Review Article | Published:

The phenotypic and genetic signatures of common musculoskeletal pain conditions

Nature Reviews Rheumatology volume 9, pages 340350 (2013) | Download Citation

Abstract

Musculoskeletal pain conditions, such as fibromyalgia and low back pain, tend to coexist in affected individuals and are characterized by a report of pain greater than expected based on the results of a standard physical evaluation. The pathophysiology of these conditions is largely unknown, we lack biological markers for accurate diagnosis, and conventional therapeutics have limited effectiveness. Growing evidence suggests that chronic pain conditions are associated with both physical and psychological triggers, which initiate pain amplification and psychological distress; thus, susceptibility is dictated by complex interactions between genetic and environmental factors. Herein, we review phenotypic and genetic markers of common musculoskeletal pain conditions, selected based on their association with musculoskeletal pain in previous research. The phenotypic markers of greatest interest include measures of pain amplification and 'psychological' measures (such as emotional distress, somatic awareness, psychosocial stress and catastrophizing). Genetic polymorphisms reproducibly linked with musculoskeletal pain are found in genes contributing to serotonergic and adrenergic pathways. Elucidation of the biological mechanisms by which these markers contribute to the perception of pain in these patients will enable the development of novel effective drugs and methodologies that permit better diagnoses and approaches to personalized medicine.

Key points

  • Musculoskeletal pain conditions such as low back pain, chronic widespread pain, fibromyalgia and temporomandibular joint disorders are highly prevalent

  • These conditions have measurable phenotypic signatures, which are heterogeneous in nature

  • Musculoskeletal pain conditions have a genetic basis, with both common and rare genetic variants contributing to the conditions and associated endophenotypes

  • Physical and psychological environmental exposures can produce epigenetic effects that alter gene expression, biological pathway activity, and thus the manifestation of clinical phenotypes of musculoskeletal pain conditions

  • Genetic association studies combined with in vitro and in vivo follow-up studies can identify effective therapeutic agents for the treatment of large subpopulations of patients with musculoskeletal pain conditions

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References

  1. 1.

    Committee on Advancing Pain Research, Care and Education, Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research, 1st edn (The National Academies Press, 2011).

  2. 2.

    & Epidemiology of chronic musculoskeletal pain. Best Pract. Res. Clin. Rheumatol. 21, 403–425 (2007).

  3. 3.

    et al. Study methods, recruitment, sociodemographic findings, and demographic representativeness in the OPPERA study. J. Pain 12 (Suppl.), T12–T26 (2011).

  4. 4.

    et al. Orofacial pain prospective evaluation and risk assessment study—the OPPERA study. J. Pain 12 (11 Suppl.), T4–T11.e2 (2011).

  5. 5.

    , , , & Idiopathic pain disorders—pathways of vulnerability. Pain 123, 226–230 (2006).

  6. 6.

    , , & Sensitivity of patients with painful temporomandibular disorders to experimentally evoked pain. Pain 63, 341–351 (1995).

  7. 7.

    , , , & Sensitivity of patients with painful temporomandibular disorders to experimentally evoked pain: evidence for altered temporal summation of pain. Pain 76, 71–81 (1998).

  8. 8.

    & Assessment of mechanisms in localized and widespread musculoskeletal pain. Nat. Rev. Rheumatol. 6, 599–606 (2010).

  9. 9.

    Central sensitization: implications for the diagnosis and treatment of pain. Pain 152 (Suppl.), S2–S15 (2011).

  10. 10.

    et al. Potential psychosocial risk factors for chronic TMD: descriptive data and empirically identified domains from the OPPERA case–control study. J. Pain 12 (Suppl.), T46–T60 (2011).

  11. 11.

    et al. Clinical findings and pain symptoms as potential risk factors for chronic TMD: descriptive data and empirically identified domains from the OPPERA case–control study. J. Pain 12 (Suppl.) T27–T45 (2011).

  12. 12.

    et al. Fibromyalgia syndrome in chronic disabling occupational musculoskeletal disorders: prevalence, risk factors, and posttreatment outcomes. J. Occup. Environ. Med. 52, 1186–1191 (2010).

  13. 13.

    et al. Role of road traffic accidents and other traumatic events in the onset of chronic widespread pain: results from a population-based prospective study. Arthritis Care Res. (Hoboken) 63, 696–701 (2011).

  14. 14.

    et al. Signaling pathways mediating β3-adrenergic receptor-induced production of interleukin-6 in adipocytes. Mol. Immunol. 46, 2256–2266 (2009).

  15. 15.

    , & Persistent postsurgical pain: risk factors and prevention. Lancet 367, 1618–1625 (2006).

  16. 16.

    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).

  17. 17.

    , , , & Genetic architecture of human pain perception. Trends Genet. 23, 605–613 (2007).

  18. 18.

    & The endophenotype concept in psychiatry: etymology and strategic intentions. Am. J. Psychiatry. 160, 636–645 (2003).

  19. 19.

    et al. Core outcome domains for chronic pain clinical trials: IMMPACT recommendations. Pain 106, 337–345 (2003).

  20. 20.

    & Reliability and validity of verbal descriptor scales of painfulness. Pain 29, 175–185 (1987).

  21. 21.

    , & The measurement of clinical pain intensity: a comparison of six methods. Pain 27, 117–126 (1986).

  22. 22.

    , , & Expanding options for developing outcome measures from momentary assessment data. Psychosom. Med. 74, 387–397 (2012).

  23. 23.

    The McGill Pain Questionnaire: major properties and scoring methods. Pain 1, 277–299 (1975).

  24. 24.

    et al. Sensory pain qualities in neuropathic pain. J. Pain 13, 58–63 (2012).

  25. 25.

    , , & Chronic myofascial temporomandibular pain is associated with neural abnormalities in the trigeminal and limbic systems. Pain 149, 222–228 (2010).

  26. 26.

    , , , & Self-reported assessment of disability and performance-based assessment of disability are influenced by different patient characteristics in acute low back pain. Eur. Spine J. 19, 633–640 (2010).

  27. 27.

    et al. Factors associated with functional capacity test results in patients with non-specific chronic low back pain: a systematic review. J. Occup. Rehabil. 21, 455–473 (2011).

  28. 28.

    , , , & Responsiveness of the physical work performance evaluation, a functional capacity evaluation, in patients with low back pain. J. Occup. Rehabil. 18, 58–67 (2008).

  29. 29.

    et al. Physical fitness in postmenopausal women with fibromyalgia. Int. J. Sports Med. 29, 408–413 (2008).

  30. 30.

    et al. Relevance of physical fitness levels and exercise-related beliefs for self-reported and experimental pain in fibromyalgia: an explorative study. J. Clin. Rheumatol. 17, 295–301 (2011).

  31. 31.

    , & The relationship between physical activity and brain responses to pain in fibromyalgia. J. Pain 12, 640–651 (2011).

  32. 32.

    , , , & Factors contributing to physical activity in a chronic low back pain clinical sample: A comprehensive analysis using continuous ambulatory monitoring. Pain 152, 2521–2527 (2011).

  33. 33.

    et al. Actigraphy-based physical activity monitoring in adolescents with juvenile primary fibromyalgia syndrome. J. Pain 11, 885–893 (2010).

  34. 34.

    , , , & The biopsychosocial approach to chronic pain: scientific advances and future directions. Psychol. Bull. 133, 581–624 (2007).

  35. 35.

    , & Psychological evaluation of patients diagnosed with fibromyalgia syndrome: a comprehensive approach. Rheum. Dis. Clin. North Am. 28, 219–233 (2002).

  36. 36.

    , , , & Mechanical injury and psychosocial factors in the work place predict the onset of widespread body pain: a two-year prospective study among cohorts of newly employed workers. Arthritis Rheum. 50, 1655–1664 (2004).

  37. 37.

    A review of psychological risk factors in back and neck pain. Spine 25, 1148–1156 (2000).

  38. 38.

    et al. The role of psychosocial factors in predicting the onset of chronic widespread pain: results from a prospective population-based study. Rheumatology (Oxford) 46, 666–671 (2007).

  39. 39.

    , , & Features of somatization predict the onset of chronic widespread pain: results of a large population-based study. Arthritis Rheum. 44, 940–946 (2001).

  40. 40.

    , & Adverse events in childhood and chronic widespread pain in adult life: results from the 1958 British Birth Cohort Study. Pain 143, 92–96 (2009).

  41. 41.

    , , & Risk factors for onset of chronic oro-facial pain--results of the North Cheshire oro-facial pain prospective population study. Pain 149, 354–359 (2010).

  42. 42.

    , , , & Trajectories of pain in adolescents: a prospective cohort study. Pain 152, 66–73 (2011).

  43. 43.

    , & 3rd. A model for predicting chronic TMD: practical application in clinical settings. J. Am. Dent. Assoc. 130, 1470–1475 (1999).

  44. 44.

    et al. Predicting persistent disabling low back pain in general practice: a prospective cohort study. Br. J. Gen. Pract. 56, 334–341 (2006).

  45. 45.

    et al. Quantitative sensory testing: a comprehensive protocol for clinical trials. Eur. J. Pain 10, 77–88 (2006).

  46. 46.

    et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1,236 patients with different neuropathic pain syndromes. Pain 150, 439–450 (2010).

  47. 47.

    et al. A cross-sectional survey of 3,035 patients with fibromyalgia: subgroups of patients with typical comorbidities and sensory symptom profiles. Rheumatology (Oxford). 49, 1146–1152 (2010).

  48. 48.

    , , , & Somatosensory profiles in subgroups of patients with myogenic temporomandibular disorders and fibromyalgia syndrome. Pain 147, 72–83 (2009).

  49. 49.

    , , , & Nondermatomal somatosensory deficits in patients with chronic pain disorder: clinical findings and hypometabolic pattern in FDG-PET. Pain 145, 252–258 (2009).

  50. 50.

    , & Somatosensory perception in patients suffering from long-term trapezius myalgia at the site overlying the most painful part of the muscle and in an area of pain referral. Eur. J. Pain 7, 267–276 (2003).

  51. 51.

    , , & Thermal detection and pain thresholds but not pressure pain thresholds are correlated with psychological factors in women with chronic whiplash-associated pain. Clin. J. Pain 28, 211–221 (2012).

  52. 52.

    , , & Mechanical and heat hyperalgesia highly predict clinical pain intensity in patients with chronic musculoskeletal pain syndromes. J. Pain 13, 725–735 (2012).

  53. 53.

    , , & Quantitative assessment of experimental pain perception: multiple domains of clinical relevance. Pain 114, 315–319 (2005).

  54. 54.

    & Wind-up and neuroplasticity: is there a correlation to clinical pain? Eur. J. Anaesthesiol. Suppl. 10, 1–7 (1995).

  55. 55.

    Wind-up and the NMDA receptor complex from a clinical perspective. Eur. J. Pain 4, 5–15 (2000).

  56. 56.

    et al. Enhanced temporal summation of second pain and its central modulation in fibromyalgia patients. Pain 99, 49–59 (2002).

  57. 57.

    et al. Recommendations on terminology and practice of psychophysical DNIC testing. Eur. J. Pain 14, 339 (2010).

  58. 58.

    et al. Deficiency in endogenous modulation of prolonged heat pain in patients with irritable bowel syndrome and temporomandibular disorder. Pain 143, 172–178 (2009).

  59. 59.

    , , & Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients. Pain 101, 167–174 (2003).

  60. 60.

    Autonomic dysfunction in fibromyalgia syndrome: postural orthostatic tachycardia. Curr. Rheumatol. Rep. 10, 463–466 (2008).

  61. 61.

    et al. Adrenergic dysregulation and pain with and without acute beta-blockade in women with fibromyalgia and temporomandibular disorder. J. Pain 10, 542–552 (2009).

  62. 62.

    et al. Attenuated adrenergic responses to exercise in women with fibromyalgia—a controlled study. Eur. J. Pain 12, 351–360 (2008).

  63. 63.

    Biology and therapy of fibromyalgia. Stress, the stress response system, and fibromyalgia. Arthritis Res. Ther. 9, 216 (2007).

  64. 64.

    , , & Altered autonomic function in patients with arthritis or with chronic myofascial pain. Pain 39, 77–84 (1989).

  65. 65.

    , , , & Orthostatic sympathetic derangement of baroreflex in patients with fibromyalgia. J. Rheumatol. 25, 823–825 (1998).

  66. 66.

    , , & Autonomic cardiovascular control and responses to experimental pain stimulation in fibromyalgia syndrome. J. Psychosom. Res. 70, 125–134 (2011).

  67. 67.

    , , & Perceived disability but not pain is connected with autonomic nervous function among patients with chronic low back pain. J. Rehabil. Med. 40, 355–358 (2008).

  68. 68.

    et al. Abnormalities of cardiovascular neural control and reduced orthostatic tolerance in patients with primary fibromyalgia. J. Rheumatol. 32, 1787–1793 (2005).

  69. 69.

    et al. The plasma endorphin, prostaglandin and catecholamine profile of patients with fibrositis treated with cyclobenzaprine and placebo: a 5-month study. J. Rheumatol. Suppl. 19, 164–168 (1989).

  70. 70.

    et al. Cerebrospinal fluid biogenic amine metabolites, plasma-rich platelet serotonin and [3H]imipramine reuptake in the primary fibromyalgia syndrome. Rheumatology (Oxford) 40, 290–296 (2001).

  71. 71.

    , , , & Plasma and urinary catecholamines in primary fibromyalgia: a controlled study. J. Rheumatol. 19, 95–97 (1992).

  72. 72.

    et al. Potential autonomic risk factors for chronic TMD: descriptive data and empirically identified domains from the OPPERA case–control study. J. Pain 12 (Suppl.), T75–T91 (2011).

  73. 73.

    et al. Cluster analysis of multiple experimental pain modalities. Pain 116, 227–237 (2005).

  74. 74.

    et al. A novel tool for the assessment of pain: validation in low back pain. PLoS Med. 6, e1000047 (2009).

  75. 75.

    , , , & Temporomandibular disorder subtypes according to self-reported physical and psychosocial variables in female patients: a re-evaluation. J. Oral Rehabil. 32, 166–173 (2005).

  76. 76.

    , & Heterogeneity of temporomandibular disorders: cluster and case–control analyses. J. Oral Rehabil. 29, 969–979 (2002).

  77. 77.

    , , & Heterogeneity within the fibromyalgia population: theoretical implications of variable tender point severity ratings. J. Rheumatol. 36, 2795–2801 (2009).

  78. 78.

    et al. Subgrouping of fibromyalgia patients on the basis of pressure-pain thresholds and psychological factors. Arthritis Rheum. 48, 2916–2922 (2003).

  79. 79.

    , , , & Delineating psychological and biomedical profiles in a heterogeneous fibromyalgia population using cluster analysis. Clin. Rheumatol. 31, 677–685 (2012).

  80. 80.

    , & The Elements of Statistical Learning: Data Mining, Inference, and Prediction. 2nd edn (Springer, New York, 2009).

  81. 81.

    , & Latent class analysis of functional somatic symptoms in a population-based sample of twins. J. Psychosom. Res. 68, 447–453 (2010).

  82. 82.

    , & Heritability of neck pain: a population-based study of 33,794 Danish twins. Rheumatology (Oxford) 45, 589–594 (2006).

  83. 83.

    , & Pain reporting at different body sites is explained by a single underlying genetic factor. Rheumatology (Oxford) 49, 1753–1755 (2010).

  84. 84.

    et al. Clustering of symptoms associated with fibromyalgia in a Finnish Twin Cohort. Eur. J. Pain 13, 744–750 (2009).

  85. 85.

    et al. Catechol-O-methyltransferase gene haplotypes in Mexican and Spanish patients with fibromyalgia. Arthritis Res. Ther. 9, R110 (2007).

  86. 86.

    et al. Significance of catechol-O-methyltransferase gene polymorphism in fibromyalgia syndrome. Rheumatol. Int. 23, 104–107 (2003).

  87. 87.

    et al. Serotonin receptor (5-HT 2A) and catechol-O-methyltransferase (COMT) gene polymorphisms: triggers of fibromyalgia? Rev. Bras. Reumatol. 50, 141–149 (2010).

  88. 88.

    et al. Influence of catechol-O-methyltransferase (COMT) gene polymorphisms in pain sensibility of Brazilian fibromialgia patients. Rheumatol. Int. 32, 427–430 (2012).

  89. 89.

    , , , & The relationship between a common catechol-O-methyltransferase (COMT) polymorphism val(158) met and fibromyalgia. Clin. Exp. Rheumatol. 27 (Suppl. 56), S51–S56 (2009).

  90. 90.

    et al. Pain sensitivity in fibromyalgia is associated with catechol-O-methyltransferase (COMT) gene. Eur. J. Pain 17, 16–27 (2013).

  91. 91.

    et al. Potential genetic risk factors for chronic TMD: genetic associations from the OPPERA case–control study. J. Pain 12 (Suppl.), T92–T101 (2011).

  92. 92.

    et al. Genetic variation in the β2-adrenergic receptor but not catecholamine-O-methyltransferase predisposes to chronic pain: results from the 1958 British Birth Cohort Study. Pain 149, 143–151 (2010).

  93. 93.

    , & Genetic polymorphisms of the β2-adrenergic receptor relate to guanosine protein-coupled stimulator receptor dysfunction in fibromyalgia syndrome. J. Rheumatol. 38, 1095–103 (2011).

  94. 94.

    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, Neuropsychiatr. Genet. 141B, 449–462 (2006).

  95. 95.

    et al. Possible association of fibromyalgia with a polymorphism in the serotonin transporter gene regulatory region. Arthritis Rheum. 42, 2482–2488 (1999).

  96. 96.

    , , & Confirmation of an association between fibromyalgia and serotonin transporter promoter region (5-HTTLPR) polymorphism, and relationship to anxiety-related personality traits. Arthritis Rheum. 46, 845–847 (2002).

  97. 97.

    et al. May genetic factors in fibromyalgia help to identify patients with differentially altered frequencies of immune cells? Clin. Exp. Immunol. 154, 346–352 (2008).

  98. 98.

    , , & Temporomandibular disorder is associated with a serotonin transporter gene polymorphism in the Japanese population. Biopsychosoc. Med. 1, 3 (2007).

  99. 99.

    et al. Possible association of temporomandibular joint pain and dysfunction with a polymorphism in the serotonin transporter gene. Am. J. Orthod. Dentofacial Orthop. 120, 308–313 (2001).

  100. 100.

    et al. The T102C polymorphism of the 5-HT2A-receptor gene in fibromyalgia. Neurobiol. Dis. 6, 433–439 (1999).

  101. 101.

    , , , & Influence of the interaction between environmental quality and T102C SNP in the HTR2A gene on fibromyalgia susceptibility. Rev. Bras. Reumatol. 51, 594–602 (2011).

  102. 102.

    , , , & T102C polymorphism of the 5-HT2A receptor gene may be associated with temporomandibular dysfunction. Oral Dis. 10, 349–352 (2004).

  103. 103.

    , & Histocompatibility antigens in the fibrositis (fibromyalgia) syndrome. Clin. Exp. Rheumatol. 4, 355–358 (1986).

  104. 104.

    , , , & HLA studies in fibromyalgia. J. Muscoskelet. Pain 4, 21–27 (1996).

  105. 105.

    , , & HLA antigens in primary fibromyalgia syndrome. J. Rheumatol. 19, 1269–1270 (1992).

  106. 106.

    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 population. J. Muscoskelet. Pain 14, 5–12 (2006).

  107. 107.

    & Fibromyalgia, mood disorders, and intense creative energy: A1AT polymorphisms are not always silent. Neurotoxicology 33, 1454–1472 (2012).

  108. 108.

    et al. The genetic influence on the cortical processing of experimental pain and the moderating effect of pain status. PLoS ONE 5, e13641 (2010).

  109. 109.

    et al. Psychological distress in fibromyalgia patients: a role for catechol-O-methyl-transferase Val158met polymorphism. Health Psychol. 31, 242–249 (2012).

  110. 110.

    , , , & Association of T102C polymorphism of the 5-HT2A receptor gene with pyschiatric status in fibromyalgia syndrome. Rheumatol. Int. 21, 58–61 (2001).

  111. 111.

    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).

  112. 112.

    et al. Study methods, recruitment, sociodemographic findings, and demographic representativeness in the OPPERA study. J. Pain 12 (Suppl.), T12–T26 (2011).

  113. 113.

    et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–713 (2010).

  114. 114.

    & Genetics of human cardiovascular disease. Cell 148, 1242–1257 (2012).

  115. 115.

    et al. Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli. Pain 125, 216–224 (2006).

  116. 116.

    et al. Comt1 genotype and expression predicts anxiety and nociceptive sensitivity in inbred strains of mice. Genes Brain Behav. 9, 933–946 (2010).

  117. 117.

    et al. Catechol-O-methyltransferase inhibition increases pain sensitivity through activation of both β2- and β3-adrenergic receptors. Pain 128, 199–208 (2007).

  118. 118.

    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).

  119. 119.

    et al. Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science 314, 1930–1933 (2006).

  120. 120.

    & Catechol-O-methyltransferase and pain. Int. Rev. Neurobiol. 95, 227–279 (2010).

  121. 121.

    et al. Association of adrenergic receptor gene polymorphisms with different fibromyalgia syndrome domains. Arthritis Rheum. 60, 2169–2173 (2009).

  122. 122.

    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. Part B 141B, 449–462 (2006).

  123. 123.

    et al. COMT moderates the relation of daily maladaptive coping and pain in fibromyalgia. Pain 152, 300–307 (2011).

  124. 124.

    et al. Genetic influences on the dynamics of pain and affect in fibromyalgia. Health Psychol. 29, 134–142 (2010).

  125. 125.

    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).

  126. 126.

    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).

  127. 127.

    , , , & Genetic contribution of catechol-O-methyltransferase variants in treatment outcome of low back pain: a prospective genetic association study. BMC Musculoskelet. Disord. 13, 76 (2012).

  128. 128.

    , , & Orthodontic treatment, genetic factors, and risk of temporomandibular disorder. Semin. Orthod. 14, 146–156 (2008).

  129. 129.

    Genetic factors in fibromyalgia syndrome. Z. Rheumatol. 57 (Suppl. 2), S61–S62 (1998).

  130. 130.

    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).

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Acknowledgements

The authors' work is supported in part by grants from NIDCR, NIA and NINDS, R01-DE16558, U01-DE017018, 1K12DSE022793, AG033906, and P01 NS045685. The authors are grateful to Kirsten Ambrose for assistance with preparation of this manuscript.

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Affiliations

  1. Regional Center for Neurosensory Disorders, Koury Oral Health Sciences Building, University of North Carolina, Chapel Hill, NC 27599-7455, USA

    • Luda Diatchenko
    • , Shad B. Smith
    •  & William Maixner
  2.  Public Health Services and Research, College of Dentistry, University of Florida, P.O. Box 100404, Gainesville, FL 32610-0404, USA

    • Roger B. Fillingim

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Contributions

All authors contributed equally to each stage of the preparation of this manuscript for publication.

Competing interests

L. Diatchenko, R. B. Fillingim, S. B. Smith and W. Maixner are consultants for and shareholders in Algynomics.

Corresponding author

Correspondence to Luda Diatchenko.

Supplementary information

Word documents

  1. 1.

    Supplementary Table 1

    Methods of clinical phenotyping and QST endophenotyping in musculoskeletal pain conditions

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    Supplementary Table 2

    Genes implicated in human musculoskeletal pain conditions

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https://doi.org/10.1038/nrrheum.2013.43

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