Disruption of the neurexin 1 gene is associated with schizophrenia - PubMed (original) (raw)

. 2009 Mar 1;18(5):988-96.

doi: 10.1093/hmg/ddn351. Epub 2008 Oct 22.

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 Olason, Gudmundur 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; GROUP Investigators; Chiara Sabatti, Roel A Ophoff, Marcella Rietschel, Markus M Nöthen, Kari Stefansson, Leena Peltonen, David St Clair, Hreinn Stefansson, David A Collier

Collaborators, Affiliations

Disruption of the neurexin 1 gene is associated with schizophrenia

Dan Rujescu et al. Hum Mol Genet. 2009.

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.

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Figures

Figure 1

Figure 1

UCSC browser output showing the positions of the 2p16.3 CNVs from the Kirov et al. (2008), Walsh et al. (2008), Friedman et al. (2008) and Szatzmar et al. (2008) studies (blue lines) relative to the NRXN1 gene, and the CNVs discovered in the present study (schizophrenia, red lines; other psychiatric diagnoses, brown lines; controls, green lines). The majority of the discovered CNVs are deletions, asterisks indicate duplications. Markers from the Illumina 300 K and 550 K arrays, segmental duplications of >1000 bp as well as LD structure of the Hapmap CEU sample (_r_2) is also shown.

Figure 2

Figure 2

UCSC browser output showing the positions of exon-disrupting CNVs discovered in the study relative to the 2p16.3 CNVs from the Kirov et al. (2008), Walsh et al. (2008), Friedman et al. (2008) and Szatzmar et al. (2008) studies and known (schizophrenia, red lines; other psychiatric diagnoses, brown lines; controls, green lines; previously described CNVs, blue lines). The four putative Neurexin isoforms are shown below the deletions, along with protein domains aligned to genomic sequence.

Figure 3

Figure 3

Protein domain organization of Neurexin 1 isoforms. NRXN1a contains an N-terminal signal peptide, six laminin G (LamG) domains, three epidermal growth factor-like (EGF) domains, a transmembrane domain and a short cytoplasmic domain. NRXN1b contains a different signal peptide, but shares the last LamG domain, transmembrane domain and cytoplasmic domain with NRXN1a. NRXN1a-2 shares the 2nd, 3rd, 4th and 5th LamG domains and the 2nd and 3rd EGF domains with NRXN1a, but does not contain a signal peptide or transmembrane domain. NRXN1a-3 has no signal peptide and has a truncated version of the 2nd LamG domain but shares all remaining domains with NRXN1a. The five regions in the NRXN1 gene where alternative splicing occurs, leading to insertion or deletion of amino acids is indicated by arrows (SS no. 1–5). Protein domain annotation was generated using SMART (

http://smart.embl-heidelberg.de/

), using swissprot accessions Q9ULB1 (NRXN1a) and P58400 (NRXN1b) and translations from the genbank transcript AK093260 (NRXN1a-2) and Ensembl transcript ENST00000331040 (NRXN1a-3).

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