Copy Number Variation in Schizophrenia in the Japanese Population

doi:10.1016/j.biopsych.2009.08.034

Biological Psychiatry

Volume 67, Issue 3, 1 February 2010, Pages 283-286

https://doi.org/10.1016/j.biopsych.2009.08.034 Get rights and content

Background

Copy number variants (CNVs) have been shown to increase the risk to develop schizophrenia. The best supported findings are at 1q21.1, 15q11.2, 15q13.3, and 22q11.2 and deletions at the gene neurexin 1 (NRXN1).

Methods

In this study, we used Affymetrix 5.0 arrays to investigate the role of rare CNVs in 575 patients with schizophrenia and 564 control subjects from Japan.

Results

There was a nonsignificant trend for excess of rare CNVs in schizophrenia (p = .087); however, we did not confirm the previously implicated association for very large CNVs (>500 kilobase [kb]) in this population. We provide support for three previous findings in schizophrenia, as we identified one deletion in a case at 1q21.1, one deletion within NRXN1, and four duplications in cases and one in a control subject at 16p13.1, a locus first implicated in autism and later in schizophrenia.

Conclusions

In this population, we support some of the previous findings in schizophrenia but could not find an increased burden of very large (>500 kb) CNVs, which was proposed recently. However, we provide support for the role of CNVs at 16p13.1, 1q21.1, and NRXN1.

Section snippets

Methods and Materials

We analyzed 1139 age- and gender-matched unrelated subjects of Japanese ethnicity (575 schizophrenic patients and 564 control subjects). Control subjects were members of the general public who had no personal history of mental disorders. This was ascertained during face-to-face interviews where subjects were asked if they had suffered an episode of depression, mania, or psychotic experiences or if they had received treatment for any psychiatric disorder. Patients were entered into the study if

Results

The numbers of rare CNVs stratified by size in cases and control subjects are listed in Table 1. Overall, we found an excess of CNVs in subjects with schizophrenia (case-control ratio = 1.16). Although not significant (p = .087, one-tailed permutation test), this is similar to that reported by the largest CNV study (4) where the case-control ratio was 1.15. The effect in that study (4) was coming mostly from deletions >500 kb and duplications in the 100 kb to 200 kb range. No subcategory of CNV

Discussion

In this study, we do not find a significant increase in the burden of CNVs in schizophrenia, either overall or for any specific size range of CNVs, as proposed in previous studies (2, 3, 4, 7). We did, however, find several trends in the same direction and of a similar magnitude as the largest global CNV survey of schizophrenia (4). Not all research has found such an increased burden, e.g., no evidence was obtained from a study in the Chinese population (5). It is possible that genuine

References (17)

S. Purcell et al.
PLINK: A tool set for whole-genome association and population-based linkage analyses
Am J Hum Genet
(2007)
E.H. Cook et al.
Copy-number variations associated with neuropsychiatric conditions
Nature
(2008)
T. Walsh et al.
Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia
Science
(2008)
B. Xu et al.
Strong association of de novo copy number mutations with sporadic schizophrenia
Nat Genet
(2008)
Rare chromosomal deletions and duplications increase risk of schizophrenia
Nature
(2008)
Y.Y. Shi et al.
A study of rare structural variants in schizophrenia patients and normal controls from Chinese Han population
Mol Psychiatry
(2008)
A.C. Need et al.
A genome-wide investigation of SNPs and CNVs in schizophrenia
PLoS Genet
(2009)
G. Kirov et al.
Support for the involvement of large CNVs in the pathogenesis of schizophrenia
Hum Mol Genet
(2009)

There are more references available in the full text version of this article.

Cited by (102)

Cell-Type-Specific Proteogenomic Signal Diffusion for Integrating Multi-Omics Data Predicts Novel Schizophrenia Risk Genes
2020, Patterns
Accumulation of diverse types of omics data on schizophrenia (SCZ) requires a systems approach to model the interplay between genome, transcriptome, and proteome. We introduce Markov affinity-based proteogenomic signal diffusion (MAPSD), a method to model intra-cellular protein trafficking paradigms and tissue-wise single-cell protein abundances. MAPSD integrates multi-omics data to amplify the signals at SCZ risk loci with small effect sizes, and reveal convergent disease-associated gene modules in the brain. We predicted a set of high-confidence SCZ risk loci followed by characterizing the subcellular localization of proteins encoded by candidate SCZ risk genes, and illustrated that most are enriched in neuronal cells in the cerebral cortex as well as Purkinje cells in the cerebellum. We demonstrated how the identified genes may be involved in neurodevelopment, how they may alter SCZ-related biological pathways, and how they facilitate drug repurposing. MAPSD is applicable in other polygenic diseases and can facilitate our understanding of disease mechanisms.
Neuroligins and neurexins
2020, Synapse Development and Maturation: Comprehensive Developmental Neuroscience
The differentiation and functional specification of synapses are critical for the assembly and function of neuronal networks. Adhesion molecules that bridge the synaptic cleft have emerged as important regulators of the establishment, maintenance, and functional characteristics of synaptic connections. This chapter focuses on one pair of such trans-synaptic interaction partners, the neurexins (NRXs) and neuroligins (NLs), which form a heterophilic adhesion complex. We will first briefly discuss the discovery of these synaptic proteins and then summarize conclusions from structural and cell biological studies on the synaptic function of NRX and NL proteins. In the last section of the chapter, we will then highlight the involvement of NRX and NL functions in neuropsychiatric and neurodevelopmental disorders.
Unravelling the genetic basis of schizophrenia and bipolar disorder with GWAS: A systematic review
2019, Journal of Psychiatric Research
Citation Excerpt :
Among SZ studies, two SNPs were identified twice: rs752016 in the PLXNA2 gene (coding a neurodevelopmental-mediating receptor) (Mah et al., 2006; Sullivan et al., 2008) and rs1344706 in ZNF804A (coding a neurodevelopmental transcription factor) (O'Donovan et al., 2008; Williams et al., 2011a), although possible sample overlap had not been verified/disclosed in the review, and thus these results are not necessarily true replications. Regarding CNVs, there was replication of significant deletions involving NRXN1 in 6 studies (SJ et al., 2008; Kirov et al., 2008a; Walsh et al., 2008; Rujescu et al., 2009; Ikeda et al., 2010; Vrijenhoek et al., 2008) and NRG3, RAPGEF6, MYO38, GST1, GSTT2 and VIPR2 in at least 2 studies (Xu et al., 2008, 2009; McCarthy et al., 2009; Need et al., 2009; Kirov et al., 2009; Rodriguez-Santiago et al., 2010; Vacic et al., 2011; Levinson et al., 2011). Some genes discussed in Lee et al. (2012a) were: 1) associated with both SZ and BD by GWA, giving credence to a long-alleged partially overlapping genetic basis in these disorders (Lee et al., 2012a); and 2) have accumulated early and suggestive evidence of impact on brain structure and function, such as ANK3, CACNA1C, NRGN and ZNF804A, plus in TCF4 and DGKH, as we reviewed elsewhere (Gurung and Prata, 2015).
To systematically review findings of GWAS in schizophrenia (SZ) and in bipolar disorder (BD); and to interpret findings, with a focus on identifying independent replications.
PubMed search, selection and review of all independent GWAS in SZ or BD, published since March 2011, i.e. studies using non-overlapping samples within each article, between articles, and with those of the previous review (Li et al., 2012).
From the 22 GWAS included in this review, the genetic associations surviving standard GWAS-significance were for genetic markers in the regions of ACSL3/KCNE4, ADCY2, AMBRA1, ANK3, BRP44, DTL, FBLN1, HHAT, INTS7, LOC392301, LOC645434/NMBR, LOC729457, LRRFIP1, LSM1, MDM1, MHC, MIR2113/POU3F2, NDST3, NKAPL, ODZ4, PGBD1, RENBP, TRANK1, TSPAN18, TWIST2, UGT1A1/HJURP, WHSC1L1/FGFR1 and ZKSCAN4. All genes implicated across both reviews are discussed in terms of their function and implication in neuropsychiatry.
Taking all GWAS to date into account, AMBRA1, ANK3, ARNTL, CDH13, EFHD1 (albeit with different alleles), MHC, PLXNA2 and UGT1A1 have been implicated in either disorder in at least two reportedly non-overlapping samples. Additionally, evidence for a SZ/BD common genetic basis is most strongly supported by the implication of ANK3, NDST3, and PLXNA2.
Catatonia in Children and Adolescents: A High Rate of Genetic Conditions
2018, Journal of the American Academy of Child and Adolescent Psychiatry
Repint of “Reframing autism as a behavioral syndrome and not a specific mental disorder: Implications of genetic and phenotypic heterogeneity”
2018, Neuroscience and Biobehavioral Reviews
Citation Excerpt :
Furthermore, Table 1 indicates clearly in the chromosomal disorders part that a duplication or deletion occurring at the same locus can both lead to a phenotype of autism (see for example, the 16p11.2, 1q21.1, 15q11-q13, 22q13.3, or 22q11.21 deletion/duplication), suggesting that genetic disequilibrium at certain loci might be more important than gene-dosage effects. Interestingly, these “hot spots” were also found in schizophrenia (Ikeda et al., 2010; Levinson et al., 2011), suggesting relationships between autism and schizophrenia. It is noteworthy that many CNVs (deletion/duplication) associated with autism are observed in schizophrenia but also in intellectual disability, epilepsy, learning disorder, bipolar disorder and many other disorders (see Table 2).
Clinical and molecular genetics have advanced current knowledge on genetic disorders associated with autism. A review of diverse genetic disorders associated with autism is presented and for the first time discussed extensively with regard to possible common underlying mechanisms leading to a similar cognitive-behavioral phenotype of autism. The possible role of interactions between genetic and environmental factors, including epigenetic mechanisms, is in particular examined. Finally, the pertinence of distinguishing non-syndromic autism (isolated autism) from syndromic autism (autism associated with genetic disorders) will be reconsidered. Given the high genetic and etiological heterogeneity of autism, autism can be viewed as a behavioral syndrome related to known genetic disorders (syndromic autism) or currently unknown disorders (apparent non-syndromic autism), rather than a specific categorical mental disorder. It highlights the need to study autism phenotype and developmental trajectory through a multidimensional, non-categorical approach with multivariate analyses within autism spectrum disorder but also across mental disorders, and to conduct systematically clinical genetic examination searching for genetic disorders in all individuals (children but also adults) with autism.
Reframing autism as a behavioral syndrome and not a specific mental disorder: Implications of genetic and phenotypic heterogeneity
2017, Neuroscience and Biobehavioral Reviews

View all citing articles on Scopus

View full text

Brief ReportCopy Number Variation in Schizophrenia in the Japanese Population

Background

Methods

Results

Conclusions

Section snippets

Methods and Materials

Results

Discussion

Am J Hum Genet

Copy-number variations associated with neuropsychiatric conditions

Nature

Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia

Science

Strong association of de novo copy number mutations with sporadic schizophrenia

Nat Genet

Rare chromosomal deletions and duplications increase risk of schizophrenia

Nature

A study of rare structural variants in schizophrenia patients and normal controls from Chinese Han population

Mol Psychiatry

A genome-wide investigation of SNPs and CNVs in schizophrenia

PLoS Genet

Support for the involvement of large CNVs in the pathogenesis of schizophrenia

Hum Mol Genet

Brief Report
Copy Number Variation in Schizophrenia in the Japanese Population