Association of the VRK2 gene rs3732136 polymorphism with schizophrenia in a Northwest Chinese Han population

Zhang, B; GAO, CHEN; Zhang, H B; Yang, Bixiu; Yin, Jiajun; Wei, Shuguang; Zhu, Yan; Jia, Xiao-Di; Li, S B

doi:10.4238/2015.august.14.4

Cited by 15 publications

(8 citation statements)

References 20 publications

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“…Following these, the Irish Schizophrenia Genomics Consortium and the Welcome Trust Case Control Consortium 2 further replicated this significant association of rs2312147 and SCZ in a European GWAS [30]. These series of studies motivated researchers worldwide to pay attention to the genetic risk for SCZ conferred by VRK2 polymorphisms, and replication studies in populations other than Europeans were also conducted [31-33]. For example, Li et al[34] replicated the association between rs2312147 and SCZ in independent Asian samples ( n = 6,565, p = 4.24 × 10 –4 ).…”

Section: Identification Of Vrk2 Variants In Psychiatric Disorders Amomentioning

confidence: 99%

VRK2, a Candidate Gene for Psychiatric and Neurological Disorders

Yue

2018

Complex Psychiatry

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Recent large-scale genetic approaches, such as genome-wide association studies, have identified multiple genetic variations that contribute to the risk of mental illnesses, among which single nucleotide polymorphisms (SNPs) within or near the vaccinia related kinase 2 (VRK2) gene have gained consistent support for their correlations with multiple psychiatric and neurological disorders including schizophrenia (SCZ), major depressive disorder (MDD), and genetic generalized epilepsy. For instance, the genetic variant rs1518395 in VRK2 showed genome-wide significant associations with SCZ (35,476 cases and 46,839 controls, p = 3.43 × 10^–8) and MDD (130,620 cases and 347,620 controls, p = 4.32 × 10^–12) in European populations. This SNP was also genome-wide significantly associated with SCZ in Han Chinese population (12,083 cases and 24,097 controls, p = 3.78 × 10^–13), and all associations were in the same direction of allelic effects. These studies highlight the potential roles of VRK2 in the central nervous system, and this gene therefore might be a good candidate to investigate the shared genetic and molecular basis between SCZ and MDD, as it is one of the few genes known to show genome-wide significant associations with both illnesses. Furthermore, the VRK2 gene was found to be involved in multiple other congenital deficits related to the malfunction of neurodevelopment, adding further support for the involvement of this gene in the pathogenesis of these neurological and psychiatric illnesses. While the precise function of VRK2 in these conditions remains unclear, preliminary evidence suggests that it may affect neuronal proliferation and migration via interacting with multiple essential signaling pathways involving other susceptibility genes/proteins for psychiatric disorders. Here, we have reviewed the recent progress of genetic and molecular studies of VRK2, with an emphasis on its role in psychiatric illnesses and neurological functions. We believe that attention to this important gene is necessary, and further investigations of VRK2 may provide hints into the underlying mechanisms of SCZ and MDD.

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Section: Identification Of Vrk2 Variants In Psychiatric Disorders Amomentioning

confidence: 99%

VRK2, a Candidate Gene for Psychiatric and Neurological Disorders

Yue

2018

Complex Psychiatry

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“…In support of this concept, recently, many genome-wide association studies suggest that VRK2 is a risk factor for neurological disorders including schizophrenia 12 13 and epilepsy 11 . VRK2 mRNA levels are upregulated in schizophrenic patient brains compared with normal control brains 12 , and VRK2 gene rs3732136 polymorphism is associated with schizophrenia in the worldwide population 32 . Therefore, genetic variations could affect expression of the VRK2 gene, and malfunctions in VRK2 kinase activity might contribute to susceptibility to neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 95%

Glycogen synthase kinase 3β suppresses polyglutamine aggregation by inhibiting Vaccinia-related kinase 2 activity

Lee

Ryu

Kim

et al. 2016

Sci Rep

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Huntington’s disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of polyglutamine repeats in the N-terminal of huntingtin. The amount of aggregate-prone protein is controlled by various mechanisms, including molecular chaperones. Vaccinia-related kinase 2 (VRK2) is known to negatively regulate chaperonin TRiC, and VRK2-facilitated degradation of TRiC increases polyQ protein aggregation, which is involved in HD. We found that VRK2 activity was negatively controlled by glycogen synthase kinase 3β (GSK3β). GSK3β directly bound to VRK2 and inhibited the catalytic activity of VRK2 in a kinase activity-independent manner. Furthermore, GSK3β increased the stability of TRiC and decreased the formation of HttQ103-GFP aggregates by inhibiting VRK2. These results indicate that GSK3β signaling may be a regulatory mechanism of HD progression and suggest targets for further therapeutic trials for HD.

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“…Also, there have been consistent reports that rs3732136, a VRK2 gene polymorphism, was associated with schizophrenia in the worldwide population (Zhang et al . ). Still, it is not clear at this time how VRK2 specifically affects schizophrenia, because the neurobiological basis of VRK2 is poorly understood.…”

Section: Discussionmentioning

confidence: 97%

“…These investigations have stated that VRK2 mRNA levels were elevated in the brains of schizophrenic patient compared to the level shown in healthy individuals (Li et al 2012). Also, there have been consistent reports that rs3732136, a VRK2 gene polymorphism, was associated with schizophrenia in the worldwide population (Zhang et al 2015). Still, it is not clear at this time how VRK2 specifically affects schizophrenia, because the neurobiological basis of VRK2 is poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Vaccinia‐related kinase 2 modulates role of dysbindin by regulating protein stability

Jeong

Choi

Lee

et al. 2018

Journal of Neurochemistry

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Vaccinia-related kinase 2 (VRK2) is a serine/threonine kinase that belongs to the casein kinase 1 family. VRK2 has long been known for its relationship with neurodegenerative disorders such as schizophrenia. However, the role of VRK2 and the substrates associated with it are unknown. Dysbindin is known as one of the strong risk factors for schizophrenia. The expression of dysbindin is indeed significantly reduced in schizophrenia patients. Moreover, dysbindin is involved in neurite outgrowth and regulation of NMDA receptor signaling. Here, we first identified dysbindin as a novel interacting protein of VRK2 through immunoprecipitation. We hypothesized that dysbindin is phosphorylated by VRK2 and further that this phosphorylation plays an important role in the function of dysbindin. We show that VRK2 phosphorylates Ser 297 and Ser 299 of dysbindin using in vitro kinase assay. In addition, we found that VRK2-mediated phosphorylation of dysbindin enhanced ubiquitination of dysbindin and consequently resulted in the decrease in its protein stability through western blotting. Over-expression of VRK2 in human neuroblastoma (SH-SY5Y) cells reduced neurite outgrowth induced by retinoic acid. Furthermore, a phosphomimetic mutant of dysbindin alleviated neurite outgrowth and affected surface expression of N-methyl-d-aspartate 2A, a subunit of NMDA receptor in mouse hippocampal neurons. Together, our work reveals the regulation of dysbindin by VRK2, providing the association of these two proteins, which are commonly implicated in schizophrenia. Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/.

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Association of the VRK2 gene rs3732136 polymorphism with schizophrenia in a Northwest Chinese Han population

Cited by 15 publications

References 20 publications

<b><i>VRK2</i></b>, a Candidate Gene for Psychiatric and Neurological Disorders

<b><i>VRK2</i></b>, a Candidate Gene for Psychiatric and Neurological Disorders

Glycogen synthase kinase 3β suppresses polyglutamine aggregation by inhibiting Vaccinia-related kinase 2 activity

Vaccinia‐related kinase 2 modulates role of dysbindin by regulating protein stability

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