Epigenetic alterations of the brain‐derived neurotrophic factor (
BDNF) gene have been associated with psychiatric disorders in humans and with differences in amygdala
BDNF mRNA levels in rodents. This human study aimed to investigate the relationship between the functional
BDNF‐Val
66Met polymorphism, its surrounding DNA methylation in
BDNF exon IX, amygdala reactivity to emotional faces, and personality traits. Healthy controls (HC,
n = 189) underwent functional MRI during an emotional face‐matching task. Harm avoidance, novelty seeking and reward dependence were measured using the Tridimensional Personality Questionnaire (TPQ). Individual
BDNF methylation profiles were ascertained and associated with several BDNF single nucleotide polymorphisms surrounding the
BDNF‐Val
66Met, amygdala reactivity, novelty seeking and harm avoidance. Higher
BDNF methylation was associated with higher amygdala reactivity (
x = 34,
y = 0,
z = ?26,
t(166) = 3.00, TFCE = 42.39,
p(FWE) = .045), whereby the
BDNF‐Val
66Met genotype per se did not show any significant association with brain function. Furthermore, novelty seeking was negatively associated with
BDNF methylation (
r = ?.19,
p = .015) and amygdala reactivity (
r = ?.17,
p = .028), while harm avoidance showed a trend for a positive association with
BDNF methylation (
r = .14,
p = .066). The study provides first insights into the relationship among
BDNF methylation,
BDNF genotype, amygdala reactivity and personality traits in humans, highlighting the multidimensional relations among genetics, epigenetics, and neuronal functions. The present study suggests a possible involvement of epigenetic
BDNF modifications in psychiatric disorders and related brain functions, whereby high
BDNF methylation might reduce
BDNF mRNA expression and upregulate amygdala reactivity.
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