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
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