Abstract
INTRODUCTION: Investigations of gene-environment (G×E) interactions in major depressive disorder (MDD) have been limited to hypothesis testing of candidate genes while poly-gene-environmental causation has not been adequately address. To this end, the present study analyzed the association between three candidate genes, two environmental factors, and MDD using a hypothesis-free testing approach. METHODS: A logistic regression model was used to analyze interaction effects; a hierarchical regression model was used to evaluate the effects of different genotypes and the dose-response effects of the environment; genetic risk score (GRS) was used to estimate the cumulative contribution of genetic factors to MDD; and protein-protein interaction (PPI) analyses were carried out to evaluate the relationship between candidate genes and top MDD susceptibility genes. RESULTS: Allelic association analyses revealed significant effects of the interaction between the candidate genes Forkhead box (Fox)O1, α2-macroglobulin (A2M), and transforming growth factor (TGF)-β1 genes and the environment on MDD. Gene-gene (G×G) and gene-gene-environment (G×G×E) interactions in MDD were also included in the model. Hierarchical regression analysis showed that the effect of environmental factors on MDD was greater in homozygous than in heterozygous mutant genotypes of the FoxO1 and TGF-β1 genes; a dose-response effect between environment and MDD on genotypes was also included in this model. Haplotype analyses revealed significant global and individual effects of haplotypes on MDD in the whole sample as well as in subgroups. There was a significant association between GRS and MDD (P = 0.029) and a GRS and environment interaction effect on MDD (P = 0.009). Candidate and top susceptibility genes were connected in PPI networks. CONCLUSIONS: FoxO1, A2M, and TGF-β1 interact with environmental factors and with each other in MDD. Multi-factorial G×E interactions may be responsible for a higher explained variance and may be associated with causal factors and mechanisms that could inform new diagnosis and therapeutic strategies, which can contribute to the personalized medicine of MDD.