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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:Infection with Plasmodium falciparum during pregnancy is one of the major causes of malaria related morbidity and mortality in newborn and mothers. The complications of pregnancy-associated malaria result mainly from massive adhesion of Plasmodium falciparum-infected erythrocytes (IE) to chondroitin sulfate A (CSA) present in the placental intervillous blood spaces. Var2CSA, a member of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family is the predominant parasite ligand mediating CSA binding. However, experimental evidence suggests that other host receptors, such as hyaluronic acid (HA) and the neonatal Fc receptor, may also support placental binding. Here we used parasites in which var2csa was genetically disrupted to evaluate the contribution of these receptors to placental sequestration and to identify additional adhesion receptors that may be involved in pregnancy-associated malaria. By comparison to the wild-type parasites, the FCR3delta var2csa mutants could not be selected for HA adhesion, indicating that var2csa is not only essential for IE cytoadhesion to the placental receptor CSA, but also to HA. However, further studies using different pure sources of HA revealed that the previously observed binding results from CSA contamination in the bovine vitreous humor HA preparation. To identify CSA-independent placental interactions, FCR3delta var2csa mutant parasites were selected for adhesion to the human placental trophoblastic BeWo cell line. BeWo selected parasites revealed a multi-phenotypic adhesion population expressing multiple var genes. However, these parasites did not cytoadhere specifically to the syncytiotrophoblast lining of placental cryosections and were not recognized by sera from malaria-exposed women in a parity dependent manner, indicating that the surface molecules present on the surface of the BeWo selected population are not specifically expressed during the course of pregnancy-associated malaria. Taken together, these results demonstrate that the placental malaria associated phenotype can not be restored in FCR3delta var2csa mutant parasites and highlight the key role of var2CSA in pregnancy malaria pathogenesis and for vaccine development.

Dataset Information

Disruption of the neurexin 1 gene is associated with schizophrenia.

Publications

Disruption of the neurexin 1 gene is associated with schizophrenia.

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