Journal of Human Genetics (2011), 1–4

& 2011 The Japan Society of Human Genetics All rights reserved 1434-5161/11 $32.00
www.nature.com/jhg

ORIGINAL ARTICLE

Q1
Functional polymorphism (5-HTTLPR) in the
serotonin transporter gene is associated with
subjective well-being: evidence from a US
nationally representative sample
Jan-Emmanuel De Neve

Variation in the promotor region of the serotonin transporter gene (5-HTTLPR) is a promising candidate for better understanding
individual heterogeneity in subjective well-being or happiness, as measured by life satisfaction. This functional polymorphism
has previously been associated with mental health and selective processing of positive and negative emotional stimuli. A case–
control association study on a representative sample of the Americans (N¼2574) finds that individuals with the transcriptionally
more efficient version of the serotonin transporter gene, report significantly higher levels of life satisfaction (P¼0.01). This new
finding may help explain the important genetic component of the individual baseline levels of happiness.

F
Journal of Human Genetics (2011) 0, 000–000. doi:10.1038/jhg.2011.39
O
Keywords: 5-HTTLPR; happiness; life satisfaction; population genetics; serotonin transporter; subjective well-being
O
INTRODUCTION protein.6–9 The long polymorphism thus results in increased gene
PR

Research on subjective well-being has produced valuable insights into expression and more serotonin transporters in the cell membrane.
the sources of individual happiness. An important finding from In turn, more serotonin is reintroduced into the pre-synaptic cell.
this literature is that people tend to have a ‘‘baseline’’ or ‘‘set point’’ This process is shown in Figure 1.
happiness level1 that shows persistent strength over time, and twin Functional variation in the serotonin transporter gene is increas-
D

studies indicate that up to 50% of the variance in happiness between ingly understood to exert strong influence on parts of the brain
individuals can be attributed to genetic influences.2,3 However, twin regulated by serotonergic neurotransmission. In particular—with
TE

studies do not identify which genes might be involved. Functional remarkable consistency—a body of neuroscientific research shows
variation in the promotor region of the serotonin transporter gene increased amygdala activation to negative emotional stimuli among
(5-HTTLPR) is a promising candidate for better understanding the carriers of short alleles.4,10–13 A morphometrical study of this genetic
EC

individual heterogeneity in subjective well-being. association reports reduced gray matter volume in short-allele carriers
Q2 The 5-HTT gene (locus symbol SLC6A4) codes for the serotonin in limbic regions critical for processing of negative emotion, particu-
transporters (5-HTT or SERT) that are placed in the cell wall and larly perigenual cingulate and amygdala.12 These authors conclude
reabsorb the neurotransmitter serotonin from the synaptic cleft. Most that 5-HTT induced variation in anatomy and function of an
R

serotonin is recycled after use and the serotonin transporter allows amygdala-cingulate feedback circuit, critical for emotional states
implicating a genetic susceptibility for depression.12 Another morpho-
R

serotonergic neurons to restock. The serotonin transporter gene has

been studied extensively, and much is known about the way different metrical study corroborates the finding that short-allele carriers
O

versions of this gene influence serotonergic neurotransmission which, show decreased volume in the affective division of the anterior
in turn, is found to influence personality and mental health.4–6 cingulate and decreased gray matter density in its pre-genual region.13
C

The 5-HTT gene contains a 44-bp variable-number tandem repeat The same study also finds that the 5-HTTLPR polymorphism is
polymorphism in the promoter region (5-HTTLPR); that is believed associated with activation changes to positive stimuli, suggesting a
N

to be responsible for variation in transcriptional efficiency. The ’’long’’ general role in emotional processing, rather than negative valence
(528 bp) and ‘‘short’’ (484 bp) polymorphism produces the same specifically.13
U

protein, but the long allele is associated with an approximately three Myriad genetic association studies also suggest that serotonin and
times higher basal activity than the shorter allele. Consequently, 5-HTT has an important role in mental health.4,5,14,15 Specifically, the
the long variant produces significantly more 5-HTT mRNA and short 5-HTTLPR allele was found to be a risk allele for depression,7,12

Department of Government, London School of Economics and Political Science, London, UK

Correspondence: Dr J-E De Neve, Department of Government, London School of Economics and Political Science, Houghton Street, London WC2A 2AE, UK.
E-mail: j.c.de-neve@lse.ac.uk or jdeneve@post.harvard.edu
Received 3 November 2010; revised 17 March 2011; accepted 19 March 2011
 5-HTTLPR and subjective well-being
J-E De Neve et al
2

Figure 1 Representation of the long/short polymorphism of the 5-HTT gene and the release, reception and recycling of serotonin in neurons. Adapted from
Canli and Lesch,6 with permission from the Nature Publishing Group.

F
and subsequent studies report that about 10% of variance in anxiety-
related traits is contingent upon serotonin transporters.16,17 However,
the role of 5-HTT in mental health remains disputed with the meta-
analysis by Risch et al.18 yielding no evidence that the serotonin
O
O
transporter is associated with an elevated risk of depression. Other
recent work shows either mixed result19 or a positive association
PR

between the short 5-HTTLPR allele and anxiety-related traits and

suicide.20,21
A recent study by Fox et al.22 suggests that long 5-HTTLPR allele
may influence optimism. The authors obtained DNA from about 100
D

participants and compared reaction times with pictures with positive,

negative and neutral emotional valence, in line with a common
TE

experiment in psychopathology research. The results show that

individuals with the transcriptionally more-efficient long 5-HTTLPR
alleles display a significant bias toward processing positive information
Figure 2 Percentage distribution of life satisfaction in Add Health
EC

and selectively avoiding negative information. This emotionally self-

(N¼2574) and the 5-HTTLPR genotype frequency for each category. No
protective pattern does not obtain in individuals carrying one or allelic frequency is reported for the ’’very dissatisfied’’ category because of
both short alleles. the small N.
Not all studies show a direct relationship between a gene variant
R

and a phenotype. Instead, developmental or concurrent environments

may moderate an association between genes and phenotypes. A well-
R

known study identifies a gene–environment (GxE) interaction for the MATERIALS AND METHODS
influence of life stress on depression.23 The authors find that indivi-
O

Sample
duals with short 5-HTTLPR alleles gene are more vulnerable to stress- Data are from the National Longitudinal Study of Adolescent Health (Add
induced depression. Among those individuals that had experienced a Health) that explores health-related behavior of adolescents. 24 By now, four
C

relatively large number of stressful life events, about 33% of the waves (1995, 1996, 2001 and 2008) of data collection have taken place and
N

carriers of the less-efficient short allele were cases of diagnosed participating individuals are around 30-years old. In Wave III, subjects were
depression as compared with only 17% of the individuals that carried asked ’’How satisfied are you with your life as a whole?’’ Answer categories
ranged from very dissatisfied, dissatisfied, neither satisfied nor dissatisfied,
U

both long alleles. Thus, in the Caspi et al.23 study the gene itself is not
satisfied, to very satisfied. Alternative answers were ’’refused’’ or ‘‘don’t know’’,
associated with depression. Rather, it is the combination of both gene
and these were discarded for the purpose of this study (less than 1% of
and environment that yields a significant association. Our study does interviewees gave such a response). Figure 2 gives the distribution of life
not report on a gene–environment interaction, but the direct associa- satisfaction. Allelic information for seven genetic markers is available for about
tion between the number of long 5-HTTLPR alleles and life satisfac- 2574 individuals as part of Wave III, including markers that identify alleles of
tion. Future research may produce new insights from exploring how 5-HTTLPR. A subset of individuals is nested in the same family, and these
environmental factors moderate the association between 5-HTTLPR sibling relationships are accounted for in the statistical model. Allele frequency
and happiness. for the transcriptionally more-efficient long allele is 57%, and 43% for the short

Journal of Human Genetics

 5-HTTLPR and subjective well-being
J-E De Neve et al
3

allele. Supplementary Tables 1–4 available in the online Supplementary As a robustness test for population stratification, we also include
Information provide detailed descriptive statistics This secondary analysis on Model 2; that is a case–control model for those subjects that uniquely
the data collected by the National Longitudinal Study of Adolescent Health24 identified themselves as being white (N¼1456). The coefficient on 5-
was reviewed and granted human subjects approval by the Human Research HTTLPR and its P-value (P¼0.043) suggests that population stratifi-
Protections Program (IRB) of the University of California, San Diego, USA (PI cation between self-reported racial categories is not driving the
James H. Fowler).
association between 5-HTTLPR and life satisfaction.
Supplementary Table 6 details and specifies a family-based test
Genotyping
through a variance-components-based association analysis for the
Details of the Add Health DNA collection and genotyping process are available
at the Add Health website25 and reproduced here. The 5-HTT gene maps to available sibling pairs.26,27 By decomposing genotype scores into
17q11.1-17q12 and contains the 44-bp variable-number tandem repeat in the between-family (b) and within-family (w) components, it is possible
5¢ regulatory region of the gene. The assay used is similar to Lesch et al.7 to control for spurious results due to population stratification, because
The primer sequences are: forward, 5¢-GGCGTTGCCGCTCTGAATGC-3¢, and only the coefficient on the between-family variance (bb) will be
reverse, 5¢-GAGGGACTGAGCTGGACAACCAC-3.¢ These primer sequences affected. The coefficient is not significant (P¼0.548), indicating that
yield products of 484 or 528 bp. population stratification is not driving this analysis. For the family-
based test, the association result is determined by the coefficient on the
Statistical analyses within-family variance (bw). The resulting coefficient in this study is
To test for genetic association, we employ a regression model with robust positive but not significant (P¼0.188). It is important to note that
cluster variance estimator to account for sibling relationships in the data: many observations are lost in the family-based test, because it only
Yij ¼ b0 +bG Gij +bk Zkij +Uj +eij includes individuals who have a different genotype than their sibling
(N¼708). As a result, this method suffers from much lower power in
where i and j index subject and family, respectively. For 5-HTTLPR, G¼2 if the detecting a true association and is thus prone to false negatives.28
subject’s genotype is LL, G¼1 for genotypes LS or SL, and G¼0 if the subject’s
genotype is SS (where L represents having a copy of a 528-bp long allele, and S DISCUSSION
represents having a copy of a 484-bp short allele). Z is a matrix of variables to The single-item life satisfaction measure used in Add Health is
control for the underlying population structure of the Add Health sample. standard in the psychology and happiness economics literatures.29–32

F
Finally, the variable U is a family random effect that controls for potential
Generally, multi-item scales are preferred because a single-item
genetic and environmental correlation among family members, and e is an
measure is more vulnerable to question specification and statistical
individual-specific error. To control for the effects of the underlying population
structure, we include indicator variables for whether a subject is self-reported as
O
noise in the data. Still, the life satisfaction scale has adequate
convergent validity. A recent overview of the measurement of sub-
O
Black, Hispanic or Asian (base category is White). Following the policy of the
United States Census, Add Health allows respondents to mark more than one jective well-being is given in Lewis et al.33 where the authors conclude
race. As this complicates the ability to control for stratification, we exclude that ‘‘The evidence to date indicates that such self-reports of happiness
PR

these individuals (N¼117), but a supplementary analysis including them yields are reliable and valid: most instruments show impressive internal
substantively equal results. The introduction of a cluster variance estimator for consistency, temporal stability, convergence with non-self-report mea-
the sibling relationships makes the model specification robust to within-cluster sures of well-being, and acceptable levels of criterion validity.’’ The life
correlation. satisfaction question has also been cross-validated with alternative
D

measures that gauge subjective well-being,3,31 and Oswald and Wu34

RESULTS provide objective confirmation of life satisfaction as a measure of
TE

Figure 2 illustrates the descriptive breakdown of the answer to ’’How subjective well-being. Still, the life satisfaction question has been
satisfied are you with your life as a whole?’’ and the 5-HTTLPR criticized for inducing a focusing illusion by drawing attention to
genotype frequency for each answer category. With increasing life people’s relative standing rather than moment-to-moment hedonic
EC

satisfaction levels, we find that the proportion of individuals that carry experience.35
both long alleles rises from 20 to about 35%. In contrast, the frequency In line with the happiness literature, a large majority of respondents
of individuals that carry both short alleles is highest in the lower life report being satisfied or very satisfied. That most people, in fact,
satisfaction categories. Carriers of the long-short or short-long alleles report a positive level of subjective well-being is the object of a paper
R

are evenly distributed across the latter, most populated, answer by Diener and Diener,30 where the authors find this distribution to be
categories. representative in a wide cross-national analysis.
R

Supplementary Table 5 (available in the online Supplementary Although these data give us a valuable opportunity to explore
Information) presents the results of several specifications of the genetic influences on subjective well-being, two limitations of the data
O

model to test the hypothesis that 5-HTTLPR is associated with need to be emphasized. First, the Add Health sample is restricted to
subjective well-being. Each of these specifications includes variables individuals who are 18–26-years old during Wave III. Still, the
C

for age, gender and race to control for population stratification. Model distribution of answers is typical of other life satisfaction surveys
N

1 shows that the long allele of 5-HTTLPR is significantly associated and may suggest some degree of generalizability. As such, the age
with increased life satisfaction (P¼0.013). Figure 1 in Supplementary limits are not likely to gravely distort our results. Second, because we
U

Information summarizes these results for 5-HTTLPR by simulating employ a case–control design our association results remain vulner-
first differences from the coefficient covariance matrix of this basic able to population stratification. We limit this potential threat to the
model. Holding all else constant and changing the 5-HTTLPR validity of our results by including controls for race and restricting the
genotype of all subjects from zero to one, long allele would increase analysis to a specific racial or ethnic group, as well as by specifying a
the reporting of being very satisfied with one’s life in this population family-based test. A family-based design eliminates population strati-
by about 8.5%. Similarly, changing the genotype from zero to two long fication, but provides much lower power in detecting a true associa-
alleles would increase the reporting of being very satisfied by about tion (false negatives). Xu and Shete28 show, based on simulation work,
17.3%. that a case–control association study using a mixed-effects regression

Journal of Human Genetics

 5-HTTLPR and subjective well-being
J-E De Neve et al
4

outperforms family-based designs in detecting an association while at 9 Glatz, K., Mossner, R., Heils, A. & Lesch, K. P. Glucocorticoid-regulated human
the same time effectively limiting type I error (false positives). serotonin transporter (5-HTT) expression is modulated by the 5-HTT gene-promotor-
linked polymorphic region. J. Neurochem. 85, 1072–1078 (2003).
This analysis suggests that genetic factors significantly influence 10 Heinz, A., Braus, D., Smolka, M., Wrase, J., Puls, I., Hermann, D. et al. Amygdala-
individual subjective well-being and a particular genotype— prefrontal coupling depends on a genetic variation of the serotonin transporter.
Nat. Neurosci. 8, 20–21 (2005).
5-HTTLPR ‘‘long’’—is identified as having a sizeable positive associa- 11 Munafo, M. R., Brown, S. M. & Hariri, A. R. Serotonin transporter (5HTTLPR) genotype
tion with self-reported life satisfaction. The 5-HTTLPR ’’short’’ and amygdala activation: a meta-analysis. Biol. Psychiatry. 63, 852–857 (2008).
genotype has been thoroughly studied as a risk allele for depression 12 Pezawas, L., Meyer-Lindenberg, A., Drabant, E. M., Verchinski, B. E., Munoz, K. E.,
Kolachana, B. S. et al. 5-HTTLPR polymorphism impacts human cingulate-amygdala
and anxiety-related disorders. This research, however, presents the interactions: a genetic susceptibility mechanism for depression. Nat. Neurosci. 8,
first evidence of the influence of this functional polymorphism on 828–834 (2005).
subjective well-being or happiness. As such, this research addresses 13 Canli, T., Omura, K., Haas, B- W., Fallgatter, A. & Constable, R- T Beyond affect a role
for genetic variation of the serotonin transporter in neural activation during a cognitive
the ’’set point’’ of subjective well-being that previous research has attention task. Proc. Natl Acad. Sci. USA. 102, 12224–12229 (2005).
identified to be of great importance.1,2,3 14 Heils, A., Teufel, A., Petri, S., Stober, G., Riederer, P., Bengel, D. et al. Allelic variation
of human serotonin transporter gene expression. J. Neurochem. 66, 2621–2624
Future work should attempt to identify other genes or gene– (1996).
environment interactions that are associated with subjective well- 15 Murakami, F., Shimomura, T., Kotani, K., Ikawa, S., Nanba, E. & Adachi, K. Anxiety
being. Finding out which genes they are and what physical function traits associated with a polymorphism in the serotonin transporter gene regulatory
region. Jpn. J. Hum. Genet. 44, 15–17 (1999).
they have will improve our understanding of the biological processes 16 Sen, S., Burmeister, M. L. & Ghosh, D. Meta-analysis of the association between
that underlie well-being and may also shed light on their evolutionary a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety related
origin.36 It is important to emphasize that there is no single ’’happi- personality traits. Am. J. Med. Genet. B. 127, 85–89 (2004).
17 Munafo, M. R., Clark, T. & Flint, J. Does measurement instrument moderate the
ness gene.’’ Instead, there is likely to be a set of genes whose expression, association between the serotonin transporter gene and anxiety-related personality
in combination with environmental factors, influences subjective traits? A meta-analysis. Mol. Psychiatry 10, 415–419 (2005).
18 Risch, N. et al. Interaction between the serotonin transporter gene (5-HTTLPR),
well-being. stressful life events, and risk of depression: a meta-analysis. J. Am. Med. Assoc.
301, 2462–2471 (2009).
CONFLICT OF INTEREST 19 Middeldorp, C. M., de Geus, E. J., Beem, A. L., Lakenberg, N., Hottenga, J. J.,
Slagboom, P. E. et al. Family based association analyses between the serotonin
The authors declare no conflict of interest. transporter gene polymorphism (5-HTTLPR) and neuroticism, anxiety and depression.
Behav. Genet. 37, 294–301 (2007).

F
ACKNOWLEDGEMENTS 20 Ishii, T., Wakabayashi, R., Kurosaki, H., Gemma, A. & Kida, K. Association of serotonin
transporter gene variation with smoking, chronic obstructive pulmonary disease, and its
Thanks to James Fowler, Dan Benjamin, Chris Dawes, Bruno Frey, Jaime Settle,
and Piero Stanig. The usual disclaimer applies. This research uses data from
Add Health, a program project directed by Kathleen Mullan Harris and
O
depressive symptoms. J. Hum. Genet. (e-pub ahead of print 28 October 2010;
doi:10.1038/jhg.2010.133).
21 Lin, P.- Y. & Tsai, G. Association between serotonin transporter gene promoter
O
designed by J Richard Udry, Peter S Bearman, and Kathleen Mullan Harris at polymorphism and suicide: results of a meta-analysis. Biol. Psychiatry. 55,
1023–1030 (2004).
the University of North Carolina at Chapel Hill, and funded by Grant P01- 22 Fox, E., Ridgewell, A. & Ashwin, C. Looking on the bright side: biased attention and the
PR

HD31921 from the Eunice Kennedy Shriver National Institute of Child Health human serotonin transporter gene. Proc. R. Soc. B. 276, 1747–1751 (2009).
and Human Development, with cooperative funding from 23 other federal 23 Caspi, A., Sugden, K., Moffitt, T., Taylor, A., Craig, I., Harrington, H. et al. Influence
of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science
agencies and foundations. Information on how to obtain the Add Health
301, 386–389 (2003).
data files is available on the Add Health website (http://www.cpc.unc.edu/ 24 Harris, K. M., Halpern, C. T., Whitsel, E., Hussey, J., Tabor, J., Entzel, P. et al.
addhealth). No direct support was received from Grant P01-HD31921 for The National Longitudinal Study of Adolescent Health: Research Design, http://
D

this analysis. www.cpc.unc.edu/projects/addhealth/design (2009).

25 Add Health Biomarker Team Biomarkers in Wave III of the Add Health Study., http://
TE

www.cpc.unc.edu/projects/addhealth/files/biomark.pdf. (2007).
26 Boehnke, M. & Langefeld, C. D. Genetic association mapping based on discordant sib
pairs: the discordant-alleles test. Am. J. Hum. Genet. 62, 950–961 (1998).
1 Diener, E. & Lucas, R. Personality and subjective well-being. In Well-being: The 27 Spielman, R. S. & Ewens, W. J. A sibship test for linkage in the presence of asso-
foundations of Hedonic Psychology ed. Kahneman, D., Diener, E. & Schwarz, ciation: the sib transmission/disequilibrium test. Am. J. Hum. Genet.. 62, 450–458
EC

N.Sage: New York, NY, (1999). (1998).

2 Lykken, D. & Tellegen, A. Happiness is a stochastic phenomenon. Psychol. Sci. 7, 186– 28 Xu, H. & Shete, S. Mixed-effects logistic approach for association following linkage
189 (1996). scan for complex disorders. Ann. Hum. Genet. 71, 230–237 (2006).
3 Bartels, M. & Boomsma, D. I. Born to be happy? The etiology of subjective well-being. 29 Di Tella, R., MacCulloch, R. & Oswald, A. J. Preferences over inflation and unemploy-
Behav. Genet. 39, 605–615 (2009). ment: evidence from surveys of happiness. Am. Econ. Rev. 91, 335–341 (2001).
R

4 Hariri, A. R., Mattay, V. S., Tessitore, A., Kolachana, B., Fera, F. & Goldman, D. 30 Diener, E. & Diener, C. Most people are happy. Psychol. Sci. 7, 181–185 (1996).
Serotonin transporter genetic variation and the response of the human amygdala. 31 Kahneman, D. & Krueger, A. B. Developments in the measurement of subjective well-
R

Science 297, 400–403 (2002). being. J. Econ. Perspect. 20, 3–24 (2006).
5 Hariri, A. R. & Holmes, A. Genetics of emotional regulation: the role of the serotonin 32 Frey, B. S. Happiness: A Revolution in Economics, MIT, (2008). Q3
transporter in neural function. Trends Cogn. Sci. 10, 182–191 (2006). 33 Lewis, M., Haviland-Jones, J. & Feldman Barrett, L. The Handbook of Emotions,
O

6 Canli, T. & Lesch, K. P. Long story short: the serotonin transporter in emotion regulation Guilford Press: NY (2008).
and social cognition. Nat. Neurosci. 10:1103–1109 (2007). 34 Oswald, A. J. & Wu, S. Objective confirmation of subjective measures of human
7 Lesch, K. P., Bengel, D., Heils, A., Sabol, S. Z., Greenberg, B. D., Petri, S. et al. well-being: evidence from the U.S.A. Science. 327, 576–579 (2010).
C

Association of anxiety-related traits with a polymorphism in the serotonin transporter 35 Kahneman, D., Krueger, A. B., Schkade, D., Schwarz, N. & Stone, A. A. Would you be
gene regulatory region. Science. 274, 1527–1531 (1996). happier if you were richer? A focusing illusion. Science. 312, 1908–1910 (2006).
N

8 Little, K. Y., McLaughlin, D. P., Zhang, L., Livermore, C. S., Dalack, G. W. & McFinton, 36 Fitzpatrick, M. J., Ben-Shahar, Y., Smid, H. M., Vet, L. E. M., Robinson, G. E. &
P. R. Cocaine, ethanol, and genotype effects on human midbrain serotonin transporter Sokolowski, M. B. Candidate genes for behavioural ecology. Trends Ecol. Evol. 20,
binding sites and mRNA levels. Am. J. Psychiatry. 155, 207–213 (1998). 96–104 (2005).
U

Supplementary Information accompanies the paper on Journal of Human Genetics website (http://www.nature.com/jhg)

Journal of Human Genetics