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Disruption of the neurexin 1 gene is associated with schizophrenia.

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.

SUBMITTER: Rujescu D

PROVIDER: S-EPMC2695245 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Disruption of the neurexin 1 gene is associated with schizophrenia.

Rujescu Dan D Ingason Andres A Cichon Sven S Pietiläinen Olli P H OP Barnes Michael R MR Toulopoulou Timothea T Picchioni Marco M Vassos Evangelos E Ettinger Ulrich U Bramon Elvira E Murray Robin R Ruggeri Mirella M Tosato Sarah S Bonetto Chiara C Steinberg Stacy S Sigurdsson Engilbert E Sigmundsson Thordur T Petursson Hannes H Gylfason Arnaldur A Olason Pall I PI Hardarsson Gudmundur G Jonsdottir Gudrun A GA Gustafsson Omar O Fossdal Ragnheidur R Giegling Ina I Möller Hans-Jürgen HJ Hartmann Annette M AM Hoffmann Per P Crombie Caroline C Fraser Gillian G Walker Nicholas N Lonnqvist Jouko J Suvisaari Jaana J Tuulio-Henriksson Annamari A Djurovic Srdjan S Melle Ingrid I Andreassen Ole A OA Hansen Thomas T Werge Thomas T Kiemeney Lambertus A LA Franke Barbara B Veltman Joris J Buizer-Voskamp Jacobine E JE Sabatti Chiara C Ophoff Roel A RA Rietschel Marcella M Nöthen Markus M MM Stefansson Kari K Peltonen Leena L St Clair David D Stefansson Hreinn H Collier David A DA

Human molecular genetics 20081022 5

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 d ...[more]

PMID: 18945720

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Project description:As the field of glycobiology grows, important roles for glycolipids and glycoproteins in neurological disorders are being increasingly appreciated. However, few studies have explored the involvement of these molecules in the pathology of psychiatric illnesses. We investigated molecular differences related to glycobiology in subjects with schizophrenia by analyzing gene expression profiles using a focused glycogene chip, a custom-designed oligonucleotide array containing genes encoding proteins related to glycobiology, including glycosyltransferases, carbohydrate-binding proteins, proteoglycans, and adhesion molecules. We measured expression profiles in prefrontal cortical (BA46) samples from schizophrenic subjects and matched controls. We find differential expression of genes particularly related to glycosphingolipid/sphingolipid metabolism and N- and O-linked glycan biosynthesis in subjects with schizophrenia. Expression decreases of seven genes associated with these pathways, UGT8, SGPP1, GALC, B4GALT6, SPTLC2, ASAH1, and GAL3ST1, were validated by quantitative PCR in schizophrenic subjects with short-term illness. Only one of these genes, SPTLC2, showed differential expression in chronic schizophrenic subjects, although an increase in expression was observed. Covariate analysis showed that the expression of five of these genes was significantly positively correlated with age in schizophrenic, but not control, subjects. These changing patterns of expression could represent an adaptive response to pathology with disease progression or a compensatory effect of antipsychotic medication, although no significant correlations between gene expression levels and drug doses were observed. Disruption of sphingolipid metabolism early in illness could result in widespread downstream effects encompassing diverse pathological deficits already described in schizophrenia, especially those involving myelination and oligodendrocyte function; hence, this system may represent an important link in schizophrenia pathology.

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Disruption of the neurexin 1 gene is associated with schizophrenia.

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Disruption of the neurexin 1 gene is associated with schizophrenia.

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