Background: Multiple studies of depression indicated a significant role of gene-by-environment interactions; however, they are mainly limited to the examination of modulating effect of recent stressful life events. Other environmental factors occurring at different stages of ante- and postnatal development may affect the association between multiple genes and depression. The study aimed to analyze the main and haplotype-based effect of serotonergic system and HPA-axis gene polymorphisms on depression and to detect gene-by-environment interaction models explaining individual variance in depression in mentally healthy young adults from Russia. Methods: Depression score was assessed using Beck Depression Inventory (BDI) in 623 healthy individuals (81% women; 17-25 years) of Caucasian origin (Russians, Tatars, Udmurts) from Russia. The main- and gene-based effects of 12 SNPs in SLC6A4 (5-HTTLPR, rs1042173), HTR2A (rs7322347), OXTR (rs7632287, rs2254298, rs13316193, rs53576, rs2228485, rs237911), AVPR1A (rs3803107, rs1042615), and AVPR1B (rs33911258) genes, and gene-by-environment interactions were tested with linear regression models (PLINK v.1.9) adjusted for multiple comparisons. Results: We observed ethnicity-specific main effect of the AVPR1A rs3803107 (P = 0.003; PFDR = 0.047) and gene-based effect of the OXTR gene (Р = 0.005; Pperm = 0.034) on BDI-measured depression, and modifying effect of paternal care on OXTR rs53576 (P = 0.004; PFDR = 0.012) and birth order on OXTR rs237911 (P = 0.006; PFDR = 0.018) association with depression level. Limitations: A hypothesis driven candidate gene approach, which examined a limited number of genetic variants in a moderately large sample, was used. Conclusions: Our preliminary findings indicate that familial environment may play a permissive role modulating the manifestation of OXTR-based depression variance in mentally healthy subjects.