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

• Published in: Progress in neuro-psychopharmacology & biological psychiatry Vol. 36; no. 2; pp. 264 - 270
• Main Authors: Grabe, Hans Jörgen, Schwahn, Christian, Mahler, Jessie, Appel, Katja, Schulz, Andrea, Spitzer, Carsten, Fenske, Kristin, Barnow, Sven, Freyberger, Harald Jürgen, Teumer, Alexander, Petersmann, Astrid, Biffar, Reiner, Rosskopf, Dieter, John, Ulrich, Völzke, Henry
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 30.03.2012; Elsevier
• Subjects: Adult; Adult and adolescent clinical studies; Aged; Aged, 80 and over; Alleles; Biological and medical sciences; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - genetics; Child; Child Abuse - psychology; Childhood abuse; Depression; Depressive Disorder - complications; Depressive Disorder - genetics; Depressive Disorder - psychology; Epistasis, Genetic - genetics; European Continental Ancestry Group - genetics; Female; Gene-Environment Interaction; Genetic Predisposition to Disease - genetics; Genotype; Humans; Male; Medical sciences; Middle Aged; Mood disorders; Neuropharmacology; Pharmacology. Drug treatments; Polymorphism, Genetic - genetics; Promoter Regions, Genetic - genetics; Psychiatric Status Rating Scales - statistics & numerical data; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Serotonin Plasma Membrane Transport Proteins - genetics; Serotonin transporter promoter polymorphism; Sex Characteristics; Victimology; CTQ; Childhood abuse; 5-HTTLPR; BDNF; Depression; MDD; LEGEND Study; Brain-derived neurotrophic factor; GxE; BDI-II; Serotonin transporter promoter polymorphism; SHIP; Gene–environment interaction; 5-HT; Mood disorder; Gene-environment interaction; Epistasis; Victimology; Promoter; Child abuse; Sensitivity; Serotonin transporter; Genotype environment interaction; Genetics; Brain derived neurotrophic factor; Polymorphism
• ISSN: 0278-5846; 1878-4216; 1878-4216
• DOI: 10.1016/j.pnpbp.2011.09.010

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. 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. 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. 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. ► 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.