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Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene

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In a prospective-longitudinal study of a representative birth cohort, we tested why stressful experiences lead to depression in some people but not in others. A functional polymorphism in the promoter region of the serotonin transporter (5-HT T) gene was found to moderate the influence of stressful life events on depression. Individuals with one or two copies of the short allele of the 5-HT T promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele. This epidemiological study thus provides evidence of a gene-by-environment interaction, in which an individual's response to environmental insults is moderated by his or her genetic makeup.
Results of multiple regression analyses estimating the association between number of stressful life events (between ages 21 and 26 years) and depression outcomes at age 26 as a function of 5-HT T genotype. Among the 146 s/s homozygotes, 43 (29%), 37 (25%), 28 (19%), 15 (10%), and 23 (16%) study members experienced zero, one, two, three, and four or more stressful events, respectively. Among the 435 s/l heterozygotes, 141 (32%), 101 (23%), 76 (17%), 49 (11%), and 68 (16%) experienced zero, one, two, three, and four or more stressful events. Among the 264 l/l homozygotes, 79 (29%), 73 (28%), 57 (21%), 26 (10%), and 29 (11%) experienced zero, one, two, three, and four or more stressful events. ( A ) Self-reports of depression symptoms. The main effect of 5-HT TLPR (i.e., an effect not conditional on other variables) was marginally significant ( b ϭ – 0.96, SE ϭ 0.52, t ϭ 1.86, P ϭ 0.06), the main effect of stressful life events was significant ( b ϭ 1.75, SE ϭ 0.23, t ϭ 7.45, P Ͻ 0.001), and the interaction between 5-HT TLPR and life events was in the predicted direction ( b ϭ – 0.89, SE ϭ 0.37, t ϭ 2.39, P ϭ 0.02). The interaction showed that the effect of life events on self-reports of depression symptoms was stronger among individuals carrying an s allele ( b ϭ 2.52, SE ϭ 0.66, t ϭ 3.82, P Ͻ 0.001 among s/s homozygotes, and b ϭ 1.71, SE ϭ 0.34, t ϭ 5.02, P Ͻ 0.001 among s/l heterozygotes) than among l/l homozygotes ( b ϭ 0.77, SE ϭ 0.43, t ϭ 1.79, P ϭ 0.08). ( B ) Probability of major depressive episode. The main effect of 5-HT TLPR was not significant ( b ϭ – 0.15, SE ϭ 0.14, z ϭ 1.07, P ϭ 0.29), the main effect of life events was significant ( b ϭ 0.37, SE ϭ 0.06, z ϭ 5.99, P Ͻ 0.001), and the G ϫ E was in the predicted direction ( b ϭ – 0.19, SE ϭ 0.10, z ϭ 1.91, P ϭ 0.056). Life events predicted a diagnosis of major depression among s carriers ( b ϭ 0.52, SE ϭ 0.16, z ϭ 3.28, P ϭ 0.001 among s/s homozygotes, and b ϭ 0.39, SE ϭ 0.09, z ϭ 4.24, P Ͻ 0.001 among s/l heterozygotes) but not among l/l homozygotes ( b ϭ 0.16, SE ϭ 0.13, z ϭ 1.18, P ϭ 0.24). ( C ) Probability of suicide ideation or attempt. The main effect of 5-HT TLPR was not significant ( b ϭ – 0.01, SE ϭ 0.28, z ϭ 0.01, P ϭ 0.99), the main effect of life events was significant ( b ϭ 0.51, SE ϭ 0.13, z ϭ 3.96, P Ͻ 0.001), and the G ϫ E interaction was in the predicted direction ( b ϭ – 0.39, SE ϭ 0.20, t ϭ 1.95, P ϭ 0.051). Life events predicted suicide ideation or attempt among s carriers ( b ϭ 0.48, SE ϭ 0.29, z ϭ 1.67, P ϭ 0.09 among s/s homozygotes, and b ϭ 0.91, SE ϭ 0.25, z ϭ 3.58, P Ͻ 0.001 among s/l heterozygotes) but not among l/l homozygotes ( b ϭ 0.13, SE ϭ 0.26, z ϭ 0.49, P ϭ 0.62). ( D ) Informant reports of depression. The main effect of 5-HT TLPR was not significant (b ϭ – 0.06, SE ϭ 0.06, t ϭ 0.98, P ϭ 0.33), the main effect of life events was significant ( b ϭ 0.23, SE ϭ 0.03, t ϭ 8.47, P Ͻ 0.001), and the G ϫ E was in the predicted direction ( b ϭ – 0.11, SE ϭ 0.04, t ϭ 2.54, P Ͻ 0.01). The effect of life events on depression was stronger among s carriers ( b ϭ 0.39, SE ϭ 0.07, t ϭ 5.23, P Ͻ 0.001 among s/s homozygotes, and b ϭ 0.17, SE ϭ 0.04, t ϭ 4.51, P Ͻ 0.001 among s/l heterozygotes) than among l/l homozygotes ( b ϭ 0.14, SE ϭ 0.05, t ϭ 2.69, P Ͻ 0.01).
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DOI: 10.1126/science.1083968
, 386 (2003); 301Science
et al.Avshalom Caspi,
by a Polymorphism in the 5-HTT Gene
Influence of Life Stress on Depression: Moderation
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tivity (25) that investigated two tasks with right
hemisphere dominance demonstrated top-down
effects that were specific for the right hemi-
sphere, i.e., from the right middle frontal gyrus
(area 46) on right extrastriate areas. It is thus
likely that our findings generalize to other later-
alized tasks. Although we cannot exclude later-
alization contingent on stimulus type in some
situations, our results are consistent with previ-
ous findings from split-brain patient studies (7)
and positron emission tomography (11) showing
hemispheric specialization based on task de-
mands. Research on hemispheric specialization
should move beyond analyses of asymmetric
regional activations and focus more strongly on
functional interactions within and between
hemispheres.
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Supporting Online Material
www.sciencemag.org/cgi/content/full/301/5631/384/DC1
Materials and Methods
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23 April 2003; accepted 6 June 2003
Influence of Life Stress on
Depression: Moderation by a
Polymorphism in the 5-HTT Gene
Avshalom Caspi,
1,2
Karen Sugden,
1
Terrie E. Moffitt,
1,2
*
Alan Taylor,
1
Ian W. Craig,
1
HonaLee Harrington,
2
Joseph McClay,
1
Jonathan Mill,
1
Judy Martin,
3
Antony Braithwaite,
4
Richie Poulton
3
In a prospective-longitudinal study of a representative birth cohort, we tested
why stressful experiences lead to depression in some people but not in others.
A functional polymorphism in the promoter region of the serotonin transporter
(5-HTT) gene was found to moderate the influence of stressful life events on
depression. Individuals with one or two copies of the short allele of the 5-HT T
promoter polymorphism exhibited more depressive symptoms, diagnosable
depression, and suicidality in relation to stressful life events than individuals
homozygous for the long allele. This epidemiological study thus provides ev-
idence of a gene-by-environment interaction, in which an individual’s response
to environmental insults is moderated by his or her genetic makeup.
Depression is among the top five leading causes
of disability and disease burden throughout the
world (1). Across the life span, stressful life
events that involve threat, loss, humiliation, or
defeat influence the onset and course of depres-
sion (25). However, not all people who en-
counter a stressful life experience succumb to
its depressogenic effect. Diathesis-stress theo-
ries of depression predict that individuals’ sen-
sitivity to stressful events depends on their ge-
netic makeup (6, 7). Behavioral genetics re-
search supports this prediction, documenting
that the risk of depression after a stressful event
is elevated among people who are at high ge-
netic risk and diminished among those at low
genetic risk (8). However, whether specific
genes exacerbate or buffer the effect of stressful
life events on depression is unknown. In this
study, a functional polymorphism in the pro-
1
Medical Research Council Social, Genetic, and Develop-
mental Psychiatry Research Centre, Institute of Psychi-
atry, King’s College London, PO80 De Crespigny Park,
London, SE5 8AF, UK.
2
Department of Psychology, Uni-
versity of Wisconsin, Madison, WI 53706, USA.
3
Dun-
edin School of Medicine,
4
Department of Pathology,
University of Otago, Dunedin, New Zealand.
*To whom correspondence should be addressed. E-
mail: t.moffitt@iop.kcl.ac.uk
Fig. 4. PPI of the right
ACC. (A) All areas are
shown that receive a sig-
nificant context-depen-
dent contribution from
right ACC during visuo-
spatial decisions, pro-
jected on the same ren-
dered brain as in Fig. 1.
Right ACC significantly
increased its influence
on posterior (28/–72/48,
t
max
4.49, P 0.015,
corrected) and anterior
parts of the right IPS
(42/–42/44, t
max
4.63, P 0.034, correct-
ed) during visuospatial decisions. Note the specificity of this result: Even when the threshold was
reduced to P 0.05, uncorrected, no other significant clusters were found throughout the brain.
(B) This schema summarizes the negative findings for right ACC: As indicated by the gray dashed
lines, right ACC shows no context-dependent contributions to any left-hemispheric area during
visuospatial decisions and none to any left- or right-hemispheric area at all during letter decisions.
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moter region of the serotonin transporter gene
(SLC6A4) was used to characterize genetic vul-
nerability to depression and to test whether
5-HTT gene variation moderates the influence
of life stress on depression.
The serotonin system provides a logical
source of candidate genes for depression, be-
cause this system is the target of selective
serotonin reuptakeinhibitor drugs that are
effective in treating depression (9). The sero-
tonin transporter has received particular at-
tention because it is involved in the reuptake
of serotonin at brain synapses (10). The pro-
moter activity of the 5-HTT gene, located on
17q11.2, is modified by sequence elements
within the proximal 5 regulatory region, des-
ignated the 5-HTT gene-linked polymorphic
region (5-HTTLPR). The short (s) allele in
the 5-HTTLPR is associated with lower tran-
scriptional efficiency of the promoter com-
pared with the long (l) allele (11).
Evidence for an association between the
short promoter variant and depression is incon-
clusive (12). Although the 5-HTT gene may not
be directly associated with depression, it could
moderate the serotonergic response to stress.
Three lines of experimental research suggest
this hypothesis of a gene-by-environment (G
E) interaction. First, in mice with disrupted
5-HTT, homozygous and heterozygous (5-HTT
/ and /) strains exhibited more fearful
behavior and greater increases in the stress hor-
mone ( plasma) adrenocorticotropin in response
to stress compared to homozygous (5-HTT
/) controls, but in the absence of stress no
differences related to genotype were observed
(13). Second, in rhesus macaques, whose length
variation of the 5-HTTLPR is analogous to that
of humans, the short allele is associated with
decreased serotonergic function [lower cerebro-
spinal fluid (CSF) 5-hydroxyindoleacetic acid
concentrations] among monkeys reared in
stressful conditions but not among normally
reared monkeys (14). Third, human neuroim-
aging research suggests that the stress response
is mediated by variations in the 5-HTTLPR.
Humans with one or two copies of the s allele
exhibit greater amygdala neuronal activity to
fearful stimuli compared to individuals ho-
mozygous for the l allele (15). Taken together,
these findings suggest the hypothesis that vari-
ations in the 5-HTT gene moderate psycho-
pathological reactions to stressful experiences.
We tested this G E hypothesis among
members of the Dunedin Multidisciplinary
Health and Development Study (16 ). This
representative birth cohort of 1037 children
(52% male) has been assessed at ages 3, 5, 7,
9, 11, 13, 15, 18, and 21 and was virtually
intact (96%) at the age of 26 years. A total of
847 Caucasian non-Maori study members,
without stratification confounds, were divid-
ed into three groups on the basis of their
5-HTTLPR genotype (11): those with two
copies of the s allele (s/s homozygotes; n
147; 17%), those with one copy of the s allele
(s/l heterozygotes; n 435; 51%), and those
with two copies of the l allele (l/l homozy-
gotes; n 265; 31%). There was no differ-
ence in genotype frequencies between the
sexes [
2
(2) 0.02, P 0.99]. Stressful life
events occurring after the 21st birthday and
before the 26th birthday were assessed with
the aid of a life-history calendar (17), a high-
ly reliable method for ascertaining life-event
histories (18). The 14 events included em-
ployment, financial, housing, health, and re-
lationship stressors. Thirty percent of the
study members experienced no stressful life
events; 25% experienced one event; 20%,
two events; 11%, three events; and 15%, four
or more events. There were no significant
differences between the three genotype
groups in the number of life events they
experienced, F(2,846) 0.56, P 0.59,
suggesting that 5-HTTLPR genotype did not
influence exposure to stressful life events.
Study members were assessed for past-year
depression at age 26 with the use of the Diag-
nostic Interview Schedule (19), which yields a
quantitative measure of depressive symptoms
and a categorical diagnosis of a major depres-
sive episode according to Diagnostic and Sta-
tistical Manual of Mental Disorders (DSM-IV)
criteria (20). 17% of study members (58% fe-
male versus 42% male; odds ratio 1.6; 95%
confidence interval from 1.1 to 2.2) met criteria
for a past-year major depressive episode, which
is comparable to age and sex prevalence rates
observed in U.S. epidemiological studies (21).
In addition, 3% of the study members reported
past-year suicide attempts or recurrent thoughts
about suicide in the context of a depressive
episode. We also collected informant reports
about symptoms of depression for 96% of study
members at age 26 by mailing a brief question-
naire to persons nominated by each study mem-
ber as someone who knows you well.
We used a moderated regression frame-
work (22), with sex as a covariate, to test the
association between depression and (i) 5-
HTTLPR genotype, (ii) stressful life events,
and (iii) their interaction (table S1). The in-
teraction between 5-HTTLPR 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 in-
dividuals carrying an s allele than among l/l
homozygotes (Fig. 1A). We further tested
whether life events could predict within-indi-
vidual increases in depression symptoms over
time among individuals with an s allele by
statistically controlling for the baseline num-
ber of depressive symptoms they had before
the life events occurred (table S1). The sig-
nificant interaction (P 0.05) showed that
individuals carrying an s allele whose life
events occurred after their 21st birthday ex-
perienced increases in depressive symptoms
from the age of 21 to 26 years (b 1.55,
SE 0.66, t 2.35, P 0.02 among s/s
homozygotes and b 1.25, SE 0.34, t
3.66, P 0.001 among s/l heterozygotes)
whereas l/l homozygotes did not (b 0.17,
SE 0.41, t 0.41, P 0.68).
The G E interaction also showed that
stressful life events predicted a diagnosis of
major depression among carriers of an s allele
but not among l/l homozygotes (P 0.056,
Fig. 1B). We further tested whether life
events could predict the onset of new diag-
nosed depression among carriers of an s allele
(table S1). We excluded from analysis study
members who were diagnosed with depres-
sion before age 21. The significant interac-
tion (P 0.02) showed that life events oc-
curring after their 21st birthdays predicted
depression at age 26 among carriers of an s
allele who did not have a prior history of
depression (b 0.79, SE 0.25, z 3.16,
P 0.002 among s/s homozygotes and b
0.41, SE 0.12, z 3.29, P 0.001 among
s/l heterozygotes) but did not predict onset of
new depression among l/l homozygotes (b
0.08, SE 0.20, z 0.42, P 0.67). Further
analyses showed that stressful life events pre-
dicted suicide ideation or attempt among in-
dividuals carrying an s allele but not among
l/l homozygotes (P 0.05, Fig. 1C). The
hypothesized G E interaction was also
significant when we predicted informant re-
ports of age-26 depression (P 0.01), an
analysis that ruled out the possibility of self-
report bias (Fig. 1D). The interaction showed
that the effect of life events on informant
reports of depression was stronger among
individuals carrying an s allele than among l/l
homozygotes. These analyses attest that the
5-HTT gene interacts with life events to pre-
dict depression symptoms, an increase in
symptoms, depression diagnoses, new-onset
diagnoses, suicidality, and an informants re-
port of depressed behavior.
This evidence that 5-HTTLPR variation
moderates the effect of life events on depres-
sion does not constitute unambiguous evi-
dence of a G E interaction, because expo-
sure to life events may be influenced by
genetic factors; if individuals have a heritable
tendency to enter situations where they en-
counter stressful life events, these events may
simply be a genetically saturated marker (23,
24). Thus, what we have identified as a
gene environment interaction predicting
depression could actually reflect a gene
gene interaction between the 5-HTTLPR
and other genes we did not measure. We
reasoned that, if our measure of life events
represents merely genetic risk, then life
events would interact with 5-HTTLPR even
if they occurred after the depression episode.
However, if our measure of life events rep-
resents environmental stress, then the timing
of life events relative to depression must
follow cause-effect order and life events that
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occur after depression should not interact
with 5-HTTLPR to postdict depression. We
tested this hypothesis by substituting the age-
26 measure of depression with depression
assessed in this longitudinal study when
study members were 21 and 18 years old,
before the occurrence of the measured life
events between the ages of 21 and 26 years.
Whereas the 5-HTTLPR life events inter-
action predicted depression at the age of 26
years, this same interaction did not postdict
depression reported at age 21 nor at the age of
18 years (table S2), indicating our finding is
a true G E interaction.
If 5-HTT genotype moderates the depres-
sogenic influence of stressful life events, it
should moderate the effect of life events that
occurred not just in adulthood but also of
stressful experiences that occurred in earlier
developmental periods. Based on this hypoth-
esis, we tested whether adult depression was
predicted by the interaction between 5-
HTTLPR and childhood maltreatment that
occurred during the first decade of life (16,
25). Consistent with the G E hypothesis,
the longitudinal prediction from childhood
maltreatment to adult depression was signif-
icantly moderated by 5-HTTLPR (table S3).
The interaction showed (P 0.05) that child-
hood maltreatment predicted adult depression
only among individuals carrying an s allele
but not among l/l homozygotes (Fig. 2).
We previously showed that variations in
the gene encoding the neurotransmitter-me-
tabolizing enzyme monoamine oxidase A
(MAOA) moderate childrens sensitivity to
maltreatment (25). MAOA has high affinity
for 5-HTT, raising the possibility that the
protective effect of the l/l allele on psychiat-
ric morbidity is further augmented by the
presence of a genotype conferring high
MAOA activity (13, 26). However, we found
that the moderation of life stress on depres-
sion was specific to a polymorphism in the
5-HTT gene, because this effect was ob-
served regardless of the individuals MAOA
gene status (tables S4 and S5).
Until this studys findings are replicated,
speculation about clinical implications is pre-
Fig. 1. Results of multiple regression analyses estimating the association between number of
stressful life events (between ages 21 and 26 years) and depression outcomes at age 26 as a
function of 5-HT T genotype. Among the 146 s/s homozygotes, 43 (29%), 37 (25%), 28 (19%), 15
(10%), and 23 (16%) study members experienced zero, one, two, three, and four or more stressful
events, respectively. Among the 435 s/l heterozygotes, 141 (32%), 101 (23%), 76 (17%), 49 (11%),
and 68 (16%) experienced zero, one, two, three, and four or more stressful events. Among the 264
l/l homozygotes, 79 (29%), 73 (28%), 57 (21%), 26 (10%), and 29 (11%) experienced zero, one,
two, three, and four or more stressful events. (A) Self-reports of depression symptoms. The main
effect of 5-HTTLPR (i.e., an effect not conditional on other variables) was marginally significant
(b 0.96, SE 0.52, t 1.86, P 0.06), the main effect of stressful life events was significant
(b 1.75, SE 0.23, t 7.45, P 0.001), and the interaction between 5-HTTLPR and life events
was in the predicted direction (b 0.89, SE 0.37, t 2.39, P 0.02). The interaction showed
that the effect of life events on self-reports of depression symptoms was stronger among
individuals carrying an s allele (b 2.52, SE 0.66, t 3.82, P 0.001 among s/s homozygotes,
and b 1.71, SE 0.34, t 5.02, P 0.001 among s/l heterozygotes) than among l/l
homozygotes (b 0.77, SE 0.43, t 1.79, P 0.08). (B) Probability of major depressive
episode. The main effect of 5-HT TLPR was not significant (b 0.15, SE 0.14, z 1.07, P
0.29), the main effect of life events was significant (b 0.37, SE 0.06, z 5.99, P 0.001), and
the G E was in the predicted direction (b 0.19, SE 0.10, z 1.91, P 0.056). Life events
predicted a diagnosis of major depression among s carriers (b 0.52, SE 0.16, z 3.28, P
0.001 among s/s homozygotes, and b 0.39, SE 0.09, z 4.24, P 0.001 among s/l
heterozygotes) but not among l/l homozygotes (b 0.16, SE 0.13, z 1.18, P 0.24). (C)
Probability of suicide ideation or attempt. The main effect of 5-HTTLPR was not significant (b
0.01, SE 0.28, z 0.01, P 0.99), the main effect of life events was significant (b 0.51, SE
0.13, z 3.96, P 0.001), and the G E interaction was in the predicted direction (b 0.39,
SE 0.20, t 1.95, P 0.051). Life events predicted suicide ideation or attempt among s carriers
(b 0.48, SE 0.29, z 1.67, P 0.09 among s/s homozygotes, and b 0.91, SE 0.25, z
3.58, P 0.001 among s/l heterozygotes) but not among l/l homozygotes (b 0.13, SE 0.26,
z 0.49, P 0.62). (D) Informant reports of depression. The main effect of 5-HT TLPR was not
significant (b 0.06, SE 0.06, t 0.98, P 0.33), the main effect of life events was significant
(b 0.23, SE 0.03, t 8.47, P 0.001), and the G E was in the predicted direction (b
0.11, SE 0.04, t 2.54, P 0.01). The effect of life events on depression was stronger among
s carriers (b 0.39, SE 0.07, t 5.23, P 0.001 among s/s homozygotes, and b 0.17, SE
0.04, t 4.51, P 0.001 among s/l heterozygotes) than among l/l homozygotes (b 0.14, SE
0.05, t 2.69, P 0.01).
Fig. 2. Results of regression analysis estimating
the association between childhood maltreat-
ment (between the ages of 3 and 11 years) and
adult depression (ages 18 to 26), as a function
of 5-HTT genotype. Among the 147 s/s ho-
mozygotes, 92 (63%), 39 (27%), and 16 (11%)
study members were in the no maltreatment,
probable maltreatment, and severe maltreat-
ment groups, respectively. Among the 435 s/l
heterozygotes, 286 (66%), 116 (27%), and 33
(8%) were in the no, probable, and severe
maltreatment groups. Among the 265 l/l ho-
mozygotes, 172 (65%), 69 (26%), and 24 (9%)
were in the no, probable, and severe maltreat-
ment groups. The main effect of 5-HT TLPR was
not significant (b 0.14, SE 0.11, z 1.33,
P 0.19), the main effect of childhood mal-
treatment was significant (b 0.30, SE 0.10,
z 3.04, P 0.002), and the G E interaction
was in the predicted direction (b 0.33, SE
0.16, z 2.01, P 0.05). The interaction
showed that childhood stress predicted adult
depression only among individuals carrying an s
allele (b 0.60, SE 0.26, z 2.31, P 0.02
among s/s homozygotes, and b 0.45, SE
0.16, z 2.83, P 0.01 among s/l het-
erozyotes) and not among l/l homozygotes
(b 0.01, SE 0.21, z 0.01, P 0.99).
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18 JULY 2003 VOL 301 SCIENCE www.sciencemag.org388
on July 30, 2010 www.sciencemag.orgDownloaded from
mature. Nonetheless, although carriers of an s
5-HTTLPR allele who experienced four or
more life events constituted only 10% of the
birth cohort, they accounted for almost one-
quarter (23%) of the 133 cases of diagnosed
depression. Moreover, among cohort mem-
bers suffering four or more stressful life
events, 33% of individuals with an s allele
became depressed, whereas only 17% of the
l/l homozygotes developed depression (Fig.
3). Thus, the G Es attributable risk and
predictive sensitivity indicate that more
knowledge about the functional properties of
the 5-HTT gene may lead to better pharma-
cological treatments for those already de-
pressed. Although the short 5-HTTLPR vari-
ant is too prevalent for discriminatory screen-
ing (over half of the Caucasian population
has an s allele), a microarray of genes might
eventually identify those needing prophylaxis
against lifes stressful events (27).
Evidence of a direct relation between the
5-HTTLPR and depression has been incon-
sistent (12), perhaps because prior studies
have not considered participants stress his-
tories. In this study, no direct association
between the 5-HTT gene and depression was
observed. Previous experimental paradigms,
including 5-HTT knockout mice (13), stress-
reared rhesus macaques (14), and human
functional neuroimaging (15), have shown
that the 5-HTT gene can interact with envi-
ronmental conditions, although these experi-
ments did not address depression. Our study
demonstrates that this G E interaction ex-
tends to the natural development of depres-
sion in a representative sample of humans.
However, we could not test hypotheses about
brain endophenotypes (28) intermediate be-
tween the 5-HTT gene and depression be-
cause of the difficulty of taking CSF or func-
tional magnetic resonance imaging measure-
ments in an epidemiological cohort.
Much genetic research has been guided by
the assumption that genes cause diseases, but
the expectation that direct paths will be found
from gene to disease has not proven fruitful for
complex psychiatric disorders (29). Our find-
ings of G E interaction for the 5-HTT gene
and another candidate gene, MAOA (25), point
to a different, evolutionary model. This model
assumes that genetic variants maintained at
high prevalence in the population probably act
to promote organisms resistance to environ-
mental pathogens (30). We extend the concept
of environmental pathogens to include traumat-
ic, stressful life experiences and propose that
the effects of genes may be uncovered when
such pathogens are measured (in naturalistic
studies) or manipulated (in experimental stud-
ies). To date, few linkage studies detect genes,
many candidate gene studies fail consistent rep-
lication, and genes that replicate account for
little variation in the phenotype (29). If repli-
cated, our G E findings will have implica-
tions for improving research in psychiatric ge-
netics. Incomplete gene penetrance, a major
source of error in linkage pedigrees, can be
explained if a genes effects are expressed only
among family members exposed to environ-
mental risk. If risk exposure differs between
samples, candidate genes may fail replication.
If risk exposure differs among participants
within a sample, genes may account for little
variation in the phenotype. We speculate that
some multifactorial disorders, instead of result-
ing from variations in many genes of small
effect, may result from variations in fewer
genes whose effects are conditional on expo-
sure to environmental risks.
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ciplinary Health and Development Study, Air New
Zealand, and the study members, their families, and
their friends. Supported by the Health Research
Council of New Zealand and the University of Wis-
consin Graduate School and by grants from the U.K.
Medical Research Council, the William T. Grant Foun-
dation, and the U.S. National Institute of Mental
Health (MH49414 and MH45070). T.E.M. is a Royal
Society–Wolfson Research Merit Award holder. The
study protocol was approved by the institutional
review boards of the participating universities.
Supporting Online Material
www.sciencemag.org/cgi/content/full/301/5631/386/
DC1
Materials and Methods
Tables S1 to S5
27 February 2003; accepted 16 June 2003
Fig. 3. The percentage
of individuals meeting
diagnostic criteria for
depression at age 26,
as a function of 5-HT T
genotype and number
of stressful life events
between the ages of
21 and 26. The figure
shows individuals with
either one or two cop-
ies of the short allele
(left) and individuals
homozygous for the long allele (right). In a hierarchical logistic regression model, the main effect
of genotype (coded as s group 0 and l group 1) was not significant, b 0.15, SE 0.21, z
0.72, P 0.47; the main effect of number of life events was significant, b 0.34, SE 0.06, z
5.70, P 0.001; and the interaction between genotype and number of life events was significant,
b 0.30, SE 0.15, z 1.97, P 0.05.
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www.sciencemag.org SCIENCE VOL 301 18 JULY 2003 389
on July 30, 2010 www.sciencemag.orgDownloaded from
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