International Journal of Obesity (2010) 34, 1028–1033
& 2010 Macmillan Publishers Limited All rights reserved 0307-0565/10 $32.00
www.nature.com/ijo
ORIGINAL ARTICLE
Association between serotonin 5-HT-2C receptor gene
(HTR2C) polymorphisms and obesity- and mental
health-related phenotypes in a large population-based
cohort
KS Vimaleswaran1, JH Zhao1, NW Wainwright2, PG Surtees2, NJ Wareham1 and RJF Loos1
1
MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, UK and 2Department of Public Health and Primary
Care, Strangeways Research Laboratory and University of Cambridge, Worts Causeway, Cambridge, UK
Objective: Studies have shown that common single-nucleotide polymorphisms (SNPs) in the serotonin 5-HT-2C receptor
(HTR2C) are associated with antipsychotic agent-induced weight gain and the development of behavioural and psychological
symptoms. We aimed to analyse whether variation in the HTR2C is associated with obesity- and mental health-related
phenotypes in a large population-based cohort.
Method: Six tagSNPs, which capture all common genetic variation in the HTR2C gene, were genotyped in 4978 men and
women from the European Prospective Investigation into Cancer (EPIC)–Norfolk study, an ongoing prospective populationbased cohort study in the United Kingdom. To confirm borderline significant associations, the 759C/T SNP (rs3813929) was
genotyped in the remaining 16 003 individuals from the EPIC–Norfolk study. We assessed social and psychological
circumstances using the Health and Life Experiences Questionnaire. Genmod models were used to test associations between
the SNPs and the outcomes. Logistic regression was performed to test for association of SNPs with obesity- and mental healthrelated phenotypes.
Results: Of the six HTR2C SNPs, only the T allele of the –759C/T SNP showed borderline significant associations with higher
body mass index (BMI) (0.23 kg m–2; (95% confidence interval (CI): 0.01–0.44); P ¼ 0.051) and increased risk of lifetime major
depressive disorder (MDD) (Odds ratio (OR): 1.13 (95% CI: 1.01–1.22), P ¼ 0.02). The associations between the 759C/T and
BMI and lifetime MDD were independent. As associations only achieved borderline significance, we aimed to validate our
findings on the –759C/T SNP in the full EPIC–Norfolk cohort (n ¼ 20 981). Although the association with BMI remained
borderline significant (b ¼ 0.20 kg m–2; 95% CI: 0.04–0.44, P ¼ 0.09), that with lifetime MDD (OR: 1.01; 95% CI: 0.94–1.09,
P ¼ 0.73) was not replicated.
Conclusions: Our findings suggest that common HTR2C gene variants are unlikely to have a major role in obesity- and mental
health-related traits in the general population.
International Journal of Obesity (2010) 34, 1028–1033; doi:10.1038/ijo.2009.292; published online 12 January 2010
Keywords: HTR2C gene; polymorphism; EPIC–Norfolk; BMI; mental health; major depressive disorder
Introduction
The serotonin (5-hydroxytryptamine (5-HT)) neurotransmitter
has been implicated in a variety of complex neurological,
psychiatric and behavioural disorders, including depression,
anxiety, schizophrenia, obsessive-compulsive disorder and
Correspondence: Dr RJF Loos, MRC Epidemiology Unit, Institute of Metabolic
Science, Box 285, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK.
E-mail: [email protected]
Received 25 June 2009; revised 8 October 2009; accepted 27 November
2009; published online 12 January 2010
appetite.1 Furthermore, animal studies using knockout mice
have shown that the serotonin 5-HT-2C receptor (HTR2C) gene,
located on chromosome Xq24, is involved in the control of
appetite and feeding behaviour and development of obesity.2–6
A functional variant (G4C polymorphism), resulting in a
Cys-to-Ser missense mutation at codon 23, was identified
by screening the HTR2C gene in a Caucasian population
comprising individuals with and without mental disorders.7
This Cys23Ser variant (rs6318) has been implicated in
eating8,9 and anxiety10 disorders and reduction in weight
gain in the treatment of obesity.11 However, other studies
failed to confirm the association of Cys23Ser variant with the
HTR2C polymorphisms, BMI and mental health
KS Vimaleswaran et al
1029
risk of bullimia, binge eating disorder and obesity.12,13
Studies in schizophrenic patients have shown significant
association between polymorphisms in the promoter of
HTR2C gene and weight gain induced by antipsychotic
drugs.14–18 The C allele of the –759C/T variant, located in the
promoter region, has been shown to associate with a higher
incidence of weight gain. Consistently, a study in 120 obese
and 104 non-obese women reported association of the
C allele with obesity (Odds ratio (OR): 1.72 (95% confidence
interval (CI): 1.13–2.64), P ¼ 0.008).19 Studies examining the
genetic variation in HTR2C have typically been small and the
largest study so far, comprising 466 non-obese and 123 obese
men, found the frequency of the C allele of the 697C/G
variant, another polymorphism in the 50 promoter region, to
be higher in non-obese than in obese men (OR: 2.5; 95% CI:
1.3–5.1, P ¼ 0.009).20 In contrast, a few studies failed to
observe an association between the HTR2C polymorphisms
in the promoter and obesity-related traits.21,22 So far, the
contribution of genetic variation in HTR2C to common
obesity and traits of depression in large-scale and population-based cohorts has not been examined.
Hence, in this study, we investigated the association
between common genetic variation in HTR2C and obesityand mental health-related traits in the European Prospective
Investigation into Cancer (EPIC)–Norfolk study. Besides the
three commonly studied single-nucleotide polymorphisms
(SNPs) (759C/T, 697C/G and Cys23Ser), we selected three
additional tagSNPs (single nucleotide polymorphisms) to
ensure full coverage of the genetic variation of the HTR2C
gene and tested for association with obesity- and mental
health-related traits in single SNP and haplotype analyses.
examined the study participants; height and weight were
measured, and BMI was calculated as weight (kg) height–2
(m2). Waist was measured at the minimum circumference at
the natural waistline between the lower rib margins and iliac
crest, or at the level of the umbilicus if there was no natural
waistline. Anthropometric measures and genotypic data
were available for 4978 men and women. Descriptive
characteristics for the cohort are shown in Table 1.
We also carried out an assessment of social and psychological circumstances using the Health and Life Experiences
Questionnaire (HLEQ). The HLEQ included a structured selfassessment approach to psychiatric symptoms that enabled
application of restricted Diagnostic and Statistical Manual of
Mental Disorders-IV25 criteria for episodic major depressive
disorder (MDD). The assessment, designed to identify those
study participants thought likely to have met a putative
diagnosis of MDD at any time in their lives, depends on
participants initially disclosing details of their most recently
experienced episode of depression (if more than one) that
has endured for 2 weeks or more and that fulfils the required
concurrent Diagnostic and Statistical Manual of Mental
Disorders-IV MDD symptom criteria. In addition, operational criteria for clinically significant impairment and help
seeking were included and participants were requested to
estimate episode onset and (if appropriate) offset timings.26
Past-year MDD was defined as any episode that was either
Table 1 Clinical characteristics of the participants in the EPIC–Norfolk study
Clinical characteristics of the initial study sample (n ¼ 4978)
Characteristics
Materials and methods
Study population
The study includes 4978 participants that were randomly
selected from the EPIC–Norfolk study, an ongoing prospective population-based cohort study comprising 25 631
residents living in the city of Norwich and its surrounding
towns and rural areas. It is an ethnically homogeneous
population of white European origin. All men and women,
aged 39–79 years from the consenting general practices,
completed a baseline health examination between 1993 and
1997. From January 1998, we invited the cohort for a second
health examination and 15 786 people had attended by
October 2000. For the purposes of this analysis, we examined
data from a random sample of 5000 participants who
attended the second health examination and who were free
of baseline disease (cancer, coronary heart disease and
diabetes) with fully arrayed DNA available, completed food
frequency questionnaire data, and blood HbA1C and body
mass index (BMI) measured at the two clinical assessments.
Full details on participant recruitment and study procedures
have been described previously.23,24 In brief, trained nurses
Age (years)
BMI (kg m–2)
Weight (kg)
Height (cm)
Waist (cm)
MHI-5
Neuroticism
Lifetime MDD, n (%)
Treatment for depression n (%)
Men (n ¼ 2187)
Women (n ¼ 2791)
Mean±s.d.
Mean±s.d.
58.3±9.3
26.2±3.0
80.1±10.6
174.5±63.9
95.2±9.1
79.7±15.2
3.6±3.1
207 (10.9)
61 (2.8)
57.0±9.2
25.6±4.0
66.9±10.9
161.5±6.1
80.7±10.1
76.3±15.8
4.8±3.2
478 (19.7)
130 (4.7)
Clinical characteristics of the whole EPIC–Norfolk cohort (n ¼ 20 981)
Characteristics
Age (years)
BMI (kg m–2)
Weight (kg)
Height (cm)
Waist (cm)
MHI-5
Neuroticism
Lifetime MDD, n (%)
Treatment for depression, n (%)
Men (n ¼ 10 349)
Women (n ¼ 10 632)
Mean±s.d.
Mean±s.d.
59.1±9.3
26.5±3.3
80.3±11.3
174.0±6.6
95.7±9.7
79.2±15.6
3.7±3.1
858 (11.6)
390 (3.8)
58.6±9.3
26.1±4.2
67.8±11.6
160.9±6.2
82.1±10.7
75.7±16.3
4.8±3.2
1458 (18.9)
761 (7.1)
Abbreviations: BMI, body mass index; EPIC, European Prospective Investigation
into Cancer; MDD, major depressive disorder; MHI, mental health inventory.
International Journal of Obesity
HTR2C polymorphisms, BMI and mental health
KS Vimaleswaran et al
1030
current at the time of HLEQ completion or ended within the
12 months preceding assessment. The HLEQ also included a
five-item version of the Mental Health Inventory (MHI-5),
with one or more items representing anxiety, depression, loss
of behavioral–emotional control and psychological wellbeing during the past 4 weeks, as part of a validated generic
measure of subjective health status, the anglicised version of
the Short Form 36.27 The MHI-5 was scored on a scale from 0
to 100 in which a lower score represents greater psychological distress. The MHI-5 has been shown to be an effective
measure of depression severity.28 In addition, the HLEQ
included an assessment of neuroticism through completion
of a short form of the Eysenck Personality Questionnaire,29
and scored within the range from 0 to 12 with higher scores
indicating increased neuroticism. Depression is a neurological disorder with a range of psychiatric symptoms and hence,
several behavioural and emotional measures are required to
capture this trait.
Antidepressant medication use during a 1-week preassessment period was obtained through self-report questionnaire, and was completed approximately 6 months
before the assessment of MDD status. Antidepressant
medication use was defined according to the British National
Formulary (section 4.3), and included tricyclic (or related)
antidepressants, monoamine-oxidase inhibitors, selective
serotonin reuptake inhibitors (and related antidepressants),
and other antidepressants.
To validate borderline associations, we genotyped the
remaining 16 003 individuals of the EPIC–Norfolk cohort
(ntotal ¼ 20 981) for one of the HTR2C SNPs (that is, 759C/
T). Descriptive characteristics are shown in Table 1.
The study was approved by the Norfolk, United Kingdom,
Health District ethics committee and all participants gave
informed consent.
TagSNP selection
The HTR2C gene is located on chromosome Xq24, spans
326.1 kb and comprises six exons. SNPs in the HTR2C gene
were selected using genotype data from the International
HapMap Phase II collected in individuals of Northern
and Western European ancestry (CEU) (HapMap data release
19 2005, dbSNP b124). The Haploview software V3.3 (http://
www.broadinstitute.org/haploview/haploview-downloads) was
used to assess the linkage disequilibrium structure between
SNPs.30 As the HTR2C gene is located on the X-chromosome,
linkage disequilibrium was assessed in women only.
Tagger software was used to select tagSNPs with the
‘pairwise tagging only’ option and an r2 threshold of 40.8.
There were 335 SNPs encompassing the HTR2C gene in the
Hapmap for the CEU population. Of these 335 SNPs, 208 met
the pre-requisite criteria (minor allele frequency X5% and
Hardy–Weinberg equilibrium P-value40.01) for inclusion in
analyses (Supplementary Figure 1). In the tagSNP selection,
we force included the three SNPs previously studied before
running tagger. In total, six tagSNPs (rs3813929 (759 C/T),
International Journal of Obesity
Figure 1 Haploview plot of HTR2C gene from EPIC–Norfolk study.
rs518147 (697 C/G), rs6318 (Ser23Cys), rs17260600
(IVS4 þ 55492A/C), rs6644093 (IVS4 þ 98007G/T) and
rs1801412 ( þ 1553T/G)) representing the entire common
genetic variations across the HTR2C gene were chosen for
the study (Figure 1).
Genotyping
The six tagSNPs were genotyped using the Taqman platform
(Applied Biosystems, Warrington, UK). The genotyping
assays were carried out on 10 ng of genomic DNA in a 5 ml
384-well TaqMan assay using a G-Storm GS4 Thermal Cycler
(GRI, Rayne, UK), cycling 95 1C for 10 min, and then 50
cycles of 15 s at 92 1C and 1 min at 60 1C. The ABI PRISM
7900HT Sequence Detection System (Applied Biosystems)
was used for end-point detection and allele calling. Genotype data were reviewed independently for each of the six
SNPs and the call rate ranged from 97 to 99%. All six SNPs
showed no significant departure from Hardy–Weinberg
equilibrium (P 40.01, Supplementary Table 1).
Statistical analysis
A likelihood ratio test was performed in women only (as
HTR2C is located on the X-chromosome) to assess whether
the observed genotypes were in Hardy–Weinberg equilibrium. We performed allelic association analyses, which
allow combining men and women in one analysis, to
preserve statistical power. Genmod models were used to test
HTR2C polymorphisms, BMI and mental health
KS Vimaleswaran et al
1031
the associations between the SNPs and the outcomes
comparing the major and minor alleles. Logistic regression
analysis adjusted for age and sex was carried out to test for
the association of HTR2C SNPs with obesity- and mental
health-related phenotypes. Mediation effects were tested by
adjusting for BMI when examining the association of the
HTR2C SNPs with depression and adjusting for depression
when examining the association of HTR2C SNPs with BMI.
Haplotype blocks were defined using Gabriel’s method, as
implemented in Haploview. Haplotype analyses were carried
out for two-marker and six-marker haplotypes. Haplotype
frequencies were estimated using the HAPLOTYPE procedure
in SAS/Genetics version 9.1 (SAS Institute Inc., Cary, NC,
USA). Haplotypes prevalent at 45% were retained for further
haplotype analyses. Haplotype trend regression analysis was
performed to test for association between common haplotypes and BMI. All statistical analyses for single point and
haplotype association tests were carried out using SAS/
Genetics version 9.1 (SAS Institute Inc.).
Table 2 Association of the HTR2C gene SNPs with BMI and waist in the EPIC–
Norfolk study (n ¼ 4978)
Obesity-related traits
rs3813929 (759C/T)
C
BMI (kg m–2) 25.9±0.05
Waist (cms)
87.8±0.14
T (18.4%)b
26.2±0.11
88.4±0.28
b (95% CI)
P-valuea
0.23 (0.01, 0.44)
0.051
0.56 (0.001, 1.12) 0.055
rs518147 (697C/G)
C
BMI (kg m–2) 25.9±0.07
Waist (cms)
87.8±0.19
G (35.2%)b
26.1±0.12
88.2±0.30
b (95% CI)
0.23 (0.01, 0.45)
0.44 (0.14, 1.01)
P-valuea
0.11
0.23
rs6318 (Cys23Ser)
C
BMI (kg m–2) 25.9±0.05
Waist (cms)
88.0±0.14
G (16.3%)b
26.1±0.11
88.1±0.29
A
BMI (kg m–2) 25.9±0.05
Waist (cms)
87.9±0.14
C (6.6%)b
26.0±0.16
88.4±0.42
G
BMI (kg m–2) 25.9±0.05
Waist (cms)
88.0±0.14
T (15.1%)b
25.9±0.11
87.9±0.30
b (95% CI)
0.09 (0.14, 0.31)
0.10 (0.49, 0.68)
P-valuea
0.46
0.75
rs17260600 (IVS4+55492A/C)
b (95% CI)
0.07 (0.27, 0.41)
0.46 (0.42, 1.33)
P-valuea
0.68
0.29
rs6644093 (IVS4+98007G/T)
Results
Of the six HTR2C SNPs, only the T allele of 759C/T showed
borderline significant association with a 0.23 kg m–2 higher
BMI compared with the C allele carriers (P ¼ 0.051) (Table 2).
The association with BMI remained unchanged after excluding individuals who use antidepressant medication (n ¼ 191)
(0.27 kg m–2 (95% CI: 0.03–0.50), P ¼ 0.04). However, the
759C/T SNP was not associated with the increased risk of
obesity (P ¼ 0.40) (Table 3). In addition, the T allele of
759C/T SNP was also associated with an increased risk of
lifetime MDD (OR: 1.11; 95% CI: 1.02–1.16, P ¼ 0.02)
(Table 3). We also tested for the association of the SNP with
lifetime MDD after excluding individuals on antidepressant
medication and found that the OR was somewhat more
pronounced (OR: 1.25; 95% CI: 1.03–1.51, P ¼ 0.02). The
associations of the 759C/T SNP with BMI and lifetime MDD
were independent; that is, the association between the
759C/T SNP and BMI remained significant and effect sizes
were similar after adjusting for lifetime MDD (b ¼ 0.27 kg m–2;
95% CI: 0.03–0.51, P ¼ 0.03) and, vice versa, the association
between the SNP and MDD remained significant after
adjusting for BMI (OR: 1.11; 95% CI: 1.02–1.22, P ¼ 0.02).
This shows that the association with BMI was not mediated
through lifetime MDD and the association with lifetime
MDD was not mediated through BMI.
As the observed associations were only borderline significant, we aimed to validate these findings in the full
EPIC–Norfolk cohort (n ¼ 20 981). We found that the association of the SNP with BMI remained borderline (b ¼ 0.20 kg m–2;
95% CI: 0.04–0.44, P ¼ 0.09), although that with MDD
disappeared (OR: 1.01; 95% CI: 0.94–1.09, P ¼ 0.73).
In addition to 759C/T SNP, the T allele of the SNP
IVS4 þ 98007G/T (rs6644093) was associated with an in-
b (95% CI)
0.04 (0.27, 0.20)
0.07 (0.67, 0.54)
P-valuea
0.76
0.83
rs1801412 (EX6+1553T/G)
G
BMI (kg m–2) 25.9±0.05
Waist (cms)
88.0±0.14
T (5.6%)b
26.2±0.20
88.6±0.50
b (95% CI)
0.27 (0.09, 0.64)
0.61 (0.34, 1.56)
P-valuea
0.17
0.22
Abbreviations: BMI, body mass index; CI, confidence interval; EPIC, European
Prospective Investigation into Cancer; HTR2C, 5-HT-2C receptor; SNPs, singlenucleotide polymorphisms. aData are adjusted for age and sex; Data are
represented as mean±s.e. bMinor allele frequency.
creased risk of lifetime MDD (OR: 1.12; 95% CI: 1.02–1.40,
P ¼ 0.02) even after adjusting for age, sex and BMI. However,
we did not observe an association of this SNP with the
obesity-related traits (Tables 2 and 3).
None of the other SNPs showed an association with
obesity traitsFBMI and waist and mental health-related
traitsFneuroticism, MHI-5, past-time and lifetime MDD.
After the single SNP allelic association, the two promoter
SNPs, 759C/T and 697C/G, were analysed as two-marker
and six-marker haplotypes. The haplotype frequencies are
presented in the Supplementary Table 2. None of the twomarker and six-marker haplotypes were significantly associated with obesity- and mental health-related phenotypes.
Discussion
In this study, we have assessed the association of six tagSNPs
and haplotypes encompassing the HTR2C gene with obesityand mental health-related phenotypes in 4958 individuals
and, because of borderline significance, we also tested
whether the associations still prevailed in the full cohort
International Journal of Obesity
HTR2C polymorphisms, BMI and mental health
KS Vimaleswaran et al
1032
Table 3
Association of the HTR2C gene SNPs with obesity and MDD in the EPIC-Norfolk study (n ¼ 4978)
HTR2C SNPs
rs3813929 (759C/T)
rs518147 (697C/G)
rs6318 (Cys23Ser)
rs17260600 (IVS4+55492A/C)
rs6644093 (IVS4+98007G/T)
rs1801412 (EX6+1553T/G)
Obesity
Lifetime MDD
Odds ratio
95% CI
P-valuea
Odds ratio
95% CI
P-valuea
0.96
0.97
0.97
1.02
1.03
0.94
0.88–1.05
0.89–1.07
0.89–1.06
0.89–1.17
0.93–1.13
0.81–1.08
0.40
0.54
0.52
0.79
0.61
0.35
1.11
1.06
0.93
0.97
1.11
1.07
1.02–1.16
0.96–1.16
0.86–1.01
0.85–1.09
1.01–1.22
0.92–1.24
0.02
0.24
0.09
0.58
0.03
0.36
Abbreviations: CI, confidence interval; EPIC, European Prospective Investigation into Cancer; HTR2C, 5-HT-2C receptor; MDD, major depressive disorder; SNPs,
single-nucleotide polymorphisms. aAdjusted for age and sex.
comprising 20 981 individuals. This is the first observational
study of this magnitude examining the HTR2C gene in
association with BMI and depression in a larger cohort of
healthy men and women.
In the 4958 individuals, we found a moderate association
of the T allele of 759C/T polymorphism (rs3813929) in the
50 promoter region of the HTR2C gene with increased BMI.
The T allele of –759C/T polymorphism increases BMI by
0.23 kg m–2 (95% CI: 0.01–0.44), which is equivalent to
B0.70 kg in body weight for a person of 1.70-m tall. This
effect is smaller compared with the genetic variation in the
fat mass and obesity-associated (FTO) gene, which has still
the largest effect on BMI in individuals of European
descent31 (each risk-allele increases BMI by B0.33 kg m–2,
which is equivalent to B0.95 kg in body weight for a person
of 1.70-m tall). The finding that the T allele of the 759C/T
polymorphism is associated with BMI in our study is in
contrast to the other investigations32,33 that found a
significant association of the C allele with increased BMI.
This could be due to the fact that these studies were
performed in patients who were on medication, although
our study included healthy individuals. In addition, we
observed that the T allele of the 759C/T polymorphism was
also associated with MDD. Given the fact that obesity and
depression are associated traits,34,35 we tested for mediation
effects and found that the association of 759C/T polymorphism with BMI was not mediated through MDD and
vice versa. As our initial association analyses showed
borderline significance for the 759C/T polymorphism, we
genotyped this SNP in the remaining 16 003 individuals
from the EPIC–Norfolk study to increase statistical power as
well as to confirm whether the observed associations were
truly positive. However, we found that the –759C/T SNP did
not show any association with BMI and MDD.
One of the main strengths of this study is the availability
of variables such as MHI-5, a more general measure of
psychological distress and a measure of depression severity28,36,37 and neuroticism, a marker of liability to major
depression,38 alongside the HLEQ measure of MDD defined
according to diagnostic criteria.
When the two promoter polymorphisms, 759C/T and
697C/G, were combined as a two-marker haplotype, there
International Journal of Obesity
was no association of the haplotypes with BMI and MDD.
This was in contrast to the findings from a Japanese study20
(n ¼ 589) and a Swedish study39 (46 schizophrenic patients),
who showed an association of the haplotypes comprising the
two promoter polymorphisms with obesity.
In summary, this large-scale population-based study
suggests that HTR2C gene variants are unlikely to have a
major role in obesity- and mental health-related traits in a
general population of white adult Europeans.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements
We are grateful to the volunteers in the EPIC–Norfolk Study,
who gave their time to take part in this study. We thank the
participants and general practitioners who took part in this
study and the staff associated with the research programme.
EPIC–Norfolk is supported by programme grants from the
Medical Research Council UK (G9502233, G0300128) and
Cancer Research UK (C865/A2883) with additional support
from the European Union, Stroke Association, British Heart
Foundation, Department of Health and the Wellcome Trust.
We thank Jian’an Luan for his assistance in haplotype
analysis.
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Supplementary Information accompanies the paper on International Journal of Obesity website (http://www.nature.com/ijo)
International Journal of Obesity