BackgroundMajor depressive disorder (MDD) is a mental illness, which is a notable public health problem that aggravates the global economic burden. This study aimed to investigate the causal relationship between education and MDD risk and the contributions of effects mediated by four modifiable factors.Materials and methodsInstrumental variables were screened from several large-scale genome-wide association study (GWAS) data (years of schooling with 766,345 participants, MDD with 59,851 cases and 113,154 controls, neuroticism with 329,821 individuals, smoking behavior with 195,068 cases and 164,638 controls, body mass index [BMI] with 336,107 individuals, and household income with 397,751 individuals). The data were used to evaluate the association of the four modifiable factors (neuroticism, smoking behavior, BMI, and household income) that mediate the effect of education on MDD risk via Mendelian randomization (MR) analysis.ResultsEach standard deviation increase in years of schooling could reduce the risk for MDD by 30.70%. Higher neuroticism and BMI were associated with a higher risk of MDD. Non-smoking status and increased household income were protective factors for MDD. Notably, the mediator neuroticism, BMI, smoking behavior, and household income explained 52.92%, 15.54%, 31.86%, and 81.30% of the effect of years of schooling on MDD risk, respectively.ConclusionsLonger years of schooling have a protective effect on MDD risk. Reasonable interventions to reduce neuroticism, BMI, smoking, and increasing household income are beneficial for MDD prevention. Our work provides new ideas for the development of prevention strategies for MDD.