Human Molecular Genetics Advance Access originally published online on October 22, 2008
Human Molecular Genetics 2009 18(5):988-996; doi:10.1093/hmg/ddn351
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Disruption of the neurexin 1 gene is associated with schizophrenia
1 Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig- Maximilians University, Munich, Germany 2 deCODE genetics, Reykjavík, Iceland 3 Research Institute of Biological Psychiatry Mental Health Centre Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark 4 Department of Genomics, Life and Brain Center 5 Institute of Human Genetics, University of Bonn, Bonn, Germany 6 Department for Molecular Medicine, National Public Health Institute, Helsinki, Finland 7 Computational Biology, GlaxoSmithKline Pharmaceuticals, Harlow, Essex, UK 8 Division of Psychological Medicine, Institute of Psychiatry, King's College, London, UK 9 Section of Psychiatry and Clinical Psychology, University of Verona, Verona, Italy 10 Department of Psychiatry, National University Hospital, Reykjavík, Iceland 11 Department of Mental Health, University of Aberdeen, Aberdeen, Scotland 12 Ravenscraig Hospital, Greenock, Scotland 13 Department of Mental Health and Addiction, National Public Health Institute, Helsinki, Finland 14 Institute of Psychiatry, University of Oslo, Oslo, Norway 15 Department of Medical Genetics, Ulleval University Hospital, Oslo, Norway 16 Department of Epidemiology and Biostatistics (133 EPIB) 17 Department of Urology (659 URO) 18 Department of Human Genetics, Radboud University Nijmejen Medical Centre, Nijmegen, The Netherlands 19 Rudolf Magnus Institute of Neuroscience, Department of Psychiatry 20 Complex Genetics Section, DBG-Department of Medical Genetics and Rudolf Magnus Institute 21 Department of Psychiatry, University Medical Centre Utrecht, Utrecht, The Netherlands 22 Departments of Human Genetics and Statistics, UCLA, Los Angeles, CA 23 UCLA Center for Neurobehavioral Genetics, Los Angeles, CA, USA 24 Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health Mannheim, University of Heidelberg, Mannheim, Germany 25 Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK 26 The Broad Institute, Cambridge, MA, USA 27 MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College, London, UK
* To whom correspondence should be addressed at: Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry (King's College London), De Crespigny Park, Denmark Hill, London MRC SE5 8AF, UK. Tel: +44 2078480631; Fax: +44 2078480802; Email: d.collier{at}iop.kcl.ac.uk
Received June 30, 2008; Accepted October 17, 2008
Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European populations (Iceland, Finland, Norway, Germany, The Netherlands, Italy and UK) using microarray data. We found 66 deletions and 5 duplications in NRXN1, including a de novo deletion: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. There was no common breakpoint and the CNVs varied from 18 to 420 kb. No CNVs were found in NRXN2 or NRXN3. We performed a Cochran–Mantel–Haenszel exact test to estimate association between all CNVs and schizophrenia (P = 0.13; OR = 1.73; 95% CI 0.81–3.50). Because the penetrance of NRXN1 CNVs may vary according to the level of functional impact on the gene, we next restricted the association analysis to CNVs that disrupt exons (0.24% of cases and 0.015% of controls). These were significantly associated with a high odds ratio (P = 0.0027; OR 8.97, 95% CI 1.8–51.9). We conclude that NRXN1 deletions affecting exons confer risk of schizophrenia.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
GROUP investigators include: René S. Kahn1, Don Linszen2, Jim van Os3, Durk Wiersma4, Richard Bruggeman4, Wiepke Cahn1, Lieuwe de Haan2, Lydia Krabbendam3, and Inez Myin-Germeys3 1. Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands; 2. Academic Medical Centre University of Amsterdam, Department of Psychiatry; Amsterdam, The Netherlands; 3. Maastricht University Medical Centre, South Limburg; Mental Health Research and Teaching Network, Maastricht, The Netherlands; 4. University Medical Centre Groningen, Department of Psychiatry, University of Groningen, The Netherlands
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