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

Prog Neuropsychopharmacol Biol Psychiatry. 2012 Mar 30;36(2):264-70. doi: 10.1016/j.pnpbp.2011.09.010. Epub 2011 Oct 2.


Background: Based 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.

Methods: 2035 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.

Results: Tobit 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.

Conclusions: Our 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Brain-Derived Neurotrophic Factor / genetics*
  • Child
  • Child Abuse / psychology*
  • Depressive Disorder / complications
  • Depressive Disorder / genetics*
  • Depressive Disorder / psychology
  • Epistasis, Genetic / genetics*
  • Female
  • Gene-Environment Interaction
  • Genetic Predisposition to Disease / genetics
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Genetic* / genetics
  • Promoter Regions, Genetic / genetics*
  • Psychiatric Status Rating Scales / statistics & numerical data
  • Serotonin Plasma Membrane Transport Proteins / genetics*
  • Sex Characteristics
  • White People / genetics


  • Brain-Derived Neurotrophic Factor
  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins