Reduced Vrk2 expression is associated with higher risk of depression in humans and mediates depressive-like behaviors in mice

Abstract

AbstractBackgroundGenome-wide association studies (GWAS) have reported single-nucleotide polymorphisms (SNPs) in the VRK serine/threonine kinase 2 gene (VRK2) showing genome-wide significant associations with major depression, but the regulation effect of the risk SNPs onVRK2as well as their roles in the illness are yet to be elucidated.MethodsBased on the summary statistics of major depression GWAS, we conducted population genetic analyses, epigenome bioinformatics analyses, dual luciferase reporter assays, and expression quantitative trait loci (eQTL) analyses to identify the functional SNPs regulatingVRK2; we also carried out behavioral assessments, dendritic spine morphological analyses, and phosphorylated 4D-label-free quantitative proteomics analyses in mice withVrk2repression.ResultsWe identified a SNP rs2678907 located in the 5’ upstream ofVRK2gene exhibiting large spatial overlap with enhancer regulatory marks in human neural cells and brain tissues. Using luciferase reporter gene assays and eQTL analyses, the depression risk allele of rs2678907 decreased enhancer activities and predicted lowerVRK2mRNA expression, which is consistent with the observations of reducedVRK2level in the patients with major depression compared with controls. Notably,Vrk2−/−mice exhibited depressive-like behaviors compared toVrk2+/+mice and specifically repressingVrk2in the ventral hippocampus using adeno-associated virus (AAV) lead to consistent and even stronger depressive-like behaviors in mice. Compared withVrk2+/+mice, the density of mushroom and thin spines in the ventral hippocampus was significantly altered inVrk2−/−mice, which is in line with the phosphoproteomic analyses showing dysregulated synapse-associated proteins and pathways inVrk2−/−mice.ConclusionsVrk2deficiency mice showed behavioral abnormalities that mimic human depressive phenotypes, which may serve as a useful murine model for studying the pathophysiology of depression.