Evidence that duplications of 22q11.2 protect against schizophrenia.
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ABSTRACT:
SUBMITTER: Rees E
PROVIDER: S-EPMC3873028 | biostudies-literature | 2014 Jan
REPOSITORIES: biostudies-literature
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Project description:22q11.2 deletion syndrome (22qDS) is a genetic syndrome associated with a chromosome 22q11.2 deletion and variable phenotypic expression that commonly includes schizophrenia. Approximately 1% of patients with schizophrenia have 22qDS. The schizophrenia in 22qDS appears broadly similar to that found in the general population with respect to core signs and symptoms, treatment response, neurocognitive profile, and MRI brain anomalies. However, individuals with a 22qDS form of schizophrenia typically have distinguishable physical features, have a lower IQ, and may differ in auxiliary clinical features. IQ, length of 22q11.2 deletions, and COMT functional allele do not appear to be major risk factors for schizophrenia in 22qDS. Ascertainment biases and small sample sizes are limitations of most studies. Larger studies over the lifespan and continuing education about this underrecognized condition are needed. 22qDS-schizophrenia is an important genetic subtype and a valuable model of neurodevelopmental mechanisms involved in the pathogenesis of schizophrenia.
| S-EPMC3129332 | biostudies-other
Project description:BackgroundDiGeorge/velocardiofacial syndrome (DGS/VCFS) is the most common deletion syndrome in humans. Low copy repeats flanking the 22q11.2 region confer a substrate for non-allelic homologous recombination (NAHR) events leading to rearrangements. This study sought to identify DGS/VCFS fathers with increased susceptibility to deletions and duplications at the 22q11.2 region in spermatozoa and to assess the particular contribution of intra-chromatid and/or inter-chromatid NAHR. Semen samples from nine DGS/VCFS fathers were analyzed by triple-color FISH using a probe combination that discriminated between normal, deleted and duplicated genotypes. Microsatellite analysis were performed in the parents and the affected children to determine the parental origin of the deleted chromosome 22.ResultsA significant increase in 22q11.2 deletions was observed in the sperm of two out of nine DGS/VCFS fathers (odds ratio 2.03-fold, P < 0.01), and in both cases the deletion in the offspring was transmitted by the father. Patients with significant increases in sperm anomalies presented a disturbed deletion:duplication 1:1 ratio (P < 0.01).ConclusionsAltogether, results support that intra-chromatid NAHR is the mechanism responsible for the higher rate of sperm deletions, which is directly related to the transmission of the deleted chromosome 22 to offspring. Accordingly, the screening of sperm anomalies in the 22q11.2 region should be taken into account in the genetic counseling of DGS/VCFS families.
| S-EPMC4247602 | biostudies-literature
Project description:BackgroundThe 22q11.2 deletion syndrome is the most frequent genomic disorder with an estimated frequency of 1/4000 live births. The majority of patients (90%) have the same deletion of 3 Mb (Typically Deleted Region, TDR) that results from aberrant recombination at meiosis between region specific low-copy repeats (LCRs).MethodsAs a first step towards the characterization of recombination rates and breakpoints within the 22q11.2 region we have constructed a high resolution recombination breakpoint map based on pedigree analysis and a population-based historical recombination map based on LD analysis.ResultsOur pedigree map allows the location of recombination breakpoints with a high resolution (potential recombination hotspots), and this approach has led to the identification of 5 breakpoint segments of 50 kb or less (8.6 kb the smallest), that coincide with historical hotspots. It has been suggested that aberrant recombination leading to deletion (and duplication) is caused by low rates of Allelic Homologous Recombination (AHR) within the affected region. However, recombination rate estimates for 22q11.2 region show that neither average recombination rates in the 22q11.2 region or within LCR22-2 (the LCR implicated in most deletions and duplications), are significantly below chromosome 22 averages. Furthermore, LCR22-2, the repeat most frequently implicated in rearrangements, is also the LCR22 with the highest levels of AHR. In addition, we find recombination events in the 22q11.2 region to cluster within families. Within this context, the same chromosome recombines twice in one family; first by AHR and in the next generation by NAHR resulting in an individual affected with the del22q11.2 syndrome.ConclusionWe show in the context of a first high resolution pedigree map of the 22q11.2 region that NAHR within LCR22 leading to duplications and deletions cannot be explained exclusively under a hypothesis of low AHR rates. In addition, we find that AHR recombination events cluster within families. If normal and aberrant recombination are mechanistically related, the fact that LCR22s undergo frequent AHR and that we find familial differences in recombination rates within the 22q11.2 region would have obvious health-related implications.
| S-EPMC1855045 | biostudies-literature
Project description:In humans, the most common genomic disorder is a hemizygous deletion of a 1.5-3 Mb region of chromosome 22q11.2. The resultant 22q11.2 deletion syndrome (22q11.2DS) can affect multiple organ systems, and most notably includes cardiac, craniofacial, and neurodevelopmental defects. Individuals with 22q11.2DS have a 20-25-fold risk of developing schizophrenia compared to individuals from the general population, making 22q11.2DS the strongest known molecular genetic risk factor for schizophrenia. Although the deleted region includes DGCR8, a gene coding for a miRNA processing protein, the exact mechanism by which this deletion increases risk is unknown. Importantly, several lines of evidence suggest that miRNAs may modulate risk for schizophrenia in other, non-22q11.2DS populations. Here we present a theory which mechanistically explains the link between 22q11.2DS, miRNAs, and schizophrenia risk. We outline the testable predictions generated by this theory and present preliminary data in support of our model. Further experimental validation of this model could provide important insights into the etiology of both 22q11.2DS and more common forms of schizophrenia.
| S-EPMC3521194 | biostudies-literature
Project description:To evaluate previously reported associations of copy number variants (CNVs) with schizophrenia and to identify additional associations, the authors analyzed CNVs in the Molecular Genetics of Schizophrenia study (MGS) and additional available data.After quality control, MGS data for 3,945 subjects with schizophrenia or schizoaffective disorder and 3,611 screened comparison subjects were available for analysis of rare CNVs (<1% frequency). CNV detection thresholds were chosen that maximized concordance in 151 duplicate assays. Pointwise and genewise analyses were carried out, as well as analyses of previously reported regions. Selected regions were visually inspected and confirmed with quantitative polymerase chain reaction.In analyses of MGS data combined with other available data sets, odds ratios of 7.5 or greater were observed for previously reported deletions in chromosomes 1q21.1, 15q13.3, and 22q11.21, duplications in 16p11.2, and exon-disrupting deletions in NRXN1. The most consistently supported candidate associations across data sets included a 1.6-Mb deletion in chromosome 3q29 (21 genes, TFRC to BDH1) that was previously described in a mild-moderate mental retardation syndrome, exonic duplications in the gene for vasoactive intestinal peptide receptor 2 (VIPR2), and exonic duplications in C16orf72. The case subjects had a modestly higher genome-wide number of gene-containing deletions (>100 kb and >1 Mb) but not duplications.The data strongly confirm the association of schizophrenia with 1q21.1, 15q13.3, and 22q11.21 deletions, 16p11.2 duplications, and exonic NRXN1 deletions. These CNVs, as well as 3q29 deletions, are also associated with mental retardation, autism spectrum disorders, and epilepsy. Additional candidate genes and regions, including VIPR2, were identified. Study of the mechanisms underlying these associations should shed light on the pathophysiology of schizophrenia.
| S-EPMC4441324 | biostudies-literature
Project description:Schizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73-90% (ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants (CNVs) have been identified in individual patients with schizophrenia and also in neurodevelopmental disorders, but large-scale genome-wide surveys have not been performed. Here we report a genome-wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high-density microarrays. For CNVs that were observed in less than 1% of the sample and were more than 100 kilobases in length, the total burden is increased 1.15-fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single-occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo-cardio-facial syndrome, which includes psychotic symptoms in 30% of patients. Associations with schizophrenia were also found for large deletions on chromosome 15q13.3 and 1q21.1. These associations have not previously been reported, and they remained significant after genome-wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome-wide and at specific loci.
| S-EPMC3912847 | biostudies-literature
Project description:It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.
| S-EPMC9237031 | biostudies-literature
Project description:Recent studies are beginning to paint a clear and consistent picture of the impairments in psychological and cognitive competencies that are associated with microdeletions in chromosome 22q11.2. These studies have highlighted a strong link between this genetic lesion and schizophrenia. Parallel studies in humans and animal models are starting to uncover the complex genetic and neural substrates altered by the microdeletion. In addition to offering a deeper understanding of the effects of this genetic lesion, these findings may guide analysis of other copy-number variants associated with cognitive dysfunction and psychiatric disorders.
| S-EPMC2977984 | biostudies-literature
Project description:22q11.2 Deletion Syndrome (22q11.2DS) is a common microdeletion syndrome with congenital and late-onset features. Testing for the genomic content of copy number variations (CNVs) may help elucidate the 22q11.2 deletion mechanism and the variable clinical expression of the syndrome including the high (25%) risk for schizophrenia. We used genome-wide microarrays to assess CNV content and the parental origin of 22q11.2 deletions in a cohort of 100 adults with 22q11.2DS (44 with schizophrenia) and controls. 22q11.2DS subjects with schizophrenia failed to exhibit de novo CNVs or any excess of novel inherited CNVs outside the 22q11.2 region. There were no significant effects of parental origin of the 22q11.2 deletion, deletion length, parental age or family history on expression of schizophrenia. There was no evidence for a general increase of de novo CNVs in 22q11.2DS. A novel finding was the relative paucity of males with de novo 22q11.2 deletions of paternal origin (P = 0.019). The Y chromosome may play a mediating role in the mechanism of 22q11.2 deletion events during spermatogenesis, resulting in the previously observed excess of maternal de novo 22q11.2 deletions. Hemizygosity of the 22q11.2 region appears to be the major CNV-related risk factor for schizophrenia in 22q11.2DS. The results reinforce the need for further efforts to identify specific molecular mechanisms underlying this expression and to identify the 1% of patients with schizophrenia who carry 22q11.2 deletions.
| S-EPMC2638574 | biostudies-literature
Project description:The aim of the investigation was to test whether genetic variants predicted to impair the functionality of SLC6A9, which codes for the GlyT-1 glycine transporter, are protective against schizophrenia. In an exome sequenced sample of 4225 schizophrenia cases and 5834 controls, variants occurring in SLC6A9 were annotated and weights were assigned using GENEVARASSOC. Genotype counts were compared using SCOREASSOC. Variants predicted to be deleterious by SIFT and damaging by PolyPhen were examined. Genotypes at 1:44466494-G/A seemed likely to be erroneous. If these were ignored then there were 15 damaging variants in controls and five in cases. The results are consistent with the hypothesis that variants which damage SLC6A9 are protective against schizophrenia but a larger sample would be required to confirm this.
| S-EPMC7882767 | biostudies-literature