The combined effects of the BDNF and GSK3B genes modulate the relationship between negative life events and major depressive disorder

For major depressive disorder (MDD), BDNF and GSK3B are logical candidate genes and an interaction between BDNF polymorphism and negative life events has been observed. Our previous study revealed that a gene–gene interaction among BDNF and GSK3B may confer the risk of MDD. In the present study, we hypothesized a gene–environment interaction between the BDNF–GSK3B combination and negative life events in the risk for developing MDD. To test this hypothesis, we conducted a case–control study in a northern Han Chinese population. A total of 404 patients with MDD and 388 age- and gender-matched control subjects were recruited. Negative life events and objective social supports were assessed using standard rating scales. Three polymorphisms of BDNF and GSK3B genes were identified by sequencing. Gene–environment interactions were analyzed by generalized multifactor dimensionality reduction (GMDR). Under a dominant model, we observed a potential association between the GSK3B rs6782799 and MDD (P = 0.07), a significant three-way interaction among BDNF rs6265, GSK3B rs6782799, and negative life events (corrected P-value, 0.011–0.012; cross-validation consistency, 7; prediction error, 0.4349). To our knowledge, this is the first report of evidence that the BDNF–GSK3B interaction may modify the relationship between negative life events and MDD in the Chinese population.