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Background: Vascular endothelial growth factor A (VEGFA) and brain‑derived neurotrophic factor (BDNF), the most abundant and widely expressed neurotrophic factors in the brain, are believed to play an important rôle in depression and anxiety. In this study, we hypothesized that single‑nucleotide polymorphisms (SNPs) within the VEGFA and BDNF genes would be linked with psychological distress through complex interactions in the general population. Methods: We analyzed 7,098 Taiwanese subjects from the Taiwan Biobank. Measures of anxiety and depression were evaluated using the Patient Health Questionnaire‑4 (PHQ‑4). Totally, 15 VEGFA and 43 BDNF polymorphisms were used in the genetic analysis. Results: In our analysis, an interaction was found between the VEGFA rs10434 and BDNF rs12418745 in significantly influencing depression state ( p < 0.01). In addition, we found that influence of interaction existed between physical activity and VEGFA genetic variants including rs3025000, rs699947, rs833068, rs833069, rs3024998, and rs3025006 in depression state. But we found no association between 15 VEGFA genetic variants and depression state, after adjusting for age and gender. Furthermore, no VEGFA SNPs showed evidence of association with PHQ‑4 scores. Conclusion: These results suggest that the VEGFA and BDNF genetic variants may contribute to psychological distress through gene-gene and gene-physical activity interactions in the general population.