Abstract
It is well established that brain-derived neurotrophic factor (BDNF) signaling pathway plays a key role in the pathophysiology of major depressive disorder (MDD) and in therapeutic mechanisms of antidepressants. We aim to identify genetic vairiants related to MDD susceptibility and antidepressant therapeutic response by using gene-based association analysis with genes related to the neurotrophic pathway. The present study investigated the role of genetic variants in the 10 neurotrophic-related genes (BDNF, NGFR, NTRK2, MTOR, VEGFA, S100A10, SERPINE1, ARHGAP33, GSK3B, CREB1) in MDD susceptibility through a case-control (455 MDD patients and 2,998 healthy controls) study and in antidepressant efficacy (n = 455). Measures of antidepressant therapeutic efficacy were evaluated using the 21-item Hamilton Rating Scale for Depression. Our single-marker and gene-based analyses with ten genes related to the neurotrophic pathway identified 6 polymorphisms that reached a significant level (p-value < 5.0 × 10−3) in both meta- and mega-analyses in antidepressant therapeutic response. One polymorphism was mapped to BDNF and 5 other polymorphisms were mapped to VEGFA. For case-control association study, we found that all of these reported polymorphisms and genes did not reach a suggestive level. The present study supported a role of BDNF and VEGFA variants in MDD therapeutic response.
Highlights
Depression is a severe mental disorder and the leading cause of disabilities worldwide[1]
Pharmacogenetics is the study of variability in drug response due to heredity, generally focusing on polymorphisms of genes related to the drug metabolizing-enzyme, drug action or disease pathophysiology[6]
We have demonstrated that the NTRK2 genetic variants interact with the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism contributing to the risk of geriatric depression[18]
Summary
Depression is a severe mental disorder and the leading cause of disabilities worldwide[1]. For candidate genes related to antidepressant therapeutic action, brain-derived neurotrophic factor (BDNF) has been a main focus of antidepressant pharmacogenetic research. The role of BDNF in depression treatments was first revealed in research conducted by Nibuya and colleagues, where long-term administration of several types of antidepressants, including SSRIs, increases in BDNF expression in the rat hippocampus[9]. In our 2003 study on 110 MDD patients, we examined the association between the BDNF Val66Met polymorphism and response to 4-week antidepressant (fluoxetine) treatment[15]. We found that genetic variants in plasminogen activator inhibitor type 1 gene (encoded by the SERPINE1 gene), which is involved in the cleavage of pro-BDNF to mature BDNF in the brain, are related to antidepressant therapeutic response and depression susceptibility[20]. An animal study demonstrated that ketamine stimulates AMPA receptor transmission and activates BDNF/TrkB-Akt/ERK-mTOR signaling cascades, leading to a sustained increase in synaptic protein synthesis and strengthening of synaptic plasticity[27]
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