Rare copy number variants (CNVs): A point of rarity in genetic risk for bipolar disorder and schizophrenia?

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, UK.
Archives of general psychiatry (Impact Factor: 14.48). 04/2010; 67(4):318-27. DOI: 10.1001/archgenpsychiatry.2010.25
Source: PubMed


Recent studies suggest that copy number variation in the human genome is extensive and may play an important role in susceptibility to disease, including neuropsychiatric disorders such as schizophrenia and autism. The possible involvement of copy number variants (CNVs) in bipolar disorder has received little attention to date.
To determine whether large (>100,000 base pairs) and rare (found in <1% of the population) CNVs are associated with susceptibility to bipolar disorder and to compare with findings in schizophrenia.
A genome-wide survey of large, rare CNVs in a case-control sample using a high-density microarray.
The Wellcome Trust Case Control Consortium.
There were 1697 cases of bipolar disorder and 2806 nonpsychiatric controls. All participants were white UK residents.
Overall load of CNVs and presence of rare CNVs.
The burden of CNVs in bipolar disorder was not increased compared with controls and was significantly less than in schizophrenia cases. The CNVs previously implicated in the etiology of schizophrenia were not more common in cases with bipolar disorder.
Schizophrenia and bipolar disorder differ with respect to CNV burden in general and association with specific CNVs in particular. Our data are consistent with the possibility that possession of large, rare deletions may modify the phenotype in those at risk of psychosis: those possessing such events are more likely to be diagnosed as having schizophrenia, and those without them are more likely to be diagnosed as having bipolar disorder.

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    • "Prompted by these findings, we focused on the EGR2 as a candidate gene for schizophrenia in this study. Schizophrenia can be attributed to the joint effects of multiple common variants with a small-to-modest effect on the risk (Cichon et al., 2009) and rare mutations with large effect (Grozeva et al., 2010; Kenny et al., 2014; Tarabeux et al., 2011; Walsh et al., 2008). Thus, we aimed to examine whether there are common or rare genetic variants of the EGR2 associated with schizophrenia. "
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    ABSTRACT: Abnormal myelination is considered as part of the pathophysiology of schizophrenia. We resequenced the genomic DNA of the EGR2, which has a specific function in the myelination of peripheral nervous system, in 543 schizophrenic patients and 554 non-psychotic controls. We identified six known SNPs, which were not associated with schizophrenia. Nevertheless, we discovered 24 rare mutations, some of them were patient-specific, including a recurrent mutation (p.P173_Y174insP), which might be associated with the pathogenesis of schizophrenia. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Full-text · Article · Jun 2015 · Psychiatry Research
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    • "The contribution of CNVs in the psychiatric disorders has been appreciated only recently with the implementation of array technologies that enable genome-wide determination of CNVs. Two studies of CNVs in BP reported no overall increase in CNV load in cases and found that controls had a significant excess of CNVs [Grozeva et al., 2010; McQuillin et al., 2011]. In a third study, a nominally significant increase in singleton CNVs in BP cases compared with controls was found [Zhang et al., 2009]. "
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    ABSTRACT: Genetic markers at the GRM7 gene have shown allelic association with bipolar disorder (BP) in several case–control samples including our own sample. In this report, we present results of resequencing the GRM7 gene in 32 bipolar samples and 32 random controls selected from 553 bipolar cases and 547 control samples (UCL1). Novel and potential etiological base pair changes discovered by resequencing were genotyped in the entire UCL case–control sample. We also report on the association between GRM7 and BP in a second sample of 593 patients and 642 controls (UCL2). The three most significantly associated SNPs in the original UCL1 BP GWAS sample were genotyped in the UCL2 sample, of which none were associated. After combining the genotype data for the two samples only two (rs1508724 and rs6769814) of the original three SNP markers remained significantly associated with BP. DNA sequencing revealed mutations in three cases which were absent in control subjects. A 3′-UTR SNP rs56173829 was found to be significantly associated with BP in the whole UCL sample (P = 0.035; OR = 0.482), the rare allele being less common in cases compared to controls. Bioinformatic analyses predicted a change in the centroid secondary structure of RNA and alterations in the miRNA binding sites for the mutated base of rs56173829. We also validated two deletions and a duplication within GRM7 using quantitative-PCR which provides further support for the pre-existing evidence that copy number variants at GRM7 may have a role in the etiology of BP. © 2014 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Published by Wiley Periodicals, Inc.
    Full-text · Article · Jun 2014 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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    • "dup 16p11.2, and dup 16p13.1; Crespi and Crofts, 2012), although others have found CNVs not to be of higher frequency in bipolar disorder (Grozeva et al., 2010). "
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    ABSTRACT: The current schizophrenia concept is built on experts' agreement on the matter, and it is basically rooted in the epidemiological and clinical evidence. However, the numerous and intensive attempts to find the biological underpinnings of this syndrome face almost constantly a low degree of replication of the results. We have reviewed previously published work to contribute to identify some reasons underlying that failure. The difficulty in replicating biological findings in schizophrenia may relate to the intrinsic heterogeneity among patient samples, acquired through the current diagnostic criteria. As a result, the necessary replication for any finding to be accepted as characteristic data for schizophrenia would be impeded. Therefore, a new frame based on identification of correlates of the most replicated biological anomalies in schizophrenia to date may contribute to overcome those difficulties.
    Full-text · Article · Sep 2013 · The Journal of nervous and mental disease
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