1. Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
2. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
3. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
4. Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
5. School of Medicine, Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff C14 4XN, UK.
6. Molecular Psychiatry Laboratory, Department of Mental Health Sciences, University College London Medical School, Windeyer Institute of Medical Sciences, 46 Cleveland Street, London W1T 4JF, UK.
7. Division of Psychiatry, School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh EH10 5HF, UK.
8. Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
9. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
10. Department of Neuroscience, Psychiatry, Ulleråker, Uppsala University, SE-750 17 Uppsala, Sweden.
11. Center for Genomic Psychiatry, University of Southern California, Los Angeles, California 90033, USA.
12. Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
13. Departments of Genetics, Psychiatry, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
14. Queensland Institute of Medical Research, 300 Herston Road, Brisbane, Queensland 4006, Australia.
15. Department of Medical Genetics, University Hospital Maichin Dom, Sofia 1431, Bulgaria.
16. Department of Psychiatry, First Psychiatric Clinic, Alexander University Hospital, Sofia 1431, Bulgaria.
17. Molecular and Cellular Therapeutics and RCSI Research Institute, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
18. West Berkshire NHS Trust, 25 Erleigh Road, Reading RG3 5LR, UK.
19. West London Mental Health Trust, Hammersmith and Fulham Mental Health Unit and St Bernard's Hospital, London W6 8RF, UK.
20. Queen Mary College, University of London and East London and City Mental Health Trust, Royal London Hospital, Whitechapel, London E1 1BB, UK.
21. Department of Mental Health, University of Aberdeen, Aberdeen AB25 2ZD, UK.
22. Ravenscraig Hospital, Inverkip Road, Greenock PA16 9HA, UK.
23. State University of New York – Upstate Medical University, Syracuse, New York 13210, USA.
24. Washington VA Medical Center, Washington, DC 20422, USA.
25. Department of Psychiatry, Georgetown University School of Medicine, Washington, DC 20057, USA.
26. Department of Psychiatry, Virginia Commonwealth University, Richmond, VA 23298, USA.
27. Department of Psychiatry, Sao Miguel, 9500-310 Azores, Portugal.
28. Department of Psychiatry, University of Coimbra, 3004-504 Coimbra, Portugal.
29. Present address: Department of Psychiatry, University of Oxford, Warneford Hospital, Headington, Oxford OX3 7JX, UK.
30. Lists of members and affiliations appear at the end of the paper.

Correspondence to: Correspondence and requests for materials should be addressed to P.S. (Email: sklar@chgr.mgh.harvard.edu).

Abstract

Schizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73–90% (ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants (CNVs) have been identified in individual patients with schizophrenia^{2, 3, 4, 5, 6, 7} and also in neurodevelopmental disorders^{8, 9, 10, 11}, but large-scale genome-wide surveys have not been performed. Here we report a genome-wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high-density microarrays. For CNVs that were observed in less than 1% of the sample and were more than 100 kilobases in length, the total burden is increased 1.15-fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single-occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo-cardio-facial syndrome, which includes psychotic symptoms in 30% of patients¹². Associations with schizophrenia were also found for large deletions on chromosome 15q13.3 and 1q21.1. These associations have not previously been reported, and they remained significant after genome-wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome-wide and at specific loci.

1. Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
2. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
3. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
4. Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
5. School of Medicine, Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff C14 4XN, UK.
6. Molecular Psychiatry Laboratory, Department of Mental Health Sciences, University College London Medical School, Windeyer Institute of Medical Sciences, 46 Cleveland Street, London W1T 4JF, UK.
7. Division of Psychiatry, School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh EH10 5HF, UK.
8. Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
9. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
10. Department of Neuroscience, Psychiatry, Ulleråker, Uppsala University, SE-750 17 Uppsala, Sweden.
11. Center for Genomic Psychiatry, University of Southern California, Los Angeles, California 90033, USA.
12. Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
13. Departments of Genetics, Psychiatry, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
14. Queensland Institute of Medical Research, 300 Herston Road, Brisbane, Queensland 4006, Australia.
15. Department of Medical Genetics, University Hospital Maichin Dom, Sofia 1431, Bulgaria.
16. Department of Psychiatry, First Psychiatric Clinic, Alexander University Hospital, Sofia 1431, Bulgaria.
17. Molecular and Cellular Therapeutics and RCSI Research Institute, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
18. West Berkshire NHS Trust, 25 Erleigh Road, Reading RG3 5LR, UK.
19. West London Mental Health Trust, Hammersmith and Fulham Mental Health Unit and St Bernard's Hospital, London W6 8RF, UK.
20. Queen Mary College, University of London and East London and City Mental Health Trust, Royal London Hospital, Whitechapel, London E1 1BB, UK.
21. Department of Mental Health, University of Aberdeen, Aberdeen AB25 2ZD, UK.
22. Ravenscraig Hospital, Inverkip Road, Greenock PA16 9HA, UK.
23. State University of New York – Upstate Medical University, Syracuse, New York 13210, USA.
24. Washington VA Medical Center, Washington, DC 20422, USA.
25. Department of Psychiatry, Georgetown University School of Medicine, Washington, DC 20057, USA.
26. Department of Psychiatry, Virginia Commonwealth University, Richmond, VA 23298, USA.
27. Department of Psychiatry, Sao Miguel, 9500-310 Azores, Portugal.
28. Department of Psychiatry, University of Coimbra, 3004-504 Coimbra, Portugal.
29. Present address: Department of Psychiatry, University of Oxford, Warneford Hospital, Headington, Oxford OX3 7JX, UK.
30. Lists of members and affiliations appear at the end of the paper.

Correspondence to: Correspondence and requests for materials should be addressed to P.S. (Email: sklar@chgr.mgh.harvard.edu).

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