Effects of VRK2 (rs2312147) on White Matter Connectivity in Patients with Schizophrenia

Abstract

Recent genome-wide association studies of schizophrenia reported a novel risk variant, rs2312147 at vaccinia-related kinase 2 gene (VRK2), in multiple Asian and European samples. However, its effect on the brain structure in schizophrenia is little known. We analyzed the brain structure of 36 schizophrenia patients and 18 healthy subjects with regard to rs2312147 genotype groups. Brain magnetic resonance scans for gray matter (GM) and white matter (WM) analysis, and genotype analysis for VRK2 rs2312147, were conducted. The Positive and Negative Syndrome Scale and the Digit Symbol Test were assessed for schizophrenia patients. There was no significant difference in either GM volume or WM connectivity with regard to rs2312147 genotype in healthy subjects. In contrast, we found significant differences in the WM connectivity between rs2312147 CC and CT/TT genotype groups of schizophrenia patients. The related brain areas included the splenium of corpus callosum, the left occipital lobe WM, the internal capsule (left anterior limb and right retrolenticular part), the bilateral temporal lobe WM, the left fornix/stria terminalis, the left cingulate gyrus WM, and the left parietal lobe WM. Voxelwise correlation analysis revealed that the Digit Symbol Test scores (age corrected) correlated with the fractional anisotropy in WM tracts that previously showed significant group differences between the CT/TT and CC genotypes in the rs2312147 CT/TT genotype group, while no significant correlation was found in the CC genotype group. Our data may provide evidence for the effect of VRK2 on WM connectivity in patients with schizophrenia.

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

“…We previously also analyzed the association between VRK2 SNPs and brain phenotypes related to psychiatric disorders [34] and found that the psychiatric risk allele [C] in rs2312147 was associated with reduced total brain volume and white matter volume in healthy individuals, which was in line with clinical characteristics in the brains of psychiatric patients compared with healthy controls [73]. This finding was further supported by Sohn et al [74], as they reported significant differences in the white matter connectivity between rs2312147 CC and CT/TT genotype groups of SCZ patients for many brain regions. These data provided initial evidence for the effects of VRK2 on white matter development, and investigations dissecting the underlying biological mechanisms and etiological relevance in psychosis and mood disorders are necessary.…”

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

“…; Sohn et al . ) and epilepsy (EPICURE Consortium and Steffens ). Especially, there has been a steady stream of reports that VRK2 is associated with schizophrenia.…”

“…Many genome-wide association studies have suggested that VRK2 is related to neurological disorders including schizophrenia (Li et al 2012;Sohn et al 2014) and epilepsy (EPICURE Consortium and Steffens 2012). Especially, there has been a steady stream of reports that VRK2 is associated with schizophrenia.…”

“…Although some proteins, such as histone H3, USP25, and NFAT-1, are known to be phosphorylated by VRK2, the role of VRK2 is still not well-known. Recently, several convincing reports illustrated that VRK2 is related to neurodegenerative disorders (EPICURE Consortium and Steffens 2012;Li et al 2012Sohn et al 2014, Kim et al 2015. From gene expression analyses in schizophrenia patients, it was found that a single-nucleotide polymorphism (SNP) located in the upstream of VRK2 caused an increase in schizophrenia susceptibility (Li et al 2012;Sohn et al 2014), However, functions of VRK2 in neurodegenerative disorders remain unclear.…”

Vaccinia‐related kinase 2 plays a critical role in microglia‐mediated synapse elimination during neurodevelopment

“…However, the endogenous functions of VRK2 have yet to be identified. Several genome-wide association studies have described several single-nucleotide polymorphisms (SNPs) of VRK2 as risk variants for schizophrenia (rs2312147, rs3732136) and epilepsy (rs1302641) (EPICURE Consortium et al, 2012;Li et al, 2012;Sohn et al, 2014;Steinberg et al, 2011;Zhang et al, 2015). Moreover, patients with 2p15-p16.1 microdeletion syndrome (including the genomic deletion of VRK2) suffer from speech delay and learning difficulties due to impaired neurodevelopment (Chabchoub, Vermeesch, de Ravel, de Cock, & Fryns, 2008;Liang et al, 2009;Lin et al, 2008;Piccione et al, 2012;Prontera et al, 2011;Rajcan-Separovic et al, 2007).…”