Major depressive disorder (MDD) is a polygenic condition with substantial heritability, with genome-wide association studies (GWAS) identifying several risk loci in European populations, including the VRK2 gene. However, the association between VRK2 and MDD in non-European populations, particularly in Han Chinese, remains underexplored.We genotyped four VRK2 SNPs (rs2678907, rs11682175, rs1568452, rs1518395) in a cohort of 1878 MDD cases and 1800 controls of Han Chinese descent. Genotyping was performed using SNaPShot, and linkage disequilibrium (LD) was assessed with SHEsis. Associations between the SNPs and MDD were evaluated via logistic regression in PLINK. VRK2 mRNA expression in the amygdala and peripheral blood was quantified by RT-qPCR, with statistical significance determined by ANCOVA and t-tests. A meta-analysis incorporating an independent East Asian GWAS cohort was also conducted.In our Han Chinese cohort, rs2678907 was significantly associated with MDD (P = 4.17 × 10-5, OR = 1.217). Meta-analysis with independent East Asian GWAS further confirmed the associations of rs2678907 with MDD. Haplotype analysis of VRK2 SNPs in Han Chinese revealed the haplotypes (T-G for rs11682175-rs2678907 and C-G for rs1568452-rs2678907) associated with an increased MDD risk and elevated VRK2 mRNA expression. Additionally, MDD patients showed significantly higher VRK2 mRNA levels in peripheral blood than controls (P = 1.85 × 10-7).These findings provide strong evidence for the role of VRK2 in MDD risk in Han Chinese individuals. Our results underscore the potential of VRK2 as a genetic and expression-based biomarker for MDD, highlighting the importance of accounting for population-specific genetic variations in psychiatric research. Further research is essential to explore the functional implications of VRK2 in MDD pathogenesis.Copyright © 2025. Published by Elsevier B.V.