The Epac2 coding gene (RAPGEF4) rs3769219 polymorphism is associated with protection against major depressive disorder in the Chinese Han population

•The association of rs3769219 variant with major depressive disorder (MDD) was studied.•Mutation in RAPGEF4 rs3769219 locus is associated with reduced risk of MDD in males.•RAPGEF4 rs3769219 variant is also associated with reduced risk of recurrent MDD. Adult hippocampal neurogenesis has been demonstrated to be associated with the occurrence of major depressive disorder (MDD). A recent study indicated that deletion of the Epac2 gene (RAPGEF4) caused downregulation of hippocampal neurogenesis. This study aimed to analyze the association between genetic variants of the RAPGEF4 gene and the risk of MDD. We recruited 502 patients with MDD and 504 healthy controls who matched for age and gender. Genomic DNA was extracted from whole blood samples and genotyping was performed by next-generation sequencing. In addition, we conducted subgroup analysis according to the gender and recurrence, respectively. We found no significant association between RAPGEF4 gene rs3769219 variant and MDD in all subjects. However, the A-allele and GA + AA genotypes at rs3769219 were significantly associated with a reduced risk of MDD in the male population but not in the female population. Similarly, our study identified the A-allele and GA + AA genotypes at rs3769219 as protective factors for recurrent MDD (rMDD). Our findings suggest that RAPGEF4 gene rs3769219 mutation is associated with a reduced risk of MDD in male population and rMDD in total population.