Disruption of the neurexin 1 gene is associated with schizophrenia

• Published in: Human Molecular Genetics
• Main Authors: Rujescu, Dan, Ingason, Andres, Cichon, Sven, Pietiläinen, Olli P.H., Barnes, Michael R., Toulopoulou, Timothea, Picchioni, Marco, Vassos, Evangelos, Ettinger, Ulrich, Bramon, Elvira, Murray, Robin, Ruggeri, Mirella, Tosato, Sarah, Bonetto, Chiara, Steinberg, Stacy, Sigurdsson, Engilbert, Sigmundsson, Thordur, Petursson, Hannes, Gylfason, Arnaldur, Olason, Pall I., Hardarsson, Gudmundur, Jonsdottir, Gudrun A., Gustafsson, Omar, Fossdal, Ragnheidur, Giegling, Ina, Möller, Hans-Jürgen, Hartmann, Annette, Hoffmann, Per, Crombie, Caroline, Fraser, Gillian, Walker, Nicholas, Lonnqvist, Jouko, Suvisaari, Jaana, Tuulio-Henriksson, Annamarie, Andreassen, Ole A., Djurovic, Srdjan, Hansen, Thomas, Werge, Thomas, Melle, Ingrid, Kiemeney, Lambertus A., Franke, Barbara, Buizer-Voskamp, Jacobine E., Ophoff, Roel A., GROUP Investigators, Rietschel, Marcella, Nöthen, Markus M., Stefansson, Kari, Peltonen, Leena, St Clair, David, Stefansson, Hreinn
• Format: Text
• Language: English
• Published: Oxford University Press 2008
• Subjects: Article; Norway; Iceland
• Online Access: http://hmg.oxfordjournals.org/cgi/content/short/ddn351v1; https://doi.org/10.1093/hmg/ddn351

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 2,977 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 18kb to 420kb. 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 (0.17% of cases and 0.020% 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.