More Genomics on propensity for Depression and Serotonin Transporter Protein genetic variation.
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1/7/2006 10:00:13 AM
Neural transmission at the serotonin synapse plays a central
role in the regulation of human mood and temperament. The serotonin
transporter protein is one of the critical elements in determining
synaptic concentrations of serotonin. There is mounting evidence
that genetic variance in the promoter region of the serotonin
transporter protein gene (
SLC6A4
) is associated with differences
in human mood, temperament, and response to stress, suggesting
this may be an important genetic variant for human behavior.
The regulatory variant (called 5-HTTLPR) in the promoter region
of
SLC6A4
has two common variants (alleles), both normal, the
short (S) and long (L). In Caucasians, the genotype frequencies
are approximately 36% L/L, 48% L/S, and 16% S/S. The S allele
has been associated with a nearly 50% reduction in expression
of the serotonin transporter protein, as well as vulnerability
for mood disorders (both anxiety and depression) and inadequate
response to SSRIs. However, studies have suggested that the
neural mechanisms underlying these associations are complex
and can be influenced by environmental conditions. Understanding
the mechanisms of these associations will allow a more specific
appreciation of normal and pathological mood regulation in humans.
We have looked at the effects of the S allele on amygdala activation
to emotional stimuli.
The human amygdala shows activation in
response to threatening environmental stimuli, like angry and
fearful faces. The figure shows that right amygdala activation
is relatively greater in those normal volunteers who have the
S allele in comparison to L allele homozygotes when responding
to the same threatening faces. These data illustrate the observation
that normal heritable variation in serotonin signaling associated
with 5-HTTLPR can result in increased amygdala response to provocative
stimuli. Evidence suggests that only in the face of environmental
duress does this genetically driven variation in amygdala reactivity
lead S allele individuals to be more likely to develop pathologic
features and illness. This genetic variant, even though associated
with increases in amygdala responsivity, does not inevitably
result in psychiatric illness, only in the propensity to a pathological
response in certain environmental circumstances.
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Anxiety
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