Kirov, G., Gumus, D., Chen, W., Norton, N., Georgieva, L., Sari, M. et al. Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum. Mol. Genet. 17, 458-465

Department of Psychological Medicine, Cardiff University, Henry Wellcome Building, Heath Park, Cardiff CF14 4XN, UK.
Human Molecular Genetics (Impact Factor: 6.39). 03/2008; 17(3):458-65. DOI: 10.1093/hmg/ddm323
Source: PubMed


Copy number variations (CNVs) account for a substantial proportion of human genomic variation, and have been shown to cause
neurodevelopmental disorders. We sought to determine the relevance of CNVs to the aetiology of schizophrenia (SZ). Whole-genome,
high-resolution, tiling path BAC array comparative genomic hybridization (array CGH) was employed to test DNA from 93 individuals
with DSM-IV SZ. Common DNA copy number changes that are unlikely to be directly pathogenic in SZ were filtered out by comparison
to a reference dataset of 372 control individuals analyzed in our laboratory, and a screen against the Database of Genomic
Variants. The remaining aberrations were validated with Affymetrix 250K SNP arrays or 244K Agilent oligo-arrays and tested
for inheritance from the parents. A total of 13 aberrations satisfied our criteria. Two of them are very likely to be pathogenic.
The first one is a deletion at 2p16.3 that was present in an affected sibling and disrupts NRXN1. The second one is a de novo duplication at 15q13.1 spanning APBA2. The proteins of these two genes interact directly and play a role in synaptic development and function. Both genes have
been affected by CNVs in patients with autism and mental retardation, but neither has been previously implicated in SZ.

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Available from: Wei Chen, May 02, 2014
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    • "The fact that rare missense variants at NRXN1 may be protective factors against schizophrenia is surprising as disruptive mutations at NRXN1 are associated with intellectual disability, autism and schizophrenia, although with incomplete penetrance (Autism Genome Project et al., 2007; Kirov et al., 2008). NRXN1 is a cell adhesion molecule present mainly at excitatory glutamatergic and inhibitory GABAergic presynaptic terminals. "
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    ABSTRACT: A fraction of genetic risk to develop schizophrenia may be due to low-frequency variants. This multistep study attempted to find low-frequency variants of high effect at coding regions of eleven schizophrenia susceptibility genes supported by genome-wide association studies (GWAS) and nine genes for the DISC1 interactome, a susceptibility gene-set. During the discovery step, a total of 125 kb per sample were resequenced in 153 schizophrenia patients and 153 controls from Galicia (NW Spain), and the cumulative role of low-frequency variants at a gene or at the DISC1 gene-set were analyzed by burden and variance-based tests. Relevant results were meta-analyzed when appropriate data were available. In addition, case-only putative damaging variants were genotyped in a further 419 cases and 398 controls. The discovery step revealed a protective effect of rare missense variants at NRXN1, a result supported by meta-analysis (OR = 0.67, 95% CI: 0.47-0.94, P = 0.021, based on 3848 patients and 3896 controls from six studies). The follow-up step based on case-only putative damaging variants revealed a promising risk variant at AKAP9. This variant, K873R, reached nominal significance after inclusion of 240 additional Spanish controls from databases. The variant, located in an ADCY2 binding region, is absent from large public databases. Interestingly, GWAS revealed an association between common ADCY2 variants and bipolar disorder, a disorder with considerable genetic overlap with schizophrenia. These data suggest a role of rare missense variants at NRXN1 and AKAP9 in schizophrenia susceptibility, probably related to alteration of the excitatory/inhibitory synaptic balance, deserving further investigation. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Apr 2015 · Journal of Psychiatric Research
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    • "development and maintenance (Kirov et al. 2008, 2009). Structural genomic deletions that delete or disrupt NXRN1 are strongly implicated in causing psychiatric and cognitive phenotypes including schizophrenia, autism and mental retardation (Bena et al. 2013). "
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    ABSTRACT: To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged < 25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged < 25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.
    Full-text · Article · Nov 2014 · Human Genetics
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    • "Neurexin-α isoforms are transcribed from a promoter upstream of exon 1, while neurexin-β isoforms are generated from an internal promoter that drives transcription from a β-specific exon (Fig. 1). Point mutations and copy number variants in the NRXN1 gene have been identified in autism (Camacho-Garcia et al., 2012) and schizophrenia (Kirov et al., 2008; Rujescu et al., 2009). "

    Full-text · Article · Sep 2014 · Schizophrenia Research
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