PMID- 18347599 OWN - NLM STAT- MEDLINE DCOM- 20080813 LR - 20221207 IS - 1476-5578 (Electronic) IS - 1359-4184 (Linking) VI - 13 IP - 7 DP - 2008 Jul TI - Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression. PG - 709-16 LID - 10.1038/mp.2008.32 [doi] AB - Complex genetic disorders such as depression likely exhibit epistasis, but neural mechanisms of such gene-gene interactions are incompletely understood. 5-HTTLPR and BDNF VAL66MET, functional polymorphisms of the serotonin (5-HT) transporter (SLC6A4) and brain-derived neurotrophic factor (BDNF) gene, impact on two distinct, but interacting signaling systems, which have been related to depression and to the modulation of neurogenesis and plasticity of circuitries of emotion processing. Recent clinical studies suggest that the BDNF MET allele, which shows abnormal intracellular trafficking and regulated secretion, has a protective effect regarding the development of depression and in mice of social defeat stress. Here we show, using anatomical neuroimaging techniques in a sample of healthy subjects (n=111), that the BDNF MET allele, which is predicted to have reduced responsivity to 5-HT signaling, protects against 5-HTTLPR S allele-induced effects on a brain circuitry encompassing the amygdala and the subgenual portion of the anterior cingulate (rAC). Our analyses revealed no effect of the 5-HTTLPR S allele on rAC volume in the presence of BDNF MET alleles, whereas a significant volume reduction (P<0.001) was seen on BDNF VAL/VAL background. Interacting genotype effects were also found in structural connectivity between amygdala and rAC (P=0.002). These data provide in vivo evidence of biologic epistasis between SLC6A4 and BDNF in the human brain by identifying a neural mechanism linking serotonergic and neurotrophic signaling on the neural systems level, and have implications for personalized treatment planning in depression. FAU - Pezawas, L AU - Pezawas L AD - Genes, Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. FAU - Meyer-Lindenberg, A AU - Meyer-Lindenberg A FAU - Goldman, A L AU - Goldman AL FAU - Verchinski, B A AU - Verchinski BA FAU - Chen, G AU - Chen G FAU - Kolachana, B S AU - Kolachana BS FAU - Egan, M F AU - Egan MF FAU - Mattay, V S AU - Mattay VS FAU - Hariri, A R AU - Hariri AR FAU - Weinberger, D R AU - Weinberger DR LA - eng GR - Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Intramural DEP - 20080318 PL - England TA - Mol Psychiatry JT - Molecular psychiatry JID - 9607835 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (SLC6A4 protein, human) RN - 0 (Serotonin Plasma Membrane Transport Proteins) SB - IM MH - Amino Acid Substitution MH - Brain/pathology MH - Brain-Derived Neurotrophic Factor/*genetics MH - Depression/*genetics/pathology MH - Depressive Disorder/*genetics/pathology MH - *Epistasis, Genetic MH - Gyrus Cinguli/pathology MH - Humans MH - Magnetic Resonance Imaging MH - Polymorphism, Genetic MH - Reference Values MH - Serotonin Plasma Membrane Transport Proteins/*genetics MH - White People/genetics EDAT- 2008/03/19 09:00 MHDA- 2008/08/14 09:00 CRDT- 2008/03/19 09:00 PHST- 2008/03/19 09:00 [pubmed] PHST- 2008/08/14 09:00 [medline] PHST- 2008/03/19 09:00 [entrez] AID - mp200832 [pii] AID - 10.1038/mp.2008.32 [doi] PST - ppublish SO - Mol Psychiatry. 2008 Jul;13(7):709-16. doi: 10.1038/mp.2008.32. Epub 2008 Mar 18.