Social Adversity, the Serotonin Transporter
(5-HTTLPR) Polymorphism and Major
Paul G. Surtees, Nicholas W.J. Wainwright, Saffron A.G. Willis-Owen, Robert Luben,
Nicholas E. Day, and Jonathan Flint
Background: Recent evidence has suggested that the short allele of the serotonin transporter (5-HTT) gene-linked polymorphic region
(5-HTTLPR of the human serotonin gene [SLC6A4]) is associated with increased risk of depressive disorder but only among individuals
exposed to social adversity. We report an investigation designed to replicate this finding.
Methods: Data were available from a non-clinical sample of 4175 adult men and women, ages 41–80 years, selected from
participants in the European Prospective Investigation into Cancer and Nutrition in Norfolk (EPIC-Norfolk, United Kingdom) study.
Evidence of past-year prevalent episodic major depressive disorder (MDD), defined by restricted DSM-IV diagnostic criteria, was
assessed through questionnaire. Adverse experiences in childhood and in adulthood (during the five years preceding assessment) were
also assessed through self-report. The 5-HTTLPR variant was genotyped according to published protocols.
Results: One-year prevalent MDD criteria were met by 298 study participants. The experience of social adversity (both in childhood
and adulthood) was strongly associated with increased rates of past-year prevalent MDD. No gene by environment (GxE) interactions
between the 5-HTTLPR genotype, social adversity, and MDD were observed.
Conclusions: This study has not replicated a previous finding of a GxE interaction between the 5-HTTLPR genotype, social adversity,
Key Words: Depression, stress, serotonin transporter, 5-HTTLPR,
SLC6A4, gene-environment interaction
arthropathies (Scofield et al 1995). Few such interactions, how-
ever, have been successfully characterized in relation to human
psychiatric phenotypes, despite clear indications from nonhu-
man mammal research that they exist. For example, investiga-
tions of the genetic contribution of the serotonin transporter
(5-HTT) to behavioral measures of anxiety in both rodents and
nonhuman primates have indicated a moderating role of social
adversity, most specifically during early stages of development
(Ansorge et al 2004; Bennett et al 2002; Champoux et al 2002).
Recently, Caspi et al (2003) reported that a length polymor-
phism (SLC6A4) in the promoter region of 5-HTT (5-HTTLPR)
mediates the influence of stressful life events on human depres-
sion. They showed that individuals carrying one or more short
(S) allele who were exposed to stressful life events were more
likely to develop depression than those homozygous for the long
(L) allele. They also reported that childhood maltreatment pre-
dicted adult depression only among individuals carrying a copy
of the S allele.
This finding is intriguing for a number of reasons. First, as one
of the few examples of a gene by environment (GxE) interaction,
it provides an opportunity to investigate the phenomenon at a
molecular level. Because of its potential importance, Caspi et al
nteractions between genetic loci and the environment are
known for a wide variety of biological phenotypes, such as
the thalassaemias (Weatherall 2001) and reactive spondylo-
have emphasized the need for its replication. Second, the
interaction effects reported seem to be present in the absence of
a main effect of the SLC6A4 promoter length polymorphism on
depression. Although, historically, studies that have addressed
this question in relation to (unipolar) depression have reached
inconsistent conclusions, a recent large multicenter case-control
study (involving 539 unipolar patients and 821 control subjects;
Mendlewicz et al 2004) and a recent meta-analysis (Lasky-Su et al
2005) have both reported no main effect, indicating that the main
effect, if present, must be very small. Third, the reported effect
was observed on depression occurring in the year before assess-
ment (at age 26) for individuals experiencing stressful life events
in the preceding five years. In contrast, the reported impact of life
events is typically limited to the 1–3 months preceding the onset
of a depressive episode (Brown et al 1973; Kendler et al 1998;
Surtees et al 1986).
We now report an attempt to replicate the GxE interaction
between SLC6A4 (5-HTTLPR) genotype, the experience of social
adversity, and DSM-IV– defined (American Psychiatric Associa-
tion 1994) major depressive disorder (MDD) among a large
non-clinical sample of men and women participating in the
European Prospective Investigation into Cancer and Nutrition in
Norfolk (EPIC-Norfolk), United Kingdom study (Day et al 1999).
Methods and Materials
During 1993–1997, EPIC-Norfolk recruited, through general
practice age-gender registers, a total of 30,414 men and women
(then) ages 40 –74 years and resident in Norfolk, England (Day et
al 1999). The study was approved by the Norwich District Health
Authority Ethics Committee and all participants gave signed
informed consent. During 1996–2000, an assessment of social
and psychological circumstances, on the basis of the Health and
Life Experiences Questionnaire (HLEQ) (Surtees et al 2003b),
was completed by a total of 20,921 participants, representing a
response rate of 73.2% of the total eligible EPIC-Norfolk sample
(28,582). A sample of 5000 participants was selected from the
From Strangeways Research Laboratory and University of Cambridge De-
Causeway, Cambridge; and the Wellcome Trust Centre for Human Ge-
netics (SAGW-O, JF), Headington, Oxford, United Kingdom.
Worts Causeway, Cambridge, CB1 8RN, United Kingdom; E-mail: paul.
Received January 31, 2005; revised June 15, 2005; accepted July 8, 2005.
BIOL PSYCHIATRY 2006;59:224–229
© 2005 Society of Biological Psychiatry
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