), the Wellcome Trust (072894/Z/03/Z, 090532/Z/09/Z, and 075491/Z/04/B), and NIMH grants (MH 41953 and MH083094).

Author information

Affiliations

  1. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Tarjinder Singh
    •  & Jeffrey C Barrett
  2. MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.

    • James T R Walters
    • , Elliott Rees
    • , Georg Kirov
    • , Michael C O'Donovan
    •  & Michael J Owen
  3. Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.

    • Mandy Johnstone
    •  & Douglas Blackwood
  4. University College London Genetics Institute, University College London, London, UK.

    • David Curtis
  5. Centre for Psychiatry, Barts and the London School of Medicine and Dentistry, London, UK.

    • David Curtis
  6. National Institute for Health and Welfare, Helsinki, Finland.

    • Jaana Suvisaari
    •  & Minna Torniainen
  7. Institute of Psychiatry, King's College London, London, UK.

    • Conrad Iyegbe
    • , Robin M Murray
    •  & Marta Di Forti
  8. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.

    • Andrew M McIntosh
  9. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Daniel Geschwind
    •  & Michael Gandal
  10. Division of Psychiatry, University College London, London, UK.

    • Elvira Bramon
  11. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Christina M Hultman
  12. Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Pamela Sklar
  13. Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.

    • Aarno Palotie
  14. Program in Medical and Population Genetics and Genetic Analysis Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Aarno Palotie
  15. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Patrick F Sullivan
  16. Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Patrick F Sullivan

Consortia

  1. INTERVAL Study

    A list of contributors is available from http://www.intervalstudy.org.uk/about-the-study/whos-involved/interval-contributors/.

  2. UK10K Consortium

    A list of members appears in the Supplementary Note.

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Contributions

T.S. and J.C.B. conceived and designed the experiments. T.S. performed the statistical analysis. T.S., J.T.R.W., M.J., D.C., J.S., M.T., E.R., and P.F.S. analyzed the data. T.S., J.T.R.W., M.J., J.S., M.T., E.R., C.I., D.B., A.M.M., G.K., D.G., R.M.M., M.D.F., E.B., M.G., C.M.H., P.S., A.P., M.C.O'D., M.J.O., and J.C.B. contributed reagents, materials, or analysis tools. T.S., D.C., M.J.O., and J.C.B. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Tarjinder Singh or Jeffrey C Barrett.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–9 and Supplementary Note.

Excel files

  1. 1.

    Supplementary Table 1

    Full results from enrichment analyses of 1,766 gene sets.

  2. 2.

    Supplementary Table 2

    Gene sets enriched for rare coding variants conferring risk for schizophrenia at FDR < 5%.

  3. 3.

    Supplementary Table 3

    Results from enrichment analyses of FDR < 5% gene sets, conditional on brain-expressed and ExAC loss-of-function-intolerant genes.

  4. 4.

    Supplementary Table 4

    Results from enrichment analyses of rare loss-of-function variants in loss-of-function-intolerant genes and developmental disorder–associated genes comparing schizophrenia cases stratified by information on cognitive function and matched controls.

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DOI

https://doi.org/10.1038/ng.3903

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