1. CNS Division, deCODE genetics, Sturlugata 8, IS-101 Reykjavík, Iceland
2. Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Genetics Research Centre, Ludwig-Maximilians-University, Nubaumstrasse 7, 80336 Munich, Germany
3. Department of Genomics, Life & Brain Center, University of Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany
4. Institute of Human Genetics, University of Bonn, Wilhelmstrasse 31, D-53111 Bonn, Germany
5. Department for Molecular Medicine, National Public Health Institute, Biomedicum, Haartmaninkatu 8, 00290 Helsinki, Finland
6. Department of Psychiatry, National University Hospital, Hringbraut, 101 Reykjavík, Iceland
7. The Netherlands Department of Medical Genetics and Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands
8. Research Institute of Biological Psychiatry, Mental Health Centre Sct. Hans Copenhagen University Hospital, DK-4000 Roskilde, Denmark
9. Centre for Pharmacogenomics, University of Copenhagen, DK-2200 Copenhagen N, Denmark
10. Medical Genetics, GlaxoSmithKline R&D, Via A. Fleming 4, 37135 Verona, Italy
11. Clinical Imaging Centre, Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Hammersmith Hospital, London W12 ONN, UK
12. Institute for Genome Sciences & Policy, Center for Population Genomics & Pharmacogenetics, 4011 GSRB II 103 Research Drive, Duke University, DUMC Box 3471, Durham, North Carolina 27708, USA
13. Department of Mental Health, University of Aberdeen, Royal Cornhill Hospital, Aberdeen AB25 2ZD, UK
14. Ravenscraig hospital, Inverkip Road, Greenock PA16 9HA, UK
15. Department of Mental Health and Addiction, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland
16. Division of Psychological Medicine and Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College, London SE5 8AF, UK
17. Section of Psychiatry and Clinical Psychology, University of Verona, Verona, 37134 Verona, Italy
18. Psychiatric Laboratory, Department of Psychiatry, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
19. Department of Clinical Immunology, Copenhagen University Hospital, DK-2200 Copenhagen N, Denmark
20. Mental Health Centre Amager, Copenhagen University Hospital, DK-2300 Copenhagen S, Denmark
21. Institute of Psychiatry, University of Oslo, PO Box 1130, Blindern, N-0318 Oslo, Norway
22. Departments of Medical Genetics and Psychiatry, Ulleval University Hospital, Kirkeveien 166, N-0407 Oslo, Norway
23. Department of Neurology, 57 Nordre Ringvej, Glostrup Hospital, Glostrup, DK-2600 Copenhagen, Denmark
24. Department of Epidemiology & Biostatistics (133 EPIB)/Department of Urology (659 URO), Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
25. Department of Human Genetics, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
26. Departments of Human Genetics and Statistics, UCLA, 695 Charles Young Drive South, Los Angeles, California 90095, USA
27. UCLA Center for Neurobehavioral Genetics, Charles E. Young Drive South, Los Angeles, California 90024, USA
28. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, J5, D-68159 Mannheim, Germany
29. Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
30. The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
31. University of Iceland, School of Medicine, Sturlugata 8, 101 Reykjavik, Iceland
32. Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
33. Academic Medical Centre University of Amsterdam, Department of Psychiatry, Amsterdam, The Netherlands.
34. Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, Maastricht, The Netherlands.
35. University Medical Centre Groningen, Department of Psychiatry, University of Groningen, The Netherlands.
36. These authors contributed equally to this work.
37. Lists of authors and affiliations appear at the end of the paper.

Correspondence to: David St Clair¹³Kari Stefansson^1,31 Correspondence and requests for materials should be addressed to D.S.C. (Email: d.stclair@abdn.ac.uk) or K.S. (Email: kari.stefansson@decode.is).

Abstract

Reduced fecundity, associated with severe mental disorders¹, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism², schizophrenia³ and mental retardation⁴. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation^{4, 5} and autism². In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.

1. CNS Division, deCODE genetics, Sturlugata 8, IS-101 Reykjavík, Iceland
2. Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Genetics Research Centre, Ludwig-Maximilians-University, Nubaumstrasse 7, 80336 Munich, Germany
3. Department of Genomics, Life & Brain Center, University of Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany
4. Institute of Human Genetics, University of Bonn, Wilhelmstrasse 31, D-53111 Bonn, Germany
5. Department for Molecular Medicine, National Public Health Institute, Biomedicum, Haartmaninkatu 8, 00290 Helsinki, Finland
6. Department of Psychiatry, National University Hospital, Hringbraut, 101 Reykjavík, Iceland
7. The Netherlands Department of Medical Genetics and Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands
8. Research Institute of Biological Psychiatry, Mental Health Centre Sct. Hans Copenhagen University Hospital, DK-4000 Roskilde, Denmark
9. Centre for Pharmacogenomics, University of Copenhagen, DK-2200 Copenhagen N, Denmark
10. Medical Genetics, GlaxoSmithKline R&D, Via A. Fleming 4, 37135 Verona, Italy
11. Clinical Imaging Centre, Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Hammersmith Hospital, London W12 ONN, UK
12. Institute for Genome Sciences & Policy, Center for Population Genomics & Pharmacogenetics, 4011 GSRB II 103 Research Drive, Duke University, DUMC Box 3471, Durham, North Carolina 27708, USA
13. Department of Mental Health, University of Aberdeen, Royal Cornhill Hospital, Aberdeen AB25 2ZD, UK
14. Ravenscraig hospital, Inverkip Road, Greenock PA16 9HA, UK
15. Department of Mental Health and Addiction, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland
16. Division of Psychological Medicine and Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College, London SE5 8AF, UK
17. Section of Psychiatry and Clinical Psychology, University of Verona, Verona, 37134 Verona, Italy
18. Psychiatric Laboratory, Department of Psychiatry, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
19. Department of Clinical Immunology, Copenhagen University Hospital, DK-2200 Copenhagen N, Denmark
20. Mental Health Centre Amager, Copenhagen University Hospital, DK-2300 Copenhagen S, Denmark
21. Institute of Psychiatry, University of Oslo, PO Box 1130, Blindern, N-0318 Oslo, Norway
22. Departments of Medical Genetics and Psychiatry, Ulleval University Hospital, Kirkeveien 166, N-0407 Oslo, Norway
23. Department of Neurology, 57 Nordre Ringvej, Glostrup Hospital, Glostrup, DK-2600 Copenhagen, Denmark
24. Department of Epidemiology & Biostatistics (133 EPIB)/Department of Urology (659 URO), Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
25. Department of Human Genetics, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
26. Departments of Human Genetics and Statistics, UCLA, 695 Charles Young Drive South, Los Angeles, California 90095, USA
27. UCLA Center for Neurobehavioral Genetics, Charles E. Young Drive South, Los Angeles, California 90024, USA
28. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, J5, D-68159 Mannheim, Germany
29. Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
30. The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
31. University of Iceland, School of Medicine, Sturlugata 8, 101 Reykjavik, Iceland
32. Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
33. Academic Medical Centre University of Amsterdam, Department of Psychiatry, Amsterdam, The Netherlands.
34. Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, Maastricht, The Netherlands.
35. University Medical Centre Groningen, Department of Psychiatry, University of Groningen, The Netherlands.
36. These authors contributed equally to this work.
37. Lists of authors and affiliations appear at the end of the paper.

Correspondence to: David St Clair¹³Kari Stefansson^1,31 Correspondence and requests for materials should be addressed to D.S.C. (Email: d.stclair@abdn.ac.uk) or K.S. (Email: kari.stefansson@decode.is).

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