| 1 | Am J Psychiatry 2011 Mar 168: 302-16 |
|---|---|
| PMID | 21285140 |
| Title | Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Curr. Genomics 2011 Nov 12: 516-24 |
| PMID | 22547958 |
| Title | The shock of the new: progress in schizophrenia genomics. |
| Abstract | A growing list of common and rare genetic risk variants are being implicated in schizophrenia susceptibility. As with other complex genetic disorders most of the variance in genetic risk is still to be attributed. What can be learned from progress to date? The available data challenges how we conceptualize schizophrenia and suggests strong aetiological links with other psychiatric and developmental disorders. With the identification of rare copy number risk variants implicating specific genes (e.g. VIPR2 and NRXN1) it is increasingly possible to investigate molecular aetiology in patient subgroups to establish whether schizophrenia represents one or many different disease processes. This review summarizes recent research progress and suggests how the tools of modern genomics and neuroscience can be applied to best understand this devastating disorder. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Expert Rev Neurother 2011 Jul 11: 937-41 |
| PMID | 21721910 |
| Title | Genome-wide investigation of rare structural variants identifies VIPR2 as a new candidate gene for schizophrenia. |
| Abstract | Research has shown that structural variation in the human genome, including rare copy number variations (CNVs), contributes to genetic susceptibility to psychiatric diseases, such as schizophrenia, a devastating complex disorder with a high genetic load. The study by Vacic et al. applied a genome-wide approach to detect novel, rare and highly penetrant CNVs. Detailed analysis of microduplications at 7q36.3 revealed that the neuropeptide receptor gene VIPR2 confers a significant risk for schizophrenia. This suggests that altered vasoactive intestinal signaling contributes to the genetic etiology of this disorder. This article recapitulates the findings of this study within the context of current knowledge of CNVs in the field of psychiatric disease. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Nature 2011 Mar 471: 499-503 |
| PMID | 21346763 |
| Title | Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia. |
| Abstract | Rare copy number variants (CNVs) have a prominent role in the aetiology of schizophrenia and other neuropsychiatric disorders. Substantial risk for schizophrenia is conferred by large (>500-kilobase) CNVs at several loci, including microdeletions at 1q21.1 (ref. 2), 3q29 (ref. 3), 15q13.3 (ref. 2) and 22q11.2 (ref. 4) and microduplication at 16p11.2 (ref. 5). However, these CNVs collectively account for a small fraction (2-4%) of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy number gains at chromosome 7q36.3 with schizophrenia. Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 (0.35%) patients versus 2 of 7,431 (0.03%) controls in the combined sample. All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene VIPR2. VIPR2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered vasoactive intestinal peptide signalling in the pathogenesis of schizophrenia and indicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Prog. Neurobiol. 2012 Oct 99: 81-91 |
| PMID | 22813947 |
| Title | Copy number variations in neurodevelopmental disorders. |
| Abstract | Common neurodevelopmental disorders (including autism, speech and language delay, schizophrenia, epilepsy and intellectual disability) have complex aetiology, which is predominantly genomic, but also environmental in origin. They share a paradox, in that high heritability is matched by lowered fecundity, placing them under negative genetic selection. This implicates variants of recent origin, such as de novo mutations or common, very low-risk polymorphisms that escape negative selection. High or moderate risk variants have been discovered by chromosome analysis, genome sequencing and copy number variant (CNV) detection, including a 3Mb deletion causing 22q11.2 deletion syndrome (Velo-Cardio-Facial Syndrome) that has penetrance of up to 50% for schizophrenia. More recently, rare, recurrent and often de novo pathogenic CNVs, including deletions at NRXN1, 1q21.2, 15q11.2 and 15q13.3, 16p11.2 and duplications at VIPR2 and 16p13.11, have also been discovered. These have several unique features that differentiate them from Mendelian disease mutations in that they have incomplete penetrance, with moderate-to-high odds ratios for risk, and show diagnostic pleiotropy, increasing risk across the neurodevelopmental disorder spectrum. Some are also syndromic, with characteristic features such as facial dysmorphology, and other specific risks such as aortic dissection or obesity, implying that they might be better classified as distinct diagnoses. The discovery of pathogenic CNVs provide new opportunities for translation leading to patent benefit, including improvements in clinical genetic diagnosis and genetic counselling, the possibility of clinician decision-making tools for risk prediction, and the identification of drug targets and implementation of personalised medicine using stratification by genotype. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Sci Rep 2013 -1 3: 2587 |
| PMID | 24002029 |
| Title | Definition and refinement of the 7q36.3 duplication region associated with schizophrenia. |
| Abstract | Using a very high-resolution oligonucleotide array for copy number variant (CNV) screening of samples comprising schizophrenic patients, we detected a novel CNV within the critical region (NCBI36/hg18, Chr7: 158,630,410-158,719,410) previously shown to be associated with schizophrenia. We investigated the association between the novel CNV identified in the current study and schizophrenia. Three independent samples were used: (1) Screening set, 300 Japanese schizophrenic patients (53.28 ± 14.66 years); (2) Confirmation set, 531 schizophrenic patients (46.03 ± 12.15 years); and (3) 711 healthy controls (47.12 ± 11.03 years). All subjects enrolled in the study were Japanese. Chromosomal position was determined using fluorescence in situ hybridization. We identified a novel duplication within the region associated with schizophrenia identified on 7q36.3 that is adjacent to VIPR2 and is not associated with schizophrenia. In the Japanese population, the 35-kb region that harbors the common, novel CNV should be excluded from the region associated with schizophrenia on 7q36.3. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Sci Rep 2013 -1 3: 2587 |
| PMID | 24002029 |
| Title | Definition and refinement of the 7q36.3 duplication region associated with schizophrenia. |
| Abstract | Using a very high-resolution oligonucleotide array for copy number variant (CNV) screening of samples comprising schizophrenic patients, we detected a novel CNV within the critical region (NCBI36/hg18, Chr7: 158,630,410-158,719,410) previously shown to be associated with schizophrenia. We investigated the association between the novel CNV identified in the current study and schizophrenia. Three independent samples were used: (1) Screening set, 300 Japanese schizophrenic patients (53.28 ± 14.66 years); (2) Confirmation set, 531 schizophrenic patients (46.03 ± 12.15 years); and (3) 711 healthy controls (47.12 ± 11.03 years). All subjects enrolled in the study were Japanese. Chromosomal position was determined using fluorescence in situ hybridization. We identified a novel duplication within the region associated with schizophrenia identified on 7q36.3 that is adjacent to VIPR2 and is not associated with schizophrenia. In the Japanese population, the 35-kb region that harbors the common, novel CNV should be excluded from the region associated with schizophrenia on 7q36.3. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Eur. J. Hum. Genet. 2013 Jul 21: 757-61 |
| PMID | 23073313 |
| Title | Low-copy repeats at the human VIPR2 gene predispose to recurrent and nonrecurrent rearrangements. |
| Abstract | Submicroscopic structural variations, including deletions, duplications, inversions and more complex rearrangements, are widespread in normal human genomes. Inverted segmental duplications or highly identical low-copy repeat (LCR) sequences can mediate the formation of inversions and more complex structural rearrangements through non-allelic homologous recombination. In a patient with 7q36 inverted duplication/terminal deletion, we demonstrated the central role of a pair of short inverted LCRs in the vasoactive intestinal peptide receptor gene (VIPR2)-LCRs in generating the rearrangement. We also revealed a relatively common VIPR2-LCR-associated inversion polymorphism disrupting the gene in almost 1% of healthy subjects, and a small number of complex duplications/triplications. In genome-wide studies of several thousand patients, a significant association of rare microduplications with variable size, all involving VIPR2, with schizophrenia was recently described, suggesting that altered vasoactive intestinal peptide signaling is likely implicated in the pathogenesis of schizophrenia. Genetic testing for VIPR2-LCR-associated inversions should be performed on available cohorts of psychiatric patients to evaluate their potential pathogenic role. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Schizophr. Res. 2014 Jun 156: 66-70 |
| PMID | 24794882 |
| Title | A competitive PCR assay confirms the association of a copy number variation in the VIPR2 gene with schizophrenia in Han Chinese. |
| Abstract | Evidence from genetic studies has revealed that genome-wide rare copy number variations (CNVs) are risk factors for neurodevelopmental disorders and this evidence has given rise to a new understanding of disease etiology, including that of schizophrenia (SCZ). Recent studies have indicated that duplication in the vasoactive intestinal peptide receptor-2 (VIPR2) gene confers the susceptibility to SCZ in Caucasians, but so far this finding has still not been confirmed in Chinese populations. In this study, we investigated the association between CNVs in VIPR2 and SCZ risk in an independent case-control study of Han Chinese using 1035 cases and 1535 controls. The CNVs were genotyped using the multiplex fluorescence competitive PCR method. In contrast with a common genotype (2-copy), a microduplication variant genotype (3-copy) was only carried by SCZ patients (4/1035). This finding indicated that CNVs in VIPR2 may impose a significantly increased risk of SCZ in Han Chinese (P=0.02646, OR=infinity, 95% CI=1.327-infinity). Thus, our results suggest that carriers of microduplication genotypes of VIPR2 are predisposed to SCZ in Han Chinese. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Proc. Natl. Acad. Sci. U.S.A. 2014 Jan 111: 361-6 |
| PMID | 24368850 |
| Title | Ohnologs are overrepresented in pathogenic copy number mutations. |
| Abstract | A number of rare copy number variants (CNVs), including both deletions and duplications, have been associated with developmental disorders, including schizophrenia, autism, intellectual disability, and epilepsy. Pathogenicity may derive from dosage sensitivity of one or more genes contained within the CNV locus. To understand pathophysiology, the specific disease-causing gene(s) within each CNV need to be identified. In the present study, we test the hypothesis that ohnologs (genes retained after ancestral whole-genome duplication events, which are frequently dosage sensitive) are overrepresented in pathogenic CNVs. We selected three sets of genes implicated in copy number pathogenicity: (i) genes mapping within rare disease-associated CNVs, (ii) genes within de novo CNVs under negative genetic selection, and (iii) genes identified by clinical array comparative genome hybridization studies as potentially pathogenic. We compared the proportion of ohnologs between these gene sets and control genes, mapping to CNVs not known to be disease associated. We found that ohnologs are significantly overrepresented in genes mapping to pathogenic CNVs, irrespective of how CNVs were identified, with over 90% containing an ohnolog, compared with control CNVs >100 kb, where only about 30% contained an ohnolog. In some CNVs, such as del15p11.2 (CYFIP1) and dup/del16p13.11 (NDE1), the most plausible prior candidate gene was also an ohnolog, as were the genes VIPR2 and NRXN1, each found in short CNVs containing no other genes. Our results support the hypothesis that ohnologs represent critical dosage-sensitive elements of the genome, possibly responsible for some of the deleterious phenotypes observed for pathogenic CNVs and as such are readily identifiable candidate genes for further study. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | Biol. Psychiatry 2015 Nov -1: -1 |
| PMID | 26795442 |
| Title | Genome-wide Analysis of the Role of Copy Number Variation in Schizophrenia Risk in Chinese. |
| Abstract | Compelling evidence suggested the role of copy number variations (CNVs) in schizophrenia susceptibility. Most of the evidence was from studies in populations with European ancestry. We tried to validate the associated CNV loci in a Han Chinese population and identify novel loci conferring risk of schizophrenia. We performed a genome-wide CNV analysis on 6588 patients with schizophrenia and 11,904 control subjects of Han Chinese ancestry. Our data confirmed increased genome-wide CNV (>500 kb and <1%) burden in schizophrenia, and the increasing trend was more significant when only >1 Mb CNVs were considered. We also replicated several associated loci that were previously identified in European populations, including duplications at 16p11.2, 15q11.2-13.1, 7q11.23, and VIPR2 and deletions at 22q11.2, 1q21.1-q21.2, and NRXN1. In addition, we discovered three additional new potential loci (odds ratio >6, p < .05): duplications at 1p36.32, 10p12.1, and 13q13.3, involving many neurodevelopmental and synaptic related genes. Our findings provide further support for the role of CNVs in the etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | Psychopharmacology (Berl.) 2015 Jun 232: 2181-9 |
| PMID | 25575489 |
| Title | Reductions in synaptic proteins and selective alteration of prepulse inhibition in male C57BL/6 mice after postnatal administration of a VIP receptor (VIPR2) agonist. |
| Abstract | An abundance of genetic and epidemiologic evidence as well as longitudinal neuroimaging data point to developmental origins for schizophrenia and other mental health disorders. Recent clinical studies indicate that microduplications of VIPR2, encoding the vasoactive intestinal peptide (VIP) receptor VPAC2, confer significant risk for schizophrenia and autism spectrum disorder. Lymphocytes from patients with these mutations exhibited higher VIPR2 gene expression and VIP responsiveness (cAMP induction), but mechanisms by which overactive VPAC2 signaling may lead to these psychiatric disorders are unknown. We subcutaneously administered the highly selective VPAC2 receptor agonist Ro 25-1553 to C57BL/6 mice from postnatal day 1 (P1) to P14 to determine if overactivation of VPAC2 receptor signaling during postnatal brain maturation affects synaptogenesis and selected behaviors. Western blot analyses on P21 revealed significant reductions of synaptophysin and postsynaptic density protein 95 (PSD-95) in the prefrontal cortex, but not in the hippocampus in Ro 25-1553-treated mice. The same postnatally restricted treatment resulted in a disruption in prepulse inhibition of the acoustic startle measured in adult mice. No effects were observed in open-field locomotor activity, sociability in the three-chamber social interaction test, or fear conditioning or extinction. Overactivation of the VPAC2 receptor in the postnatal mouse results in a reduction in synaptic proteins in the prefrontal cortex and selective alterations in prepulse inhibition. These findings suggest that the VIPR2-linkage to mental health disorders may be due in part to overactive VPAC2 receptor signaling during a critical time of synaptic maturation. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 13 | Meth. Enzymol. 2015 -1 552: 325-49 |
| PMID | 25707284 |
| Title | Sleep and circadian rhythm disruption and recognition memory in schizophrenia. |
| Abstract | schizophrenia patients often show irregularities in sleep and circadian rhythms and deficits in recognition memory. Similar phenotypes are seen in schizophrenia-relevant genetic mouse models, such as synaptosomal associated protein of 25 kDa (Snap-25) point mutant mice, vasoactive intestinal peptide receptor 2 (VIPR2) knockout mice, and neuregulin 1 (Nrg1)-deficient mice. Sleep and circadian abnormalities and impaired recognition memory may be causally related in both schizophrenia patients and schizophrenia-relevant mouse models, since sleep deprivation, abnormal photic input, and the manipulation of core clock genes (cryptochrome 1/2) can all disrupt object recognition memory in rodent models. The recognition deficits observed in patients and mouse models (both schizophrenia-related and -unrelated) are discussed here in terms of the dual-process theory of recognition, which postulates that there are two recognition mechanisms-recollection versus familiarity-that can be selectively impaired by brain lesions, neuropsychiatric conditions, and putatively, sleep and circadian rhythm disruption. However, based on this view, the findings from patient studies and studies using genetic mouse models (Nrg1 deficiency) seem to be inconsistent with each other. schizophrenia patients are impaired at recollection (and to a lesser extent, familiarity judgments), but Nrg1-deficient mice are impaired at familiarity-based object recognition, raising concerns regarding the validity of using these genetically modified mice to model recognition phenotypes observed in patients. This issue can be resolved in future animal studies by examining performance in different variants of the spontaneous recognition task-the standard, perirhinal cortex-dependent, object recognition task versus the hippocampus-dependent object-place recognition task-in order to see which of the two recognition mechanisms is more disrupted. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 14 | Psychiatry Res 2016 Apr 241: 104-107 |
| PMID | 27156032 |
| Title | Analysis of the association of VIPR2 polymorphisms with susceptibility to schizophrenia. |
| Abstract | In a previous study, we confirmed that copy number variants (CNVs) within the VIPR2 gene in Han Chinese individuals exhibit an increased risk of schizophrenia (SCZ). Herein, we further analyzed the association of eight tagged single nucleotide polymorphisms (tagSNPs) from the HapMap database with SCZ susceptibility. However, we found no significant positive signals in overall association and haplotypes analyses. Interestingly, significant SNP-SNP interaction signals associated with the risk of SCZ were observed using Multifactor Dimensionality Reduction (MDR) analysis. Furthermore, the 'CC' genotype of the VIPR2 gene was nominally associated with an increased risk of SCZ in male patients. |
| SCZ Keywords | schizophrenia, schizophrenic |