Transcript Caspi et al 5HTT.

Presented by: Caitlin Cleary
Depression
• Depression is among the top five leading
causes of disability and disease burden
throughout the world
• Stressful events involve threat, loss,
humiliation, or defeat
– Influence the onset and course of depression
Predisposition
• Stress theories of depression predict that
an individual’s sensitivity to stressful
events depends on their genetic makeup
• Gene x environment (GxE) interaction
– Do specific genes exacerbate or buffer the
effect of stressful life events on depression?
5-HTT Gene Polymorphism
• The serotonin system is a logical source of
candidate genes for depression (SSRI)
• Serotonin transporter gene (SLC6A4) has
a functional polymorphism in the 5’
promoter region
• The short “s” allele is associated with
lower transcriptional efficiency of the
promoter compared with the long “l” allele
http://www.psycheducation.org/mechanism/images/1Moral5.gif
Previous studies
• Have shown inconclusive evidence for an
association between the short promoter
variant and depression
• The 5-HTT gene may not be directly
associated with depression, but could be
the result of a GxE interaction
• Referenced three supporting studies
First Study- D.L. Murphy et al., 2001
• Homozygous and heterozygous (5-HTT -/and +/-) mice exhibited more fearful
behavior, and had higher levels of stress
hormones as compared to control
homozygous (5-HTT +/+) mice
• No observed differences between strains
in the absence of stress
Second Study- A.J. Bennett et al., 2002
• The short allele variation of the 5-HTTLPR
(gene-linked polymorphic region) in rhesus
macaques is associated with decreased
serotonergic function in monkeys reared in
stressful conditions but not among
normally reared monkeys
Third Study- A.R. Hariri et al., 2002
• Human neuroimaging research suggests
that the stress response is mediated by 5HTTLPR
• Humans with 1 or 2 copies of the “s” allele
exhibit greater amygdala neuronal activity
to fearful stimuli than individuals
homozygous for the “l” allele
Purpose
To test whether 5-HTT gene variation
moderates the influence of life stress on
depression
• To characterize genetic vulnerability to
depression
• (why do stressful experiences lead to
depression in some people, but not
others?)
Methods
• Prospective-longitudinal study of a
representative birth cohort
• 847 Caucasian members (M/F), followed
from age 21 to 26, divided into groups:
1) s/s homozygotes n=147, 17%
2) s/l heterozygotes n=435, 51%
3) l/l homozygotes n=265, 31%
Methods cont.
• Stressful life events occurring after the 21st
birthday and before the 26th birthday were
assessed with a life-history calendar
• These events included employment, financial,
housing, health and relationship stressors
• There was no significant difference between the
genotype groups in the number of life events
they experienced (suggesting that 5-HTT doesn’t
influence exposure to stress)
Methods cont.
• Study members were assessed for
depression using a quantitative measure
of depressive symptoms and a categorical
diagnosis according to the DSM-IV criteria
• Also collected informant reports about
symptoms of depression at age 26 from
“someone who knows you well”
• Data was analyzed with regression and
statistical analysis
Figure 1A.
The interaction
between genotype
and life events
showed that the
effect of life events
on self reports of
depression
symptoms at age
26 was significantly
stronger (P=0.02)
among individuals
carrying an “s”
allele than among
l/l homozygotes
Figure 1B.
Stressful life events
predicted a diagnosis
of major depression
among carriers of an s
allele, but not among
l/l homozygotes
(P=0.056)
Figure 1C.
Stressful life events
predicted suicide
ideation or attempt
among individuals
carrying an s allele but
not among l/l
homozygotes (P=0.05)
Figure 1D.
GxE interaction
shows that the
effect of life events
on informant
reports of
depression was
stronger among
individuals
carrying an s allele
than among l/l
homozygotes
GxE
• If 5-HTT genotype moderates the
depressogenic influence of stressful life
events, it should moderate the effect of life
events that occurred not just in adulthood,
but also in earlier developmental stages
Figure 2
The interaction
between GxE
shows that
childhood
maltreatment (that
occurred during the
first decade of life)
predicted adult
depression only
among individuals
with an s allele and
not among l/l
homozygotes
(P=0.05)
MAOA involvement?
• They have previously shown that
monoamine oxidase A moderates
children’s sensitivity to maltreatment
• MAOA has a high affinity for 5-HTT, but
does not have a protective effect on l/l
because the moderation of life stress on
depression was observed regardless of
MAOA gene status (S4/S5)
Figure 3.
The percentage of individuals meeting diagnostic
criteria for depression at age 26, as a function of 5HTT genotype and the number of stressful events
between ages 21-26
Among cohort members suffering 4 or more stressful
life events, 33% of individuals with an s allele
became depressed, whereas only 17% of l/l
homozygotes developed depression
Conclusions
• GxE interaction extends to the natural development of
depression in a representative sample of humans
• Individuals with 1 or 2 copies of an short allele
polymorphism in the promoter region of 5-HTT exhibited
more depressive symptoms, diagnosable depression,
and suicidality in relation to stressful life events than
individuals homozygous for the long allele
• GxE attributable risk and protective sensitivity indicate
that more knowledge of the 5-HTT gene may lead to
better pharmacology and prophylaxis for depression
resulting from life’s stressful events
Critique
• Lack of consistency between evidence for a
direct relation between 5-HTTLPR and
depression – this study doesn’t disprove
anything and can’t be taken any farther until
their results are replicated
• The absence of clearly labeled axes on graphs
and asterisks indicating significance
• Missing methods on how to determine the
genotype
• Doesn’t show the linkage maps for candidate
genes –does another gene demonstrate similar
results?