Impact of BDNF Val66Met and 5-HTTLPR polymorphism variants on neural substrates related to sadness and executive function.
The brain-derived neurotrophic factor (BDNF) Val(66) Met allelic variation is linked to both the occurrence of mood disorders and antidepressant response. These findings are not universally observed, and the mechanism by which this variation results in increased risk for mood disorders is unclear. One possible explanation is an epistatic relationship with other neurotransmitter genes associated with depression risk, such as the serotonin-transporter-linked promotor region (5-HTTLPR). Further, it is unclear how the coexistence of the BDNF Met and 5-HTTLPR S variants affects the function of the affective and cognitive control systems. To address this question, we conducted a functional magnetic resonance imaging (fMRI) study in 38 older adults (20 healthy and 18 remitted from major depressive disorder). Subjects performed an emotional oddball task during the fMRI scan and provided blood samples for genotyping. Our analyses examined the relationship between genotypes and brain activation to sad distractors and attentional targets. We found that 5-HTTLPR S allele carriers exhibited stronger activation in the amygdala in response to sad distractors, whereas BDNF Met carriers exhibited increased activation to sad stimuli but decreased activation to attentional targets in the dorsolateral prefrontal and dorsomedial prefrontal cortices. In addition, subjects with both the S allele and Met allele genes exhibited increased activation to sad stimuli in the subgenual cingulate and posterior cingulate. Our results indicate that the Met allele alone or in combination with 5-HTTLPR S allele may increase reactivity to sad stimuli, which might represent a neural mechanism underlying increased depression vulnerability.
Brain Imaging and Analysis Center, Duke University, Durham, NC, USA.
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Wang
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Ashley-Koch
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DC
Steffens
K R R
KR
Krishnan
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WD
Taylor
D000368:Aged; D000483:Alleles; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency / Q000235:genetics*; D003866:Depressive Disorder / Q000235:genetics* / Q000378:metabolism* / Q000523:psychology; D056344:Executive Function / Q000502:physiology*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011110:Polymorphism, Genetic / Q000235:genetics; D050486:Serotonin Plasma Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics*; D014633:Valine / Q000235:genetics
D019208:Brain-Derived Neurotrophic Factor; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D008715:Methionine; D014633:Valine