Rodriguez-Santiago B, Brunet A et al. Association of common copy number variants at the glutathione S-transferase genes and rare novel genomic changes with schizophrenia. Mol Psychiatry 15: 1023-1033

Unitat de Genètica, Universitat Pompeu Fabra, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
Molecular Psychiatry (Impact Factor: 14.5). 07/2009; 15(10):1023-33. DOI: 10.1038/mp.2009.53
Source: PubMed


Copy number variants (CNVs) are a substantial source of human genetic diversity, influencing the variable susceptibility to multifactorial disorders. Schizophrenia is a complex illness thought to be caused by a number of genetic and environmental effects, few of which have been clearly defined. Recent reports have found several low prevalent CNVs associated with the disease. We have used a multiplex ligation-dependent probe amplification-based (MLPA) method to target 140 previously reported and putatively relevant gene-containing CNV regions in 654 schizophrenic patients and 604 controls for association studies. Most genotyped CNVs (95%) showed very low (<1%) population frequency. A few novel rare variants were only present in patients suggesting a possible pathogenic involvement, including 1.39 Mb overlapping duplications at 22q11.23 found in two unrelated patients, and duplications of the somatostatin receptor 5 gene (SSTR5) at 16p13.3 in three unrelated patients. Furthermore, among the few relatively common CNVs observed in patients and controls, the combined analysis of gene copy number genotypes at two glutathione S-transferase (GST) genes, GSTM1 (glutathione S-transferase mu 1) (1p13.3) and GSTT2 (glutathione S-transferase theta 2) (22q11.23), showed a statistically significant association of non-null genotypes at both loci with an additive effect for increased vulnerability to schizophrenia (odds ratio of 1.92; P=0.0008). Our data provide complementary evidences for low prevalent, but highly penetrant chromosomal variants associated with schizophrenia, as well as for common CNVs that may act as susceptibility factors by disturbing glutathione metabolism.

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    • "Phencyclidine, another drug of abuse that promotes schizophrenia-relevant behaviors and cognitive dysfunction, also reduced glutathione levels and antioxidant defense enzymes in the rodent brain (Radonjic et al., 2010; Stojković et al., 2012). Interestingly, copy number variants in genes encoding glutathione S-transferase may be involved in susceptibility to schizophrenia (Rodriguez-Santiago et al., 2010). Here we also showed repeated adolescent THC exposure upregulated the expression of heat shock protein 70 kDa in the hippocampus. "
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    ABSTRACT: Neuregulin 1 () is linked to an increased risk of developing schizophrenia and cannabis dependence. Mice that are hypomorphic for ( HET mice) display schizophrenia-relevant behavioral phenotypes and aberrant expression of serotonin and glutamate receptors. HET mice also display idiosyncratic responses to the main psychoactive constituent of cannabis, Δ-tetrahydrocannabinol (THC). To gain traction on the molecular pathways disrupted by hypomorphism and -cannabinoid interactions we conducted a proteomic study. Adolescent wildtype (WT) and HET mice were exposed to repeated injections of vehicle or THC and their hippocampi were submitted to 2D gel proteomics. Comparison of WT and HET mice identified proteins linked to molecular changes in schizophrenia that have not been previously associated with . These proteins are involved in vesicular release of neurotransmitters such as SNARE proteins; enzymes impacting serotonergic neurotransmission, and proteins affecting growth factor expression. HET mice treated with THC expressed a distinct protein expression signature compared to WT mice. Replicating prior findings, THC caused proteomic changes in WT mice suggestive of greater oxidative stress and neurodegeneration. We have previously observed that THC selectively increased hippocampal NMDA receptor binding of adolescent HET mice. Here we observed outcomes consistent with heightened NMDA-mediated glutamatergic neurotransmission. This included differential expression of proteins involved in NMDA receptor trafficking to the synaptic membrane; lipid raft stabilization of synaptic NMDA receptors; and homeostatic responses to dampen excitotoxicity. These findings uncover novel proteins altered in response to hypomorphism and -cannabinoid interactions that improves our molecular understanding of signaling and -mediated genetic vulnerability to the neurobehavioral effects of cannabinoids.
    Frontiers in Cellular Neuroscience 02/2013; 7:15. DOI:10.3389/fncel.2013.00015 · 4.29 Impact Factor
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    • "All MLPA reactions were analyzed on an ABI PRISM 3100 Genetic analyzer according to manufacturers' instructions. Each MLPA signal was normalized and compared to the corresponding peak height obtained in control samples [32], [33]. "
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    ABSTRACT: Congenital malformations are present in approximately 2-3% of liveborn babies and 20% of stillborn fetuses. The mechanisms underlying the majority of sporadic and isolated congenital malformations are poorly understood, although it is hypothesized that the accumulation of rare genetic, genomic and epigenetic variants converge to deregulate developmental networks. We selected samples from 95 fetuses with congenital malformations not ascribed to a specific syndrome (68 with isolated malformations, 27 with multiple malformations). Karyotyping and Multiplex Ligation-dependent Probe Amplification (MLPA) discarded recurrent genomic and cytogenetic rearrangements. DNA extracted from the affected tissue (46%) or from lung or liver (54%) was analyzed by molecular karyotyping. Validations and inheritance were obtained by MLPA. We identified 22 rare copy number variants (CNV) [>100 kb, either absent (n = 7) or very uncommon (n = 15, <1/2,000) in the control population] in 20/95 fetuses with congenital malformations (21%), including 11 deletions and 11 duplications. One of the 9 tested rearrangements was de novo while the remaining were inherited from a healthy parent. The highest frequency was observed in fetuses with heart hypoplasia (8/17, 62.5%), with two events previously related with the phenotype. Double events hitting candidate genes were detected in two samples with brain malformations. Globally, the burden of deletions was significantly higher in fetuses with malformations compared to controls. Our data reveal a significant contribution of rare deletion-type CNV, mostly inherited but also de novo, to human congenital malformations, especially heart hypoplasia, and reinforce the hypothesis of a multifactorial etiology in most cases.
    PLoS ONE 10/2012; 7(10):e45530. DOI:10.1371/journal.pone.0045530 · 3.23 Impact Factor
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    • "TaqMan assays were conducted at the Genotyping Core Facility – National Cancer Institute (CGF-NCI), USA, using the SNP500CancerID: GSTM1-02 probe [8]. MLPA assays were performed at the Pompeu Fabra University (UPF, Barcelona) by using optimized custom probes described elsewhere [22]. A genome-wide Illumina Infinium 1 M SNP-array scan was performed at the CGF-NCI, USA [7]. "
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    ABSTRACT: Structural variations such as copy number variants (CNV) influence the expression of different phenotypic traits. Algorithms to identify CNVs through SNP-array platforms are available. The ability to evaluate well-characterized CNVs such as GSTM1 (1p13.3) deletion provides an important opportunity to assess their performance. 773 cases and 759 controls from the SBC/EPICURO Study were genotyped in the GSTM1 region using TaqMan, Multiplex Ligation-dependent Probe Amplification (MLPA), and Illumina Infinium 1 M SNP-array platforms. CNV callings provided by TaqMan and MLPA were highly concordant and replicated the association between GSTM1 and bladder cancer. This was not the case when CNVs were called using Illumina 1 M data through available algorithms since no deletion was detected across the study samples. In contrast, when the Log R Ratio (LRR) was used as a continuous measure for the 5 probes contained in this locus, we were able to detect their association with bladder cancer using simple regression models or more sophisticated methods such as the ones implemented in the CNVtools package. This study highlights an important limitation in the CNV calling from SNP-array data in regions of common aberrations and suggests that there may be added advantage for using LRR as a continuous measure in association tests rather than relying on calling algorithms.
    BMC Genomics 07/2012; 13(1):326. DOI:10.1186/1471-2164-13-326 · 3.99 Impact Factor
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