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

Abstract

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.

The FBXW2–MSX2–SOX2 axis regulates stem cell property and drug resistance of cancer cells

“…VRK2 was first identified in 1997 as a putative serine/threonine kinase with structural similarity to vaccinia virus B1R kinase (40), and was recently characterized as a candidate gene for psychiatric and neurological disorders (41). Involvement of VRK2 in human cancer is much less studied, with few reports on its interactions with p53 (42), Bcl-xL (43), and Akt (44) and its inhibition of MAPK (45).…”

Further confirmation of netrin 1 receptor (DCC) as a depression risk gene via integrations of multi-omics data

“…Intriguingly, the significant associations between these two genes with the risk of depression were again observed in Europeans (P MAGMA = 1.01 × 10 −11 for LRFN5, P MAGMA = 2.85 × 10 −12 for DCC, Table 1). Given the emerging evidence supporting the notion that vital genetic markers for psychiatric disorders are normally associated with the disease across different ethnic populations 65 (e.g., psychiatric risk loci in ZNF804A, FADS1, and VRK2 show significant associations in both Europeans and East Asians [66][67][68][69][70][71] ), we then examined whether LRFN5 and DCC were also associated with depression in Han Chinese subjects through MAGMA gene-level analyses using a published Han Chinese GWAS dataset (5303 cases and 5337 controls) 24 . Notably, DCC was associated with depression as well in Han Chinese despite the lower level of statistical significance compared with that in Europeans (P MAGMA = 3.21 × 10 −4 , Table 1), but LRFN5 was not associated with depression in Han Chinese (P MAGMA = 0.406, Table 1).…”

Association of SYNE1 locus with bipolar disorder in Chinese population

“…However, it is intriguing that the “minor” allele of rs9371601 in Europeans is different from that in Han Chinese populations, providing possible explanations for the inconsistent allelic effects discussed earlier. Given that risk genes for one psychiatric disorder usually exhibit robust associations with multiple other psychiatric illnesses as well [53–55], researchers have also conducted a cross-diagnosis analysis rs9371601. This SNP was nominally associated with major depressive disorder (MDD) in the Green study of European individuals, and the T-allele (i.e., BPD risk allele in Europeans) predicted increased risk of MDD [26].…”