Supplementary Table 2 | Genes implicated in human musculoskeletal pain conditions
Gene
ADRA1A (α1A adrenergic
receptor)
Disease
FibromyalgiaS47
Associated intermediate phenotype
FIQ total score and disability, morning stiffness and
tiredness upon awakening scoresS47
ADRB2 (β2 adrenergic receptor)
FibromyalgiaS47,S48
TMDS49
CWPS50
APOE (apolipoprotein E)
NA
Sleep dysfunction in fibromyalgia,S48 lower PBMC
basal and isoproterenol-stimulated cAMP levels,S48
psychological distress: somatic awareness, anxiety,
depression and high blood pressureS49
Interaction with high stressS51and with traumaS52 in
fibromyalgia
BDNF (brain-derived neurotrophic
factor)
NA
Altered cortical pain processing in LBP,S53
BMI and serum high-sensitivity CRP in fibromyalgiaS54
CACNA2D3 (voltage-dependent
calcium channel subunit α2δ3)
COMT (Catechol Omethyltransferase)
LBPS55
NA
Fibromyalgia S56–S61
TMDS62
CRHBP (corticotropin-releasing
factor-binding protein)
DRD3 (D3 dopamine receptor)
DRD4 (D4 dopamine receptor)
ESR1 (estrogen receptor)
NA
In fibromyalgia: FIQ total score,S56,S60 and pain,
fatigue, sleep disturbance, morning stiffness and
disability scores;S56 number of tender pressure
points;S58 thermal and pressure pain sensitivity;S61pain
and positive affect interaction;S63 pain
catastrophizing;S64 pain level during elevated pain
attention;S64 psychological distressS65
In TMD: experimental pain sensitivity;S62 interaction
with orthodontic treatment;S66 efficacy of propranolol
treatmentS67
In LBP: altered cortical pain processing;S53 pain
intensity;S68 and treatment outcomeS68–S70
Number of painful body sitesS71
NA
FibromyalgiaS73
TMDS74
DNIC efficacy,S72 thermal pain thresholdS72
TPQ: novelty-seeking personality traitsS73
Craniofacial morphology in TMD,S75 and pain
sensitivity in temporomandibular joint osteoarthritis S76
GABRB3 (γ-aminobutyric acid
receptor subunit β3)
GCH1 (GTP cyclohydrolase 1)
HLA/MHC region
HTR2A (5-hydroxytryptamine
receptor 2A)
FibromyalgiaS77
NA
LBPS78
FibromyalgiaS80–S82
FibromyalgiaS83,S84
TMDS85
Treatment outcome in LBPS79
NA
TPC,S83 lower perception of environmental quality,S84
SCL-90-R total and subscales of somatization,
anxiety, psychosis, obsessive-compulsive, hostility,
global severity index, interpersonal sensitivity, phobic
anxiety, depression;S86 pain intensity in
fibromyalgia;S86 somatic symptom countS87
IL1A (IL-1α)
IL1B (IL-1β)
IL1RN (IL-1 receptor antagonist)
KCNS1 (potassium voltage-gated
channel subfamily S member 1)
MAOA (amine oxidase-A)
MC2R (adrenocorticotropic
hormone receptor)
MEFV (pyrin)
OPRM1 (μ-type opioid receptor)
POMC (pro-opiomelanocortin)
SCN9A (sodium channel protein
type 9 subunit α)
SERPINA1 (α1-antitrypsin)
NA
NA
LBPS88
LBPS89
Pain intensity in LBPS88
Frequency of pain in LBPS88
Pain intensity in LBPS88
NA
FibromyalgiaS90
CWPS71
FIQ total scoreS90
NA
FibromyalgiaS91
NA
NA
FibromyalgiaS93
Plasma IL-1β levelS91
Treatment outcome in LBPS92
Number of painful body sitesS71
FIQ totalS93
SLC6A4 (sodium-dependant
serotonin transporter)
FibromyalgiaS94,S95
CWP S71
FibromyalgiaS96–S98
TMDS99,S100
TAAR1 (trace amine-associated
FibromyalgiaS77
‘Intense creative energy’ risk phenotype,S95
number of painful body sitesS71
BDI score,S96 SCL-90-R,S96 TPQ harm avoidance
trait,S97 salivary cortisol level,S98 leukocyte count,S98
SCL-90 somatization,S99 SCL-90 anger,S99
NA
1
receptor 1)
TPH1 (tryptophan 5-hydroxylase
TMDS101
NA
1)
TPH2 (tryptophan 5-hydroxylase
NA
somatic symptom countS87
2)
Abbreviations: BDI, Beck Depression Index; cAMP, cyclic adenosine monophosphate; CRP, C-reactive protein;
CWP, chronic widespread pain; DNIC, diffuse noxious inhibitory controls; FIQ, Fibromyalgia Impact
Questionnaire; LBP, low back pain; NA, not applicable; PBMC, peripheral blood mononuclear cell; SCL-90,
symptom checklist-90; SCL-90-R, SCL-90 Revised; TMD, temporomandibular joint disorder; TPC, tender point
count; TPQ, Tridimensional Personality Questionnaire; VAS, visual analog scale.
S47.
Vargas-Alarcón, G. et al. Association of adrenergic receptor gene polymorphisms with different
fibromyalgia syndrome domains. Arthritis Rheum. 60, 2169–2173 (2009).
S48.
Xiao, Y., He, W. & Russell, I. J. Genetic polymorphisms of the β2-adrenergic receptor relate to guanosine
protein-coupled stimulator receptor dysfunction in fibromyalgia syndrome. J. Rheumatol. 38, 1095–1103
(2011).
S49.
Diatchenko, L. et al. Three major haplotypes of the β2 adrenergic receptor define psychological profile,
blood pressure, and the risk for development of a common musculoskeletal pain disorder. Am. J. Med. Genet.
B 141B, 449–462 (2006).
S50.
Hocking, L. J. et al. Genetic variation in the β2-adrenergic receptor but not
catecholamine-O-methyltransferase predisposes to chronic pain: results from the British Birth Cohort Study.
Pain 149, 143–151 (2010) (1958).
S51.
Becker, R. M. et al. Association between environmental quality, stress, and APOE gene variation in
fibromyalgia susceptibility determination. Rev. Bras. Reumatol. 50, 617–24 (2010).
S52.
Reeser, J. C., Payne, E., Kitchner, T. & McCarty, C. A. Apolipoprotein E4 genotype increases the risk of
being diagnosed with posttraumatic fibromyalgia. PM R 3, 193–197 (2011).
S53.
Vossen, H. et al. The genetic influence on the cortical processing of experimental pain and the moderating
effect of pain status. PLoS One 5, e13641 (2010).
S54.
Xiao, Y., Russell, I. & Liu, Y. G. A brain-derived neurotrophic factor polymorphism Val66Met identifies
fibromyalgia syndrome subgroup with higher body mass index and C-reactive protein. Rheumatol. Int. 32, 1–7
(2011).
S55.
Neely, G. G. et al. A genome-wide Drosophila screen for heat nociception identifies α2δ3 as an
evolutionarily conserved pain gene. Cell 143, 628–638 (2010).
S56.
Vargas-Alarcón, G. et al. Catechol-O-methyltransferase gene haplotypes in Mexican and Spanish patients
with fibromyalgia. Arthritis Res. Ther. 9, R110 (2007).
S57.
Gursoy, S. et al. Significance of catechol-O-methyltransferase gene polymorphism in fibromyalgia
syndrome. Rheumatol. Int. 23, 104–107 (2003).
S58.
Cohen, H., Nuemann, L., Glazer, Y., Ebstein, R. P. & Buskila, D. The relationship between a common
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S59.
Matsuda, J. B. et al. Serotonin receptor (5-HT 2A) and catechol-O-methyltransferase (COMT) gene
polymorphisms: triggers of fibromyalgia? Rev. Bras. Reumatol. 50, 145–149 (2010).
S60.
Barbosa, F. et al. Influence of catechol-O-methyltransferase (COMT) gene polymorphisms in pain
sensibility of Brazilian fibromialgia patients. Rheumatol. Int. 32, 427–430 (2012).
S61.
Martínez-Jauand, M. et al. Pain sensitivity in fibromyalgia is associated with catechol-O-methyltransferase
(COMT) gene. Eur. J. Pain 17, 16–27 (2012).
S62.
Diatchenko, L. et al. Genetic basis for individual variations in pain perception and the development of a
chronic pain condition. Hum. Mol. Genet. 14, 135–143 (2005).
S63.
Finan, P. H. et al. Genetic influences on the dynamics of pain and affect in fibromyalgia. Health Psychol.
29, 134–142 (2010).
S64.
Finan, P. H. et al. COMT moderates the relation of daily maladaptive coping and pain in fibromyalgia. Pain
152, 300–307 (2011).
S65.
Desmeules, J. et al. Psychological distress in fibromyalgia patients: A role for
catechol-O-methyltransferase Val158met polymorphism. Health Psychol. 31, 242–249 (2012).
S66.
Slade, G., Diatchenko, L., Ohrbach, R. & Maixner, W. Orthodontic treatment, genetic factors, and risk of
temporomandibular disorder. Semin. Orthod. 14, 146–156 (2008).
S67.
Tchivileva, I. E. et al. Effect of catechol-O-methyltransferase polymorphism on response to propranolol
therapy in chronic musculoskeletal pain: a randomized, double-blind, placebo-controlled, crossover pilot study.
Pharmacogenet. Genomics 20, 239–248 (2010).
S68.
Jacobsen, L. M. et al. The COMT rs4680 Met allele contributes to long-lasting low back pain, sciatica and
disability after lumbar disc herniation. Eur. J. Pain 16, 1064–1069 (2012).
S69.
Dai, F. et al. Association of catechol-O-methyltransferase genetic variants with outcome in patients
undergoing surgical treatment for lumbar degenerative disc disease. Spine J. 10, 949–957 (2010).
S70.
Omair, A., Lie, B., Reikeras, O., Holden, M. & Brox, J. Genetic contribution of
catechol-O-methyltransferase variants in treatment outcome of low back pain: a prospective genetic
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S71.
Holliday, K. L. et al. Genetic variation in the hypothalamic-pituitary-adrenal stress axis influences
2
susceptibility to musculoskeletal pain: results from the EPIFUND study. Ann. Rheum. Dis. 69, 556–560 (2010).
S72.
Potvin, S. et al. DRD3 Ser9Gly polymorphism is related to thermal pain perception and modulation in
chronic widespread pain patients and healthy controls. J. Pain 10, 969–975 (2009).
S73.
Buskila, D., Cohen, H., Neumann, L. & Ebstein, R. P. An association between fibromyalgia and the
dopamine D4 receptor exon III repeat polymorphism and relationship to novelty seeking personality traits. Mol.
Psychiatry 9, 730–731 (2004).
S74.
Ribeiro-Dasilva, M. C. et al. Estrogen receptor-α polymorphisms and predisposition to TMJ disorder. J.
Pain 10, 527–533 (2009).
S75.
Lee, D. G., Kim, T. W., Kang, S. C. & Kim, S. T. Estrogen receptor gene polymorphism and craniofacial
morphology in female TMJ osteoarthritis patients. Int. J. Oral Maxillofac. Surg. 35, 165–169 (2006).
S76.
Kang, S. C. et al. Association between estrogen receptor polymorphism and pain susceptibility in female
temporomandibular joint osteoarthritis patients. Int. J. Oral Maxillofac. Surg. 36, 391–394 (2007).
S77.
Smith, S. B. et al. Large candidate gene association study reveals genetic risk factors and therapeutic
targets for fibromyalgia. Arthritis Rheum. 64, 584–593 (2012).
S78.
Tegeder, I. et al. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence.
Nat. Med. 12, 1269–1277 (2006).
S79.
Kim, D. H. et al. Polymorphic variation of the guanosine triphosphate cyclohydrolase 1 gene predicts
outcome in patients undergoing surgical treatment for lumbar degenerative disc disease. Spine 25, 1909–1914
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S80.
Burda, C., Cox, F. & P, O. Histocompatibility antigens in the fibrositis (fibromyalgia) syndrome. Clin. Exp.
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S81.
Branco, J. C., Tavares, V., Abreu, I., Correia, M. M. & Caetano, J. A. HLA studies in fibromyalgia. J.
Muscoskelet. Pain 4, 21–27 (1996).
S82.
Yunus, M. B. Genetic factors in fibromyalgia syndrome. Z. Rheumatol. 57, S61–S62 (1998).
S83.
Bondy, B. et al. The T102C polymorphism of the 5-HT2A receptor gene in fibromyalgia. Neurobiol. Dis. 6,
433–439 (1999).
S84.
Mergener, M., Becker, R. M., dos Santos, A. F., dos Santos, G. A. & de Andrade, F. M. Influence of the
interaction between environmental quality and T102C SNP in the HTR2A gene on fibromyalgia susceptibility.
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S85.
Mutlu, N., Erdal, M., Herken, H., Oz, G. & Bayazit, Y. T102C polymorphism of the 5-HT2A receptor gene
may be associated with temporomandibular dysfunction. Oral Dis. 10, 349–352 (2004).
S86.
Gursoy, S., Erdal, E., Herken, H., Madenci, E. & Alasehirli, B. Association of T102C polymorphism of the
5-HT2A receptor gene with pyschiatric status in fibromyalgia syndrome. Rheumatol. Int. 21, 58–61 (2001).
S87.
Holliday, K. L. et al. Genetic variation in neuroendocrine genes associates with somatic symptoms in the
general population: Results from the EPIFUND study. J. Psychosom. Res. 68, 469–474 (2010).
S88.
Solovieva, S. et al. Possible association of interleukin 1 gene locus polymorphisms with low back pain.
Pain 109, 8–19 (2004).
S89.
Costigan, M. et al. Multiple chronic pain states are associated with a common amino acid-changing allele
in KCNS1. Brain 133, 2519–2527 (2010).
S90.
Gursoy, S. et al. Which genotype of MAO gene that the patients have are likely to be most susceptible to
the symptoms of fibromyalgia? Rheumatol. Int. 28, 307–311 (2008).
S91.
Feng, J. et al. Missense mutations in the MEFV gene are associated with fibromyalgia syndrome and
correlate with elevated IL-1β plasma levels. PLoS ONE 4, e8480 (2009).
S92.
Olsen, M. B. et al. Pain intensity the first year after lumbar disc herniation is associated with the A118G
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S93.
Vargas-Alarcón, G. et al. A SCN9A gene-encoded dorsal root ganglia sodium channel polymorphism
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S94.
Blanco, I. et al. α1-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
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S95.
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S96.
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S97.
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S98.
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S99.
Herken, H. et al. Possible association of temporomandibular joint pain and dysfunction with a
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