Association of BDNF Val66Met Polymorphism and Brain BDNF Levels with Major Depression and Suicide

摘要

Background Brain-derived neurotrophic factor is implicated in the pathophysiology of major depressive disorder and suicide. Both are partly caused by early life adversity, which reduces brain-derived neurotrophic factor protein levels. This study examines the association of brain-derived neurotrophic factor Val66Met polymorphism and brain brain-derived neurotrophic factor levels with depression and suicide. We hypothesized that both major depressive disorder and early life adversity would be associated with the Met allele and lower brain brain-derived neurotrophic factor levels. Such an association would be consistent with low brain-derived neurotrophic factor mediating the effect of early life adversity on adulthood suicide and major depressive disorder. Methods Brain-derived neurotrophic factor Val66Met polymorphism was genotyped in postmortem brains of 37 suicide decedents and 53 nonsuicides. Additionally, brain-derived neurotrophic factor protein levels were determined by Western blot in dorsolateral prefrontal cortex (Brodmann area 9), anterior cingulate cortex (Brodmann area 24), caudal brainstem, and rostral brainstem. The relationships between these measures and major depressive disorder, death by suicide, and reported early life adversity were examined. Results Subjects with the Met allele had an increased risk for depression. Depressed patients also have lower brain-derived neurotrophic factor levels in anterior cingulate cortex and caudal brainstem compared with nondepressed subjects. No effect of history of suicide death or early life adversity was observed with genotype, but lower brain-derived neurotrophic factor levels in the anterior cingulate cortex were found in subjects who had been exposed to early life adversity and/or died by suicide compared with nonsuicide decedents and no reported early life adversity. Conclusions This study provides further evidence implicating low brain brain-derived neurotrophic factor and the brain-derived neurotrophic factor Met allele in major depression risk. Future studies should seek to determine how altered brain-derived neurotrophic factor expression contributes to depression and suicide. brain-derived neurotrophic factor , single nucleotide polymorphism , depression , suicide , childhood adversity Significance Statement This is the first study to examine the relationship between both brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and brain BDNF protein level and major depression, death by suicide, and reported childhood adversity. The Met allele (a minor variant of the BDNF gene) is associated with an increased risk for depression. Depressed patients also had lower BDNF levels in 2 brain regions, namely the anterior cingulate cortex (ACC) and caudal brainstem (pons), compared with nondepressed subjects. Additionally, lower BDNF levels in ACC were found in subjects who had been exposed to early life adversity and/or died by suicide compared with nonsuicide decedents and no reported childhood adversity. This study may aid in identifying the possible mechanism by which altered BDNF expression contributes to MDD and suicide.