Genetic epistasis between the brain-derived neurotrophic factor Val66Met polymorphism and the 5-HTT promoter polymorphism moderates the susceptibility to depressive disorders after childhood abuse

BackgroundBased on biological interactions between the serotonergic system and the brain-derived neurotrophic factor (BDNF), BDNF is a plausible candidate for a gene–gene–environment interaction moderating the interaction between the s/l- promoter polymorphism of the serotonin transporter (5-HTTLPR) and childhood abuse. We tested the hypothesis of a three-way interaction with respect to depressive symptoms.Methods2035 Caucasian subjects from the Study of Health in Pomerania (German general population) completed the Beck Depression Inventory (BDI-II) and the Childhood Trauma Questionnaire. All subjects were genotyped for the BDNF Val66Met (rs6265) and the s/l 5-HTTLPR polymorphisms.ResultsTobit regression analyses revealed a three-way-interaction between the three genotypes of 5-HTTLPR and the BDNF genotypes and overall childhood abuse for the BDI-II score (p = 0.02). Emotional abuse carried the main effect of the interaction (p = 0.008). The s/s genotype of the 5-HTTLPR exerted its negative impact on mental health after childhood abuse only in the presence of the BDNF Val/Val genotype but not in the presence of the BDNF Met allele. In contrast, the l allele of the 5-HTTLPR also emerged as a genetic risk factor for depression in carriers of one or two Met alleles.ConclusionsOur results point to a gene–gene–environment interaction that relevantly impacts on the role of the s/s genotype of the 5-HTTLPR in childhood abuse: Depending on the BDNF background (Val/Val versus Met allele) the s/s genotype showed either protective or risk properties with regard to depressive symptoms.

► There is an interaction between the 5-HTTLPR and the BDNF Val66Met polymorphism in depression.
► This interaction only emerges in subjects with childhood abuse.
► Risk effects of the s/s genotype only emerge in abused carriers of the Val/Val genotype.
► The BDNF Met-alleles “protected” against the depressiogenic effects of the s/s genotype.
► This three-way interaction points to a biological epistasis between the 5-HTTLPR and the BDNF.