Exploring the genetic susceptibility of chronic widespread pain: the
tender points in genetic association studies
K. L. Limer*, B. I. Nicholl*, W. Thomson and J. McBeth
Chronic widespread pain (CWP) is a prevalent disorder associated with a low pain threshold and increased levels of psychological distress.
Evidence indicates that there is a genetic component to CWP syndromes and pain sensitivity. Here we have identified and reviewed the
current literature on genetic association (GA) studies of CWP and pain sensitivity by searching MEDLINE and EMBASE between January
1990 and May 2007. Of the 18 candidate genes studied to date, no definitive susceptibility genes have been identified. This review highlights
the key issues for consideration when interpreting the findings from existing studies and in designing future studies to ensure robust
and comparable findings in this field. Well-designed GA studies are essential if the genetic component to CWP aetiology is to be fully
KEY WORDS: Fibromyalgia, Chronic widespread pain, Pain sensitivity, Genetics, Study design.
The term chronic non-inflammatory musculoskeletal pain cap-
tures a number of disorders that are common in their lack of
a clear pathological aetiology. These are considered as either
regional [including low back pain (LBP), knee, shoulder and neck
pain] or widespread disorders. Of interest here is chronic
widespread pain (CWP), defined by ACR as pain that involves
two contralateral quadrants of the body and the axial skeleton
that persists for 3 months or longer . It has a prevalence of
?11% in the general population  and is the distinguishing
feature of the fibromyalgia (FM) syndrome.
Despite the unclear aetiology of CWP and FM, an emerging
evidence base has identified psychological and stress-related
factors as important predictors of onset . Whether these factors
are moderated by a genetic susceptibility is unknown. A number
of studies have repeatedly demonstrated the familial aggregation
of FM [3–6]. Evidence from twin studies, although limited,
supports a heritability component to CWP. Kato et al.  con-
ducted a study of 4170 monozygotic (MZ), 5881 same-sex and
5755 opposite-sex dizygotic (DZ) twin pairs from the Swedish
Twin Registry. The overall heritability estimates for CWP were
reported to be 48–54% with no difference in type or size of genetic
contribution noted between genders. This heritability component
in CWP reflects that of regional pain disorders including LBP and
neck pain (heritability estimates range from 52% to 68% and 35%
to 68%, respectively) .
Classification criteria for FM require the presence of wide-
spread tenderness, as measured by a high tender point count (?11
of 18), in addition to the presence of CWP . A tender point
count, pain threshold and tolerance testing are commonly used
methods to assess pain sensitivity. Subjects with CWP have lower
pain thresholds  and higher tender point counts [9, 10] than
those free of pain or with regional pain. Ethnic and gender
differences in pain sensitivity  suggest that it may also be under
genetic control. Given the available evidence and the close
relationship with CWP, pain sensitivity renders itself as an
important area of research when investigating a genetic suscepti-
bility to CWP.
Genetic association (GA) studies allow the proposed genetic
susceptibility of CWP and pain sensitivity to be explored by
investigating the role of variation within candidate genes. Our aim
was to assess the current knowledge in this field by performing a
comprehensive narrative review of the current literature on GA
studies for both CWP disorders and pain sensitivity and to discuss
the findings in the context of study design issues in order to guide
further research in this field.
MEDLINE and EMBASE (on OVID) were searched for publi-
cations using a combination of a pain outcome term (PAIN
or CHRONIC WIDESPREAD PAIN or FIBROMYALGIA)
and a genetics-related term (GENETIC or GENE or POLY-
MORPHISM or GENOTYPE or HAPLOTYPE or SNP or
ALLELE or VARIANT) in the title in order to identify all GA
papers with an outcome of CWP or pain sensitivity. The search
was limited to English language journals and human studies from
January 1990 to May 2007. The reference lists in the relevant
identified articles and previous pain and genetics review papers
were also checked to identify further relevant papers. Study design
information and results were extracted from each paper and the
information was verified by a second independent reader.
Discussion of findings
A total of 207 papers were identified by the search, 20 of which
were suitable for review. Unsuitable papers included studies on
gene therapy (n¼30), review articles (n¼36), rare mutations/
familial pain insensitivity syndromes (n¼18), twin/family studies
(n¼9), other types of pain (including regional, post-operative,
cancer and neuropathic pain: n¼52) and inapplicable (n¼42).
A further two relevant papers identified from a hand search were
also reviewed. The 22 papers report on GA analysis with 18 genes
in over 10 different study populations. The study population,
markers, outcome of interest and findings from the GA studies for
each gene are detailed separately for CWP/FM (Table 1) and pain
sensitivity (Table 2).
The neurophysiology of pain involves a complex network of
systems in both the peripheral and central nervous systems
[12, 13], and in fact, the majority of neurotransmission pathways
have been to some extent linked to pain. This has made the
Arthritis Research Campaign Epidemiology Unit, University of Manchester,
Submitted 28 August 2007; revised version accepted 11 January 2008.
Correspondence to: K. L. Limer, ARC Epidemiology Unit, University of
Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT.
?KL Limer and BI Nicholl equally contributed to this work.
Advance Access publication 5 March 2008
? The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: firstname.lastname@example.org
by guest on June 12, 2013
potential candidate gene list extensive; however, the majority of
genes studied are inter-linked. To date, 10 genes have been tested
as candidates for CWP disorders and they have largely focused on
aspects of neurotransmission, in particular, genes involved in the
action of serotonin (5-HT), a neurotransmitter involved in the
regulation of many bodily functions. Lower serum concentrations
of 5-HT have been observed in patients with FM . Genes
investigated include the monoamine oxidase A (MAOA) gene,
serotonin receptor genes (HTR2A, HTR3A and HTR3B) and a
serotonin transporter gene (SLC6A4). MAOA degrades serotonin
and its enzymatic activity has been shown to have high inter-
individual variability. Consequently, the role of a synonymous
SNP (single nucleotide polymorphism), rs6323 in the MAOA gene,
which reportedly affects the activity of the enzyme , was
investigated in FM; however, no association was seen in a
Taiwanese population . In HTR2A, a single synonymous
SNP, T102C, has been studied. Bondy et al.  found the TT
genotype of T102C to be less frequent in FM but conversely it
resulted in higher pain scores. Gursoy et al.  reported no
association with FM but a lower pain threshold in TT
homozygotes. The HTR3A and HTR3B genes have been more
comprehensively studied than HTR2A but no association with
FM has been observed . In two case–control studies of FM the
short allele (SS) genotype of the promoter region 44 bp indel
(insertion/deletion) (also known as 5HTTPLR) in SLC6A4 was
observed at a significantly higher frequency in FM [20, 21].
Contrary to this finding, Gursoy  reported no association
between FM and the indel or a variable number tandem repeat
(VNTR) polymorphism in SLC6A4.
Dopamine is an important neurohormone that has wide-
ranging influences throughout the body. In an Israeli population,
the dopamine receptor gene DRD4 was found to have a reduced
frequency of the seven repeat allele of the 48 bp exonic VNTR in
patients with FM. This allele was also associated with increased
novelty-seeking behaviour that is low in FM .
A number of inflammatory mediators: endothelial nitric oxide
synthase (NOS3), SERPINA1 (a protease inhibitor that protects
tissues from the enzymes of inflammatory cells) and the
anti-inflammatory cytokine IL4, have also been investigated
as candidate genes for FM. An increased frequency of the
SERPINA1 PI?Z allele was observed in FM in a Spanish case–
control study . No association was observed between the single
SNPs studied in IL4 and NOS3 with FM [16, 25].
To date, the most widely studied gene is COMT, which codes
for catechol-O-methyltransferase, an enzyme that degrades
catecholamine neurotransmitters, including dopamine, epinephr-
ine and norepinephrine. The variant allele V158M results in
reduced enzymatic activity due to its effect on thermostability 
and has been associated with reduced ?-opioid activity in response
to pain stimuli resulting in increased pain sensitivity . The low
(MM) and intermediate (VM) activity genotypes were signifi-
cantly increased in frequency in FM patients in two case–control
studies [28, 29], however, a much larger Norwegian cohort study
(the HUNT study) found no association between the polymorph-
ism and CWP .
Studies have also looked at the relationship between this SNP
and others in the COMT gene with pain sensitivity. Diatchenko
et al.  genotyped common SNPs across the gene in healthy
women and identified a haplotype block that could discriminate
individuals with low, average or high pain sensitivity and
functional studies suggest that this is due to altering mRNA
secondary structure . They subsequently showed that the
V158M associates with temporal summation of pain  and
proposed differing roles for the variants in the gene on the
membrane-bound and soluble forms of COMT. Kim et al. 
also reported associations between SNPs in COMT and heat and
cold pain sensitivities.
A further eight genes have also been tested for GA with pain
sensitivity. GTP cyclohydrolase (GCH1), an enzyme involved in
the production of tetrahydrobiopterin, a co-factor of enzymes
involved in the synthesis of neurotransmitters including NO, is the
most comprehensively studied of these genes. Testing for
association between SNPs across GCH1 and post-operative pain
identified multiple SNPs and a haplotype associated with lower
TABLE 1. Genetic association analysis of CWP disorders
GeneMarkers genotypedNo. of casesNo. of controlsSexEthnicityOutcome criteriaResultRef.
COMTrs4680 (V158M)6161FTurkishFM—ACRrs4680 (MM and VM gen-
otypes more frequent and
VV genotype less frequent
rs4680 (MM and VM
genotypes more frequent
Decrease in frequency of
7repeats genotype in FM
TT genotype underrepre-
sented in cases; cases with
TT genotype had higher
TT associated with lower
PI?Z frequency increased
Increased frequency of SS
(5HTTPLR) genotype in
DRD448 bp VNTR in exon 381458FIsraeli FM
HTR2A102T!C168 115 M/FCaucasianFM—ACR
Intron 3 SNP
5-HTTLPR, 17 bp
VNTR in intron 2
99559FJewish and Arab FM—ACR5HTTLPR (significant
increase frequency of SS
genotype in FM in both
SNQ: Standardized Nordic Questionnaire.
Genetics of chronic widespread pain573
by guest on June 12, 2013
pain scores. Healthy individuals with this pain-protective haplo-
type showed reduced pain responses to a mechanical stimulus .
Kim and Dionne , however, subsequently found no associa-
tion between haplotypes in GCH1 with cold or heat pain sensi-
tivity in healthy individuals.
GA studies of pain sensitivity have considered the role of
genetic variation in opioid receptors (OPRD1 and OPRM1) that
have crucial roles in pain mediation. In OPRD1, a non-
synonymous SNP was found to be a determinant of heat pain
sensitivity . In OPRM1, research has centred on the A118G
polymorphism as the variant allele increases the protein’s binding
ability to the ligand ?-endorphin . In Fillingim et al. 
carrying the G allele was associated with reduced pain sensitivity.
OPRM1 is involved in modulation of the hypothalamic–pituitary–
adrenal (HPA) axis, the innate stress response axis, and the G
allele of A118G SNP has also been associated with an increased
cortisol response to opioid receptor blockage . Individuals with
non-synonymous variants in melanocortin-1 receptor (MC1R), a
key hormone in stress response, which renders it non-functional,
show reduced pain sensitivity ; however, the majority of these
SNPs are rare and therefore unlikely to have a broad impact.
Kim et al. [34, 37] investigated GA with pain sensitivity in
FAAH (breaks down a cannabinoid receptor agonist believed to
have a role in pain perception) and TRPA1, TRPM8 and TRPV1
(ion channels involved in pain transmission, which are activated
by different stimuli). SNPs and/or haplotypes in FAAH, TRPA1
and TRPV1 showed association with pain sensitivity in a healthy
US Caucasian population.
Design considerations for GA studies of pain
Two key reviews by Cardon and Bell  and Cordell and Clayton
 consider appropriate study design and the related issues when
conducting a GA analysis. Some of these issues have also been
discussed in the context of neuropathic pain (pain due to injury to
the nervous system) research in Belfer et al. . GA analysis is in
its relative infancy in this field compared with other complex
diseases, e.g. type II diabetes where expectations to fulfil these
criteria are consequently higher. In order for us to have confidence
in our findings, it is important that the guidelines adhered to in
GA studies of other complex diseases are also followed when
researching the genetics of chronic pain.
Ascertainment of pain phenotype
The ascertainment of the phenotype of interest can often be a
major source of contention. GA studies of chronic pain involving
FM have used the 1990 standard ACR criteria to classify cases .
The use of this standard classification allows for direct compar-
ison of homogeneous groups with respect to their pain status.
However, CWP relies on self-reported measures and in the past
the ACR classification criteria has been criticized for being too
inclusive  and stricter criteria may be more appropriate.
TABLE 2. Genetic association analysis of pain sensitivity
GeneMarkers genotyped No.Ethnicity Sex
Assessment of pain
COMT rs4680 (V158M)
US (85% CAU)
Heat and CPI (VAS)
Summated Z-score for
cutaneous and deep
muscle pain based on
pressure, thermal and
ischaemic pain thresholds
Threshold and tolerance to
heat, thermal and ischae-
mic stimuli and temporal
summation to heat pain
Heat and CPI (VAS)
rs6269 and rs4818, and
haplotype (rs6269, rs4633,
rs4818, rs4680) associated
with pain tolerance
rs6269, rs4633, rs4818 and rs4680202 US (85% CAU)F
rs4680 associated with rate
of temporal summation to
Multiple SNPs 368 US CAUM/F Haplotype block asso-
ciated with CPI in females;
rs4646312 and rs6269 with
Haplotype blocks asso-
ciated with CPI and CWT in
males. rs932816 and
rs2295633 associated with
CPI and rs4141964 with
CPI and CWT.
Identified pain protective
FAAHMultiple SNPs 368US CAU M/F Heat and CPI (VAS)
GCH1Multiple SNPs547 US CAU M/FZ-score for thermal,
mechanical and ischaemic
Heat and CPI (VAS)
Pain tolerance to electrical
Dutch and Scottish
Increased pain tolerance/
analgesia with MC1R
rs1042114a determinant of
heat pain sensitivity
G allele (rs1799971) car-
riers have reduced pain
Haplotype block asso-
ciated with heat pain
intensity and CWT in
women, rs11988795 asso-
ciated with CWT.
rs8065080a determinant of
response to cold stimuli
OPRD1rs2234918 and rs1042114(F27C)500US mixed M/F Heat and CPI (VAS)
rs1799971, 17C!T, ?sat
rs1799971 (N40D) and 17C!T
Heat and CPI (VAS)
Pain tolerant vs intolerant
Pressure and thermal pain
threshold, tolerance and
Heat and CPI (VAS)
TRPA1Multiple SNPs368US CAUM/F
rs222747 (M315V), rs8065080 (I585V)
Heat and CPI (VAS)
Heat and CPI (VAS)
Multiple SNPs368US CAUM/FHeat and CPI (VAS) 
CPI: cold pain intensity; CWT: cold withdrawal time; CAU: Caucasian.
574K. L. Limer et al.
by guest on June 12, 2013
Pain sensitivity and tolerance are subjective measures and
are difficult to ascertain. Numerous techniques, as recorded in
Table 2, have been used to measure pain sensitivity, which has
been demonstrated to have high inter-individual variation ,
but as of yet no ‘gold standard’ has been determined. Heat and
cold stimuli are frequently used. Kim et al. [34, 37] asked healthy
subjects to report the intensity of pain experienced when exposed
to cold and thermal stimuli using a visual analogue scale (VAS).
In contrast, Diatchenko et al.  derived their own unit measure
of pain sensitivity using a summated Z-score for cutaneous and
deep muscle pain based on pressure, thermal and ischaemic pain
thresholds and tolerances. Similar methods were used in a study of
GCH1 haplotypes in a group of healthy subjects, findings from
which supported the group’s earlier work on persistent LBP
following a discectomy .
Choice of control group
In case–control studies, the selection of control subjects is equally
as important as the selection of cases. Controls must be eligible to
become a case if they develop the disease of interest and therefore
should be selected from the same source population as cases .
If cases, however, are taken from a specialist sample, such as a
clinic population, then the best source of controls is less clear,
although their eligibility to become a case should always remain.
In general, in the GA studies of FM reviewed for this article, little
information on controls has been provided.
Candidate gene selection
Candidate gene selection in the association studies thus far has
been based on a strong biological rationale such as a role of the
resulting protein in nociception. Experimental evidence is useful in
prioritizing candidates and has also been a factor in the selection
of many of the candidate genes chosen. The following criteria add
weight to the hypothesis of a genetic effect. The first is location
within a region of linkage for the desired outcome. To date,
human linkage studies with pain outcomes have only investigated
the HLA, SLC6A4 and HTR2A loci [47, 48], and quantitative trait
loci (QTL) mapping using mice has identified MC1R  and
OPRD1 . The second is a previously reported GA between the
gene and the desired or a related outcome, although this can be
somewhat uninformative if previous studies were under-powered
and negative results may not have been reported due to publi-
cation bias. The third is known functional polymorphism/s, e.g.
A118G in OPRD1 and V158M in COMT have functional effects.
The last is differential expression of the gene in pain phenotypes,
which to date has been widely examined in animal models but not
in humans  and gene knockouts or disruption in transgenic
mice causing a pain phenotype . Gene expression profiling and
gene knockouts, however, tell us only that the gene functions in
pain and does not inform about the effects of common variants
within the gene on a pain outcome.
Genetic marker selection
A large proportion of the published GA analyses within this field
have only tested for association with a SNP of known or
purported function, e.g. the V158M SNP in COMT. This
approach does not account for other variants within the gene or
its regulatory regions, which may act synergistically with the
known functional variant. It is, therefore, more useful to use a
systematic approach whereby the common variation within the
gene is examined by selecting markers for genotyping based on
patterns of linkage disequilibrium (LD). With the role of the
majority of SNPs being unknown this method allows identifica-
tion of variants that may be important, e.g. due to location in
unknown regulatory regions. Few of the studies reviewed here
have used this approach but alternatively have genotyped
common SNPs spaced across the gene of interest, which can
subsequently be used to examine LD in the specific population.
They have however, demonstrated the importance of looking at
multiple SNPs in the gene. Diatchenko et al.  genotyped
common SNPs across COMT and identified a haplotype block of
four SNPs, including the functional SNP V158M, that consists of
three common haplotypes. These were shown to be associated
with pain sensitivity and COMT activity in vitro; however, this
was not simply due to the functional SNP as it occurred in both
high and low pain sensitivity haplotypes.
Sample size and power
Power is the most prevalent problem in the literature reviewed.
If pain disorders are indeed polygenic, and affected by environ-
mental influences, as they are proposed to be, then the risk
of developing the disease conferred from a single variant or gene
is likely to be very small and consequently a large sample size
is required to detect it. To date most sample sizes used, as
summarized in Table 1, have been insufficient to detect the
reported effects, with many studies having <100 cases and 100
controls. For example, two studies testing for a GA between the
V158M SNP in COMT and FM: Gursoy et al.  used 61 cases
and 61 controls and Garcia-Fructoso et al.  used 46 cases and
40 controls. A simple power calculation shows that to detect the
difference in allele frequency reported between cases and controls
in the two studies (?12%) ?250 cases and 250 controls would be
required to have 80% power and 5% type I error. Other factors,
however, such as lower allele frequency and testing multiple SNPs
will increase sample size requirement further. In the case of
chronic pain disorders, inadequate sample size may in part be due
to their low prevalence (e.g. 2% for FM), which could make it
more difficult to establish an appropriate study population. Power
is greater when using a continuous outcome such as pain
sensitivity rather than a binary outcome of a pain disorder.
Many of the studies testing for associations between genes and
pain sensitivity, however, are also likely to have been under-
powered and larger groups of healthy volunteers are required to
validate such findings, e.g. the relationship implicated between
GCH1 and pain sensitivity , which was not replicated in a
second study .
Interpreting results from GA studies
GA analysis is based on the assumption that if a variant within a
gene contributes to a disease phenotype then it will be more
prevalent in individuals with the phenotype. Current statistical
methods for GA analysis of single SNPs and haplotypes are
detailed in Balding . Results from the reviewed GA studies
need to be interpreted with caution as a significant association
has three possible explanations: (i) it is a real association with
the variant having a direct effect on the pain outcome, (ii) it is
due to the associated polymorphism being in LD with the
causal polymorphism or (iii) the association has occurred by
chance. Chance findings may occur due to insufficient power
(as previously discussed), population stratification, confounding
or multiple testing.
Population stratification occurs when cases and controls have
different allele frequencies due to diversity in the background
population rather than association with disease . Methodology
studies have shown that population stratification will only bias the
odds ratio in a case–control study where there is a large difference
in genotype frequency between the admixed populations and that
the overall bias from population stratification is small . For
example, Diatchenko et al.  tested for association between
variants in COMT and pain sensitivity in an American population
that is 85% Caucasian. They report no significant differences in
the results when stratifying to Caucasians only. There are known
Genetics of chronic widespread pain 575
by guest on June 12, 2013
ethnic differences in both pain perception and reporting ,
which may in part be attributable to differences in disease
vulnerability, access to care and socioeconomic factors .
In contrast, however, differences in experimental pain sensitivity
have been reported with African–Americans reporting higher pain
levels  than Caucasians. These differences and the known
genetic differences between ethnic groups mean that populations
in GA studies should be ethnically homogeneous and preferably
from a geographically defined region.
Confounding has been somewhat overlooked in the GA studies of
chronic pain disorders to date. FM, in particular, has repeatedly
been demonstrated to be associated with high levels of psycho-
logical distress and depression, e.g. Benjamin et al. . Many of
the candidate genes studied thus far with FM have previously been
associated with neuropsychiatric disorders such as anxiety and
depression e.g. COMT, DRD4, HTR2A, MAOA and SLC6A4.
Despite this, attempts to adjust, and therefore account for the
influence of psychological status on the findings reported have
been rare. In Cohen et al.  and Offenbaecher et al.  the SS
(short allele) genotype for the 44 bp indel promoter polymorphism
in the serotonin transporter gene, SLC6A4, was observed in
increased prevalence in FM cases. Offenbaecher et al. 
observed a trend for increased frequency of the S allele after
removing individuals with high scores on Beck’s Depression Index
(BDI) and the Symptoms Checklist SCL-90R, a multi-domain
measure of psychological distress, from the analysis. There was a
strong association of depression and distress with FM, therefore
the number of cases was reduced from 62 to 20 and 18 for each
analysis, respectively resulting in low statistical power .
In contrast, Cohen et al.  found that adjusting for psycholo-
gical factors rendered the association non-significant. Gursoy
et al.  also found that there was no association between the
indel and FM in mentally healthy individuals. The S allele of this
indel has previously been associated with anxiety-related person-
ality traits  and the literature suggests that the association
observed in FM may be due to the confounding effect of
A number of other factors are known to be associated with
both chronic pain and genetics; these include gender, ethnicity,
drug use and menstruation, all of which may act as potential
confounders to any GA observed.
Multiple testing must also be considered when interpreting results;
this is also uncommon in the reviewed literature, yet is a
requirement for a high-quality GA study, particularly in studies
examining novel candidates or a large number of variants.
Bonferroni correction is often used but can be too conservative
when linked variants are being tested. More appropriate methods
include generating an empirical P-value using permutations or
calculating false discovery rate .
Replication of findings
If an association is interpreted as real, then the true test is whether
or not it replicates in an independent data set. Only 7 of the 18
genes considered here have been analysed in multiple publications.
They are often heterogeneous in nature with different outcomes,
differing ethnicity and different markers being genotyped and
therefore there are only a few examples where the data are
comparable. For the COMT gene two studies have observed an
increased frequency of the M allele of the V158M polymorphism
in FM cases in Turkish  and Spanish populations .
Although this may be deemed a replication, the sample size used
in both studies was small and a larger study is required to confirm
Kim and Dionne  recently attempted to replicate the
findings of Tegeder et al.  of an association between a pain-
protective haplotype of GCH1 and pain sensitivity, without
success. There are, however, a number of reasons why this may
be the case. First, the studies report differing haplotype block
structures despite both being American Caucasian populations.
Second, the outcomes measured are also different with Tegeder
et al.  using Z-scores for thermal, mechanical and ischaemic
pain tolerance and Kim and Dionne  using VAS scores for
pain sensitivity to hot and cold stimuli and finally despite seeing a
trend with thermal pain, Tegeder et al.  did not report a
significant association within their 547 healthy volunteers, only
with mechanical pain. It is not unsurprising then that Kim and
Dionne  failed to replicate the result in their sample of 368
Caucasians. They also stratified their analysis by gender, further
reducing sample size and power. Replication studies have a
tendency to show smaller effect sizes than initial studies reporting
a GA , therefore, replication studies require a larger sample
size to detect the same association.
No definitive pain susceptibility genes have yet been identified but
the field is in its relative infancy compared with many complex
diseases. However, many of the genes reviewed here warrant
further investigation. The existing studies are subject to many
study design issues. Careful consideration needs to be given to
these issues when interpreting findings from existing studies and
when designing future studies into the genetic susceptibility of
CWP and pain sensitivity, in order for reported findings to be as
robust as possible.
We conclude that future GA studies of chronic pain disorders
should have adequate sample size for sufficient power to detect
associations. Candidate gene selection should be based on strong
biological rationale with supporting evidence from experimental
and genetic studies and methods that capture the variation within
the genes of interest based on LD should be used. Appropriate
information on pain status and potential environmental and
psychological confounders is also required. Finally, significant
associations must be replicated in an independent data set. This
type of study is essential if the genetic component to CWP
aetiology is to be fully elucidated.
Funding: The study was funded by a grant from the Arthritis
Research Campaign, grant Ref: 17552.
Disclosure statement: The authors have declared no conflicts of
1 Wolfe F, Smythe HA, Yunus MB, Bennett R, Bombardier C. The American College of
Rheumatology 1990 criteria for the classification of fibromyalgia. Arthritis Rheum
2 Gupta A, Silman AJ, Ray D et al. The role of psychosocial factors in predicting the
onset of chronic widespread pain: results from a prospective population-based study.
3 Pellegrino MJ, Waylonis GW, Sommer A. Familial occurrence of primary
fibromyalgia. Arch Phys Med Rehabil 1989;70:61–3.
Rheumatology key message
? The susceptibility genes for CWP syndromes have not been
identified partly due to poor study design, which should be noted
when interpreting existing findings and addressed when designing
576 K. L. Limer et al.
by guest on June 12, 2013
4 Buskila D, Neumann L, Hazanov I, Carmi R. Familial aggregation in fibromyalgia
syndrome. Semin Arthritis Rheum 1996;26:605–11.
5 Buskila D, Neumann L. Fibromyalgia syndrome (FM) and nonarticular tenderness in
relatives of patients with FM. J Rheumatol 1997;24:941–4.
6 Arnold LM, Hudson JI, Hess EV et al. Family study of fibromyalgia. Arthritis Rheum
7 Kato K, Sullivan PF, Evengard B, Pedersen NL. Importance of genetic influences on
chronic widespread pain. Arthritis Rheum 2006;54:1682–6.
8 MacGregor AJ, Andrew T, Sambrook PN, Spector TD. Structural, psychological, and
genetic influences on low back and neck pain: a study of adult female twins. Arthritis
9 Wolfe F, Ross K, Anderson J, Russell IJ. Aspects of fibromyalgia in the general
population: sex, pain threshold, and fibromyalgia symptoms. J Rheumatol
10 Croft P, Schollum J, Silman A. Population study of tender point counts and pain as
evidence of fibromyalgia. Br Med J 1994;309:696–9.
11 Mogil JS. The genetic mediation of individual differences in sensitivity to pain and its
inhibition. Proc Natl Acad Sci USA 1999;96:7744–51.
12 Schaible HG, Vanegas H. How do we manage chronic pain? Baillieres Best Pract
Res Clin Rheumatol 2000;14:797–811.
13 Aguggia M. Neurophysiology of pain. Neurol Sci 2003;24(Suppl. 2):S57–60.
14 Russell IJ, Vipraio GA, Lopez YG. Serum serotonin in fibromyalgia syndrome,
rheumatoid arthritis and healthy normol controls. Arthritis Rheum 1993;36:S222.
15 Hotamisligil G, Breakefield X. Human monoamine oxidase A gene determines levels
of enzyme activity. Am J Hum Genet 1991;49:383–92.
16 Su SY, Chen JJ, Lai CC, Chen CM, Tsai FJ. The association between fibromyalgia
and polymorphism of monoamine oxidase A and interleukin-4. Clin Rheumatol
17 Bondy B, Spaeth M, Offenbaecher M et al. The T102C polymorphism of the 5-HT2A-
receptor gene in fibromyalgia. Neurobiol Dis 1999;6:433–9.
18 Gursoy S, Erdal E, Herken H, Madenci E, Alasehirli B. Association of T102C
polymorphism of the 5-HT2A receptor gene with psychiatric status in fibromyalgia
syndrome. Rheumatol Int 2001;21:58–61.
19 Frank B, Niesler B, Bondy B et al. Mutational analysis of serotonin receptor genes:
HTR3A and HTR3B in fibromyalgia patients. Clin Rheumatol 2004;23:338–44.
20 Offenbaecher M, Bondy B, de Jonge S et al. Possible association of fibromyalgia with
a polymorphism in the serotonin transporter gene regulatory region. Arthritis Rheum
21 Cohen H, Buskila D, Neumann L, Ebstein RP. Confirmation of an association
between fibromyalgia and serotonin transporter promoter region (5- HTTLPR)
polymorphism, and relationship to anxiety-related personality traits. Arthritis Rheum
22 Gursoy S. Absence of association of the serotonin transporter gene polymorphism
with the mentally healthy subset of fibromyalgia patients. Clin Rheumatol
23 Buskila D, Cohen H, Neumann L, Ebstein RP. An association between fibromyalgia
and the dopamine D4 receptor exon III repeat polymorphism and relationship to
novelty seeking personality traits. Mol Psychiatry 2004;9:730–1.
24 Blanco I, Arbesu D, Al Kassam D, De Serres F, Fernandez-Bustillo E, Rodriguez C.
Alpha1-antitrypsin polymorphism in fibromyalgia syndrome patients from the Asturias
Province in Northern Spain: a significantly higher prevalence of the PI?Z deficiency
allele in patients than in the general population. J Musculoskelet Pain 2006;14:5–12.
25 Alasehirli B, Demiryurek S, Arica E, Gursoy S, Demiryurek AT. No evidence for an
association between the Glu298Asp polymorphism of the endothelial nitric oxide
synthase gene and fibromyalgia syndrome. Rheumatol Int 2007;27:275–80.
26 Syvanen AC, Tilgmann C, Rinne J, Ulmanen I. Genetic polymorphism of catechol-O-
methyltransferase (COMT): correlation of genotype with individual variation of
S-COMT activity and comparison of the allele frequencies in the normal population
and Parkinsonian patients in Finland. Pharmacogenetics 1997;7:65–71.
27 Zubieta JK, Heitzeg MM, Smith YR et al. COMT val158met genotype affects
mu-opioid neurotransmitter responses to a pain stressor. Science 2003;299:1240–3.
28 Gursoy S, Erdal E, Herken H, Madenci E, Alasehirli B, Erdal N. Significance of
Rheumatol Int 2003;23:104–7.
29 Garcia-Fructoso F, Beyer K, Lao-Villadoniga J. Analysis of Val158Met genotype
polymorphisms in the COMT locus and correlation with IL-6 and IL-10 expression in
fibromyalgia syndrome. J Clin Res 2006;9:1–10.
30 Hagen K, Pettersen E, Stovner LJ, Skorpen F, Zwart JA. No association between
chronic musculoskeletal complaints and Val158Met polymorphism in the catechol-O-
methyltransferase gene. The HUNT study. BMC Musculoskelet Disord 2006;7:40.
31 Diatchenko L, Slade GD, Nackley AG et al. Genetic basis for individual variations in
pain perception and the development of a chronic pain condition. Hum Mol Genet
32 Nackley AG, Shabalina SA, Tchivileva IE et al. Human catechol-O-methyltransferase
haplotypes modulate protein expression by altering mRNA secondary structure.
33 Diatchenko L, Nackley AG, Slade GD et al. Catechol-O-methyltransferase gene
polymorphisms areassociated with
34 Kim H, Mittal DP, Iadarola MJ, Dionne RA. Genetic predictors for acute experimental
cold and heat pain sensitivity in humans. J Med Genet 2006;43:e40.
35 Tegeder I, Costigan M, Griffin RS et al. GTP cyclohydrolase and tetrahydrobiopterin
regulate pain sensitivity and persistence. Nat Med 2006;12:1269–77.
36 Kim H, Dionne RA. Lack of influence of GTP cyclohydrolase gene (GCH1) variations
on pain sensitivity in humans. Mol Pain 2007;3:6.
37 Kim H, Neubert JK, San MA et al. Genetic influence on variability in human acute
experimental pain sensitivity associated with gender, ethnicity and psychological
temperament. Pain 2004;109:488–96.
38 Bond C, LaForge KS, Tian M et al. Single-nucleotide polymorphism in the human mu
opioid receptor gene alters beta-endorphin binding and activity: possible implications
for opiate addiction. Proc Natl Acad Sci USA 1998;95:9608–13.
39 Fillingim RB, Kaplan L, Staud R et al. The A118G single nucleotide polymorphism of
the mu-opioid receptor gene (OPRM1) is associated with pressure pain sensitivity in
humans. J Pain 2005;6:159–67.
40 Wand GS, McCaul M, Yang X et al. The mu-opioid receptor gene polymorphism
(A118G) alters HPA axis activation induced by opioid receptor blockade.
41 Mogil JS, Ritchie J, Smith SB et al. Melanocortin-1 receptor gene variants affect pain
and mu-opioid analgesia in mice and humans. J Med Genet 2005;42:583–7.
42 Cardon LR, Bell JI. Association study designs for complex diseases. Nat Rev Genet
43 Cordell HJ, Clayton DG. Genetic association studies. Lancet 2005;366:1121–31.
44 Belfer I, Wu T, Kingman A, Krishnaraju RK, Goldman D, Max MB. Candidate gene
studies of human pain mechanisms: methods for optimizing choice of polymorphisms
and sample size. Anesthesiology 2004;100:1562–72.
45 Schochat T, Croft P, Raspe H. The epidemiology of fibromyalgia. Workshop of the
Standing Committee on Epidemiology European League Against Rheumatism
(EULAR), Bad Sackingen, 19–21 November 1992. Br J Rheumatol 1994;33:783–6.
46 Wacholder S, Garcia-Closas M, Rothman N. Study of genes and environmental
factors in complex diseases. Lancet 2002;359:1155.
47 Yunus MB, Khan MA, Rawlings KK, Green JR, Olson J, Shah S. Genetic linkage
analysisof multicasefamilies with
48 Arnold LM, Iyengar SK, Khan MA et al. Genetic linkage of fibromyalgia to the
serotonin receptor 2A region on chromosome 13 and the HLA region on
chromosome 6. Arthritis Rheum 2003;48:S228–9.
49 Mogil JS, Wilson SG, Chesler EJ et al. The melanocortin-1 receptor gene mediates
female-specific mechanisms of analgesia in mice and humans. Proc Natl Acad Sci
50 Mogil JS, Richards SP, O’Toole LA et al. Identification of a sex-specific quantitative
trait locus mediating nonopioid stress-induced analgesia in female mice. J Neurosci
51 Costigan M, Befort K, Karchewski L et al. Replicate high-density rat genome
oligonucleotide microarrays reveal hundreds of regulated genes in the dorsal root
ganglion after peripheral nerve injury. BMC Neurosci 2002;3:16.
52 Lichtman AH, Shelton CC, Advani T, Cravatt BF. Mice lacking fatty acid amide
hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia. Pain
53 Balding DJ. A tutorial on statistical methods for population association studies.
Nat Rev Genet 2006;7:781–91.
54 Cardon LR, Palmer LJ. Population stratification and spurious allelic association.
55 Wang Y, Localio R, Rebbeck TR. Evaluating bias due to population stratification
in case-control association studies of admixed populations. Genet Epidemiol
56 Edwards CL, Fillingim RB, Keefe F. Race, ethnicity and pain. Pain 2001;94:133–7.
57 Reyes-Gibby CC, Aday LA, Todd KH, Cleeland CS, Anderson KO. Pain in aging
community-dwelling adults in the United States: non-Hispanic whites, non-Hispanic
blacks, and Hispanics. J Pain 2007;8:75–84.
58 Campbell CM, Edwards RR, Fillingim RB. Ethnic differences in responses to multiple
experimental pain stimuli. Pain 2005;113:20–6.
59 Benjamin S, Morris S, McBeth J, Macfarlane GJ, Silman AJ. The association
between chronic widespread pain and mental disorder: a population-based study.
Arthritis Rheum 2000;43:561–7.
60 Lesch KP, Bengel D, Heils A et al. Association of anxiety-related traits with a
polymorphism in the serotonin transporter gene regulatory region. Science 1996;274:
61 Ioannidis JP. Why most published research findings are false. PLoS Med
62 Compton P, Geschwind DH, Alarcon M. Association between human mu-opioid
receptor gene polymorphism, pain tolerance, and opioid addiction. Am J Med Genet
B Neuropsychiatr Genet 2003;121:76–82.
Genetics of chronic widespread pain577
by guest on June 12, 2013