Disruption of the neurexin 1 gene is associated with schizophrenia

Dan Rujescu, Andres Ingason, Sven Cichon, Olli P H Pietiläinen, Michael R. Barnes, Timothea Toulopoulou, Marco Picchioni, Evangelos Vassos, Ulrich Ettinger, Elvira Bramon, Robin Murray, Mirella Ruggeri, Sarah Tosato, Chiara Bonetto, Stacy Steinberg, Engilbert Sigurdsson, Thordur Sigmundsson, Hannes Petursson, Arnaldur Gylfason, Pall I OlasonGudmundur Hardarsson, Gudrun A Jonsdottir, Omar Gustafsson, Ragnheidur Fossdal, Ina Giegling, Hans-Jürgen Möller, Annette M Hartmann, Per Hoffmann, Caroline Crombie, Gillian Fraser, Nicholas Walker, Jouko Lonnqvist, Jaana Suvisaari, Annamari Tuulio-Henriksson, Srdjan Djurovic, Ingrid Melle, Ole A Andreassen, Thomas Hansen, Thomas Werge, Lambertus A Kiemeney, Barbara Franke, Joris Veltman, Jacobine E Buizer-Voskamp, Chiara Sabatti, Roel A Ophoff, Marcella Rietschel, Markus M Nöthen, Kari Stefansson, Leena Peltonen, David St Clair, GROUP Investigators

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350 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)988-996
Number of pages9
JournalHuman Molecular Genetics
Volume18
Issue number5
Early online date22 Oct 2008
DOIs
Publication statusPublished - 2009

Keywords

  • adolescent
  • adult
  • case-control studies
  • European continental ancestry group
  • exons
  • female
  • gene deletion
  • gene dosage
  • gene duplication
  • gene silencing
  • genetic predisposition to disease
  • humans
  • male
  • nerve tissue proteins
  • schizophrenia
  • young adult

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    Rujescu, D., Ingason, A., Cichon, S., Pietiläinen, O. P. H., Barnes, M. R., Toulopoulou, T., Picchioni, M., Vassos, E., Ettinger, U., Bramon, E., Murray, R., Ruggeri, M., Tosato, S., Bonetto, C., Steinberg, S., Sigurdsson, E., Sigmundsson, T., Petursson, H., Gylfason, A., ... GROUP Investigators (2009). Disruption of the neurexin 1 gene is associated with schizophrenia. Human Molecular Genetics, 18(5), 988-996. https://doi.org/10.1093/hmg/ddn351