Copy number variation and neuropsychiatric illness

Rees, Elliott; Kirov, George

doi:10.1016/j.gde.2021.02.014

Cited by 65 publications

(50 citation statements)

References 58 publications

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“…There is evidence that both common and rare genetic variants, as well as diverse environmental factors contribute to its etiology [ 1 ]. Specific copy number variants (CNVs) have also been shown to be associated with schizophrenia [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

What genes are differentially expressed in individuals with schizophrenia? A systematic review

et al. 2022

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Schizophrenia is a severe, complex mental disorder characterized by a combination of positive symptoms, negative symptoms, and impaired cognitive function. Schizophrenia is highly heritable (~80%) with multifactorial etiology and complex polygenic genetic architecture. Despite the large number of genetic variants associated with schizophrenia, few causal variants have been established. Gaining insight into the mechanistic influences of these genetic variants may facilitate our ability to apply these findings to prevention and treatment. Though there have been more than 300 studies of gene expression in schizophrenia over the past 15 years, none of the studies have yielded consistent evidence for specific genes that contribute to schizophrenia risk. The aim of this work is to conduct a systematic review and synthesis of case–control studies of genome-wide gene expression in schizophrenia. Comprehensive literature searches were completed in PubMed, EmBase, and Web of Science, and after a systematic review of the studies, data were extracted from those that met the following inclusion criteria: human case–control studies comparing the genome-wide transcriptome of individuals diagnosed with schizophrenia to healthy controls published between January 1, 2000 and June 30, 2020 in the English language. Genes differentially expressed in cases were extracted from these studies, and overlapping genes were compared to previous research findings from the genome-wide association, structural variation, and tissue-expression studies. The transcriptome-wide analysis identified different genes than those previously reported in genome-wide association, exome sequencing, and structural variation studies of schizophrenia. Only one gene, GBP2, was replicated in five studies. Previous work has shown that this gene may play a role in immune function in the etiology of schizophrenia, which in turn could have implications for risk profiling, prevention, and treatment. This review highlights the methodological inconsistencies that impede valid meta-analyses and synthesis across studies. Standardization of the use of covariates, gene nomenclature, and methods for reporting results could enhance our understanding of the potential mechanisms through which genes exert their influence on the etiology of schizophrenia. Although these results are promising, collaborative efforts with harmonization of methodology will facilitate the identification of the role of genes underlying schizophrenia.

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Section: Introductionmentioning

confidence: 99%

What genes are differentially expressed in individuals with schizophrenia? A systematic review

et al. 2022

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“…As a major kind of contributors to structural genetic diversity, copy number variations (CNVs) are key players in psychiatric and neurodevelopmental disorders, including SCZ, autism spectrum disorder (ASD), and intellectual disability ( Kirov et al., 2014 ; Weiss et al., 2008 ), and are also associated with neuropsychiatric traits in both disease and general population ( Guyatt et al., 2018 ; Hubbard et al., 2020 ). Case-control association analysis has revealed the global and large rare CNV burden in SCZ cases ( Marshall et al., 2017 ; Rees and Kirov, 2021 ) and has discovered numerous CNV hotspots for SCZ susceptibility, including 1q21.1 deletion/duplication (del/dup), 2p16.3 del ( NRXN1 ), 3q29 del/dup, 7p36.3 dup ( VIPR2 ), 15q13.3 del, 16p11.2 dup, 16p13.1 dup, 17p12 del, and so on ( Ingason et al., 2011 ; Kirov et al., 2009 , 2012 ; Levinson et al., 2011 ; McCarthy et al., 2009 ; Szatkiewicz et al., 2014 ; Yuan et al., 2017 ). These findings, together with genetic variation studies, outline the possible gene pathways involved in SCZ development, where that anatomical abnormality, dysfunctional neurotransmission, and stress-associated signaling cascade dysregulation are the three main causes of SCZ ( Fatani et al., 2017 ; Marshall et al., 2017 ; Rees and Kirov, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Case-control association analysis has revealed the global and large rare CNV burden in SCZ cases ( Marshall et al., 2017 ; Rees and Kirov, 2021 ) and has discovered numerous CNV hotspots for SCZ susceptibility, including 1q21.1 deletion/duplication (del/dup), 2p16.3 del ( NRXN1 ), 3q29 del/dup, 7p36.3 dup ( VIPR2 ), 15q13.3 del, 16p11.2 dup, 16p13.1 dup, 17p12 del, and so on ( Ingason et al., 2011 ; Kirov et al., 2009 , 2012 ; Levinson et al., 2011 ; McCarthy et al., 2009 ; Szatkiewicz et al., 2014 ; Yuan et al., 2017 ). These findings, together with genetic variation studies, outline the possible gene pathways involved in SCZ development, where that anatomical abnormality, dysfunctional neurotransmission, and stress-associated signaling cascade dysregulation are the three main causes of SCZ ( Fatani et al., 2017 ; Marshall et al., 2017 ; Rees and Kirov, 2021 ). However, the detailed mechanisms underlying SCZ have yet to be fully understood.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide study of copy number variation implicates multiple novel loci for schizophrenia risk in Han Chinese family trios

Cong

Shen

et al. 2021

iScience

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Summary Schizophrenia (SCZ) is a severe neuropsychiatric disorder that affects 1% of the global population. Copy number variations (CNVs) have been shown to play a critical role in its pathophysiology; however, only case-control studies on SCZ susceptibility CNVs have been conducted in Han Chinese. Here, we performed an array comparative genomic hybridization-based genome-wide CNV analysis in 100 Chinese family trios with SCZ. Burden test suggested that the SCZ probands carried more duplications than their healthy parents and unrelated healthy controls. Besides, five CNV loci were firstly reported to be associated with SCZ here, including both unbalanced transmitted CNVs and enriched de novo CNVs. Moreover, two genes ( CTDSPL and MGAM ) in these CNVs showed significant SCZ relevance in the expression level. Our findings support the crucial role of CNVs in the etiology of SCZ and provide new insights into the underlying mechanism of SCZ pathogenesis.

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“…Copy number variations (CNVs) are genetic variations resulting from the rearrangements of DNA segments. Accumulating studies show that rare CNVs (including microduplications and microdeletions) contribute a significant part to the genetic etiology of schizophrenia [ 3 , 4 ]. Identifying the genetic bases of psychiatric disorders can aid in achieving the etiological diagnosis of patients with psychiatric disorders and may help elucidate the pathophysiology of psychiatric disorders and hopefully improve psychiatric treatment in the future [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Translational Study of Copy Number Variations in Schizophrenia

Cheng

Chien

Huang

et al. 2021

IJMS

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Rare copy number variations (CNVs) are part of the genetics of schizophrenia; they are highly heterogeneous and personalized. The CNV Analysis Group of the Psychiatric Genomic Consortium (PGC) conducted a large-scale analysis and discovered that recurrent CNVs at eight genetic loci were pathogenic to schizophrenia, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.23, 15q13.3, distal 16p11.2, proximal 16p11.2, and 22q11.2. We adopted a two-stage strategy to translate this knowledge into clinical psychiatric practice. As a screening test, we first developed a real-time quantitative PCR (RT-qPCR) panel that simultaneously detected these pathogenic CNVs. Then, we tested the utility of this screening panel by investigating a sample of 557 patients with schizophrenia. Chromosomal microarray analysis (CMA) was used to confirm positive cases from the screening test. We detected and confirmed thirteen patients who carried CNVs at these hot loci, including two patients at 1q21.1, one patient at 7q11.2, three patients at 15q13.3, two patients at 16p11.2, and five patients at 22q11.2. The detection rate in this sample was 2.3%, and the concordance rate between the RT-qPCR test panel and CMA was 100%. Our results suggest that a two-stage approach is cost-effective and reliable in achieving etiological diagnosis for some patients with schizophrenia and improving the understanding of schizophrenia genetics.

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Copy number variation and neuropsychiatric illness

Cited by 65 publications

References 58 publications

What genes are differentially expressed in individuals with schizophrenia? A systematic review

What genes are differentially expressed in individuals with schizophrenia? A systematic review

Genome-wide study of copy number variation implicates multiple novel loci for schizophrenia risk in Han Chinese family trios

Translational Study of Copy Number Variations in Schizophrenia

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