1932

Abstract

Pain is an immense clinical and societal challenge, and the key to understanding and treating it is variability. Robust interindividual differences are consistently observed in pain sensitivity, susceptibility to developing painful disorders, and response to analgesic manipulations. This review examines the causes of this variability, including both organismic and environmental sources. Chronic pain development is a textbook example of a gene-environment interaction, requiring both chance initiating events (e.g., trauma, infection) and more immutable risk factors. The focus is on genetic factors, since twin studies have determined that a plurality of the variance likely derives from inherited genetic variants, but sex, age, ethnicity, personality variables, and environmental factors are also considered.

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2021-07-08
2024-12-05
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Literature Cited

  1. Albertsen HM, Chettier R, Farrington P, Ward K 2013. Genome-wide association study link novel loci to endometriosis. PLOS ONE 8:e58257
    [Google Scholar]
  2. Altshuler D, Daly MJ, Lander ES 2008. Genetic mapping in human disease. Science 322:881–88
    [Google Scholar]
  3. Aubrun F, Langeron O, Quesnel C, Coriat P, Riou B 2003. Relationships between measurement of pain using visual analog score and morphine requirements during postoperative intravenous morphine titration. Anesthesiology 98:1415–21
    [Google Scholar]
  4. Bair MJ, Robinson RL, Katon W, Kroenke K 2003. Depression and pain comorbidity: a literature review. Arch. Intern. Med. 163:2433–45
    [Google Scholar]
  5. Barrett CF, van den Maagdenberg AMJM, Frants RR, Ferrari MD 2008. Familial hemiplegic migraine. Adv. Genet. 63:57–83
    [Google Scholar]
  6. Becker JB, Prendergast BJ, Liang JW 2016. Female rats are not more variable than male rats: a meta-analysis of neuroscience studies. Biol. Sex Diff. 7:34
    [Google Scholar]
  7. Belfer I, Segall SK, Lariviere WR, Smith SB, Dai F et al. 2013. Pain modality- and sex-specific effects of COMT functional variants. Pain 154:1368–76
    [Google Scholar]
  8. Beuno CH, Pereira DD, Pattussi MP, Grossi PK, Grossi ML 2018. Gender differences in temporomandibular disorders in adult populational studies: a systematic review and meta-analysis. J. Oral Rehab. 45:720–29
    [Google Scholar]
  9. Bisgaard T, Klarskov B, Rosenberg J, Kehlet H 2001. Characteristics and prediction of early pain after laparoscopic cholecystectomy. Pain 90:261–69
    [Google Scholar]
  10. Bjornsdottir G, Benonisdottir S, Sveinbjornsson G, Styrkarsdottir U, Thorleifsson G et al. 2017. Sequence variant at 8q24.21 associates with sciatica caused by lumbar disc herniation. Nat. Commun. 8:14265
    [Google Scholar]
  11. Boogard S, Heymans MW, De Vet H, Peters ML, Loer SA et al. 2015. Predictors of persistent neuropathic pain—a systematic review. Pain Physician 18:433–57
    [Google Scholar]
  12. Boyle EA, Li YI, Pritchard JK 2017. An expanded view of complex traits: from polygenic to omnigenic. Cell 169:1177–86
    [Google Scholar]
  13. Bruce J, Drury N, Poobalan AS, Jeffrey RR, Smith WCS, Chambers WA 2003. The prevalence of chronic chest and leg pain following cardiac surgery: a historical cohort study. Pain 104:265–73
    [Google Scholar]
  14. Burri A, Ogata S, Rice D, Williams F 2018. Pain catastrophizing, neuroticism, fear of pain, and anxiety: defining the genetic and environmental factors in a sample of female twins. PLOS ONE 13:e0194562
    [Google Scholar]
  15. Burri A, Ogata S, Williams F 2017. Female sexual pain: epidemiology and genetic overlap with chronic widespread pain. Eur. J. Pain 21:1408–16
    [Google Scholar]
  16. Callahan BL, Gil ASC, Levesque A, Mogil JS 2008. Modulation of mechanical and thermal nociceptive sensitivity in the laboratory mouse by behavioral state. J. Pain 9:174–84
    [Google Scholar]
  17. Chatterjee N, Wheeler B, Sampson J, Hartge P, Chanock SJ, Park J-H 2013. Projecting the performance of risk prediction based on polygenic analyses of genome-wide association studies. Nat. Genet. 45:400–5
    [Google Scholar]
  18. Chaturvedi S, Bhatnagar P, Bean CJ, Steinberg MH, Milton JN et al. 2017. Genome-wide association study to identify variants associated with acute severe vaso-occlusive pain in sickle cell anemia. Blood 130:686–88
    [Google Scholar]
  19. Chesler EJ, Wilson SG, Lariviere WR, Rodriguez-Zas SL, Mogil JS 2002a. Identification and ranking of genetic and laboratory environment factors influencing a behavioral trait, thermal nociception, via computational analysis of a large data archive. Neurosci. Biobehav. Rev. 26:907–23
    [Google Scholar]
  20. Chesler EJ, Wilson SG, Lariviere WR, Rodriguez-Zas SL, Mogil JS 2002b. Influences of laboratory environment on behavior. Nat. Neurosci. 5:1101–2
    [Google Scholar]
  21. Chidambaran V, Ashton M, Martin LJ, Jegga AG 2020. Systems biology-based approaches to summarize and identify novel genes and pathways associated with acute and chronic postsurgical pain. J. Clin. Anesth. 62:109738
    [Google Scholar]
  22. Choi JC, Park Y-H, Park SK, Lee JS, Kim J et al. 2017. Testosterone effects on pain and brain activation patterns. Acta Anaesthesiol. Scand. 61:668–75
    [Google Scholar]
  23. Cogan R, Spinnato JA. 1986. Pain and discomfort thresholds in late pregnancy. Pain 27:63–68
    [Google Scholar]
  24. Coghill RC, McHaffie JG, Yen Y-F 2003. Neural correlates of interindividual differences in the subjective experience of pain. PNAS 100:8538–42
    [Google Scholar]
  25. Cook-Sather SD, Li J, Goebel TK, Sussman EM, Rehman MA, Hakonarson H 2014. TAOK3, a novel genome-wide association study locus associated with morphine requirement and postoperative pain in a retrospective pediatric day surgery population. Pain 155:1773–83
    [Google Scholar]
  26. Costigan M, Belfer I, Griffin RS, Dai F, Barrett LB et al. 2010. Multiple chronic pain states are associated with a common amino acid–changing allele in KCNS1. Brain 133:2519–27
    [Google Scholar]
  27. Davis KD, Aghaeepour N, Ahn AH, Angst MS, Borsook D et al. 2020. Discovery and validation of biomarkers to aid the development of safe and effective pain therapeutics: challenges and opportunities. Nat. Rev. Neurol. 16:381–400
    [Google Scholar]
  28. Day-Williams AG, Southam L, Panoutsopoulou K, Rayner NW, Esko T et al. 2011. A variant in MCF2L is associated with osteoarthritis. Am. J. Hum. Genet. 89:446–50
    [Google Scholar]
  29. de Vries B, Anttila V, Freilinger T, Wessman M, Kaunisto MA et al. 2016. Systematic re-evaluation of genes from candidate gene association studies in migraine using a large genome-wide association data set. Cephalalgia 36:604–14
    [Google Scholar]
  30. Deandrea S, Corli O, Consonni D, Vallani W, Greco MT, Apolone G 2013. Prevalence of breakthrough cancer pain: a systematic review and a pooled analysis of published literature. J. Pain Symptom Manag. 47:57–76
    [Google Scholar]
  31. Devor M. 2004. Evidence for heritability of pain in patients with traumatic neuropathy. Pain 108:200–1
    [Google Scholar]
  32. Docampo E, Escaramis G, Gratacos M, Villatoro S, Puig A et al. 2014. Genome-wide analysis of single nucleotide polymorphisms and copy number variants in fibromyalgia suggest a role for the central nervous system. Pain 155:1102–9
    [Google Scholar]
  33. Doehring A, Kusener N, Fluhr K, Neddermeyer TJ, Schneider G, Lötsch J 2011. Effect sizes in experimental pain produced by gender, genetic variants and sensitization procedures. PLOS ONE 6:e17724
    [Google Scholar]
  34. Dorsey SG, Renn CL, Griffioen M, Lassiter CB, Zhu S et al. 2019. Whole blood transcriptomic profiles can differentiate vulnerability to chronic low back pain. PLOS ONE 14:e0216539
    [Google Scholar]
  35. Driban JB, Lo GH, Eaton CB, Price LL, Lu B, McAlindon TE 2015. Knee pain and a prior injury are associated with increased risk of a new knee injury: data from the osteoarthritis initiative. J. Rheumatol. 42:1463–69
    [Google Scholar]
  36. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS et al. 2006. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314:1461–63
    [Google Scholar]
  37. El Tumi H, Johnson MI, Dantas PBF, Maynard MJ, Tashani OA 2017. Age-related changes in pain sensitivity in healthy humans: a systematic review with meta-analysis. Eur. J. Pain 21:955–64
    [Google Scholar]
  38. Felson DT, Lawrence RC, Dieppe PA, Hirsch R, Helmick CG et al. 2000. Osteoarthritis: new insights. Part 1: the disease and its risk factors. Ann. Intern. Med. 133:635–46
    [Google Scholar]
  39. Ferreira PH, Beckenkamp P, Maher CG, Hopper JL, Ferreira ML 2013. Nature or nurture in low back pain? Results of a systematic review of studies based on twin samples. Eur. J. Pain 17:957–71
    [Google Scholar]
  40. Feuerstein M, Sult S, Houle M 1985. Environmental stressors and chronic low back pain: life events, family and work environment. Pain 22:295–307
    [Google Scholar]
  41. Fillingim RB, Ohrbach R, Greenspan JD, Knott C, Diatchenko L et al. 2013. Psychological factors associated with development of TMD: the OPPERA prospective cohort study. J. Pain 14:T75–90
    [Google Scholar]
  42. Finlay CR, Chan DS, Garrison S, Korownyk C, Kolber MR et al. 2018. What are the most common conditions in primary care. ? Can. Fam. Physician 64:832–40
    [Google Scholar]
  43. Finnerup NB, Sindrup SH, Jensen TS 2010. The evidence for pharmacological treatment of neuropathic pain. Pain 150:573–81
    [Google Scholar]
  44. Forbes HJ, Thomas SL, Smeeth L, Clayton T, Farmer R et al. 2016. A systematic review and meta-analysis of risk factors for postherpetic neuralgia. Pain 157:30–54
    [Google Scholar]
  45. Ford AC, Marwaha A, Sood R, Moayyedi P 2015. Global prevalence of, and risk factors for, uninvestigated dyspepsia: a meta-analysis. Gut 64:1049–57
    [Google Scholar]
  46. Foulkes T, Wood JN. 2008. Pain genes. PLOS Genet 4:e1000086
    [Google Scholar]
  47. Friedin MB, Tsepilov YA, Palmer M, Karssen LC, Suri P et al. 2019. Insight into the genetic architecture of back pain and its risk factors from a study of 509,000 individuals. Pain 160:1361–73
    [Google Scholar]
  48. Gagliese L, Melzack R. 1997. Chronic pain in elderly people. Pain 70:3–14
    [Google Scholar]
  49. Galvan A, Skorpen F, Klepstad P, Knudsen AK, Fladvad T et al. 2011. Multiple loci modulate opioid therapy response for cancer pain. Clin. Cancer Res. 17:4581–87
    [Google Scholar]
  50. Gasperi M, Krieger JN, Panizzon MS, Goldberg J, Buchwald D, Afari N 2019. Genetic and environmental influences on urinary conditions in men: a classical twin study. Urology 129:54–59
    [Google Scholar]
  51. GBD 2017 Dis. Inj. Incidence Preval. Collab 2018. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392:1789–858
    [Google Scholar]
  52. George SZ, Dover GC, Wallace MR, Sack BK, Herbstman DM et al. 2008. Biopsychosocial influence on exercise-induced delayed onset muscle soreness at the shoulder: pain catastrophizing and catechol-O-methyltransferase (COMT) diplotype predict pain ratings. Clin. J. Pain 24:793–801
    [Google Scholar]
  53. George SZ, Parr JJ, Wallace MR, Wu SS, Borsa PA et al. 2014. Biopsychosocial influence on exercise-induced injury: genetic and psychological combinations are predictive of shoulder pain phenotypes. J. Pain 15:68–80
    [Google Scholar]
  54. Gintzler AR. 1980. Endorphin-mediated increases in pain threshold during pregnancy. Science 210:193–95
    [Google Scholar]
  55. Gormley P, Anttila V, Winsvold BS, Palta P, Esko T et al. 2016. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat. Genet. 48:856–66
    [Google Scholar]
  56. Gupta RM, Hadaya J, Trehan A, Zekavat SM, Roselli C et al. 2017. Genetic variant associated with five vascular diseases is a distal regulator of endothelin-1 gene expression. Cell 170:522–33
    [Google Scholar]
  57. Gureje O. 2008. Comorbidity of pain and anxiety disorders. Curr. Psychiat. Rep. 10:318–22
    [Google Scholar]
  58. Hocking LJ, Scotland G, Morris AD, Dominiczak AF, Porteous DJ, Smith BH 2012. Heritability of chronic pain in 2195 extended families. Eur. J. Pain 16:1053–63
    [Google Scholar]
  59. Holmes RJ, McManus KJ, Koulouglioti C, Hale B 2020. Risk factors for poststroke shoulder pain: a systematic review and meta-analysis. J. Stroke Cerebrovasc. Dis. 29:104787
    [Google Scholar]
  60. Holmgaard H, Hansen EO, Dong NPT, Dixen LB, Nielsen GARN et al. 2017. Individuals with dark eyes and hair exhibit higher pain sensitivity. Somatosens. Mot. Res. 34:21–26
    [Google Scholar]
  61. IOM (Inst. Med.) 2011. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research Washington, DC: Natl. Acad. Press
    [Google Scholar]
  62. Isselee H, De Laat A, Lesaffre E, Lysens R 1997. Short-term reproducibility of pressure pain thresholds in masseter and temporalis muscles of symptom-free subjects. Eur. J. Oral Sci. 105:583–87
    [Google Scholar]
  63. Jackson T, Wang Y, Wang Y, Fan H 2014. Self-efficacy and chronic pain outcomes: a meta-analytic review. J. Pain 15:800–14
    [Google Scholar]
  64. Jahre H, Grotle M, Smedbraten K, Dunn KM, Oiestad BE 2020. Risk factors for non-specific neck pain in young adults. A systematic review. BMC Musculoskelet. Disord. 21:366
    [Google Scholar]
  65. Jamieson DG, Moss A, Kennedy M, Jones S, Nenadic G et al. 2014. The pain interactome: connecting pain-specific protein interactions. Pain 155:2243–52
    [Google Scholar]
  66. Janicki PK, Alexander GM, Eckert J, Postula M, Schwartzman RJ 2016. Analysis of common single nucleotide polymorphisms in complex regional pain syndrome: genome wide association study approach and pooled DNA strategy. Pain Med 17:2344–52
    [Google Scholar]
  67. Jayaram A, Singh P, Carp H 1995. SCH 32615, an enkephalinase inhibitor, enhances pregnancy-induced analgesia in mice. Anesth. Analg. 80:944–48
    [Google Scholar]
  68. Jensen MP, Turner JA, Romano JM, Karoly P 1991. Coping with chronic pain: a critical review of the literature. Pain 47:249–83
    [Google Scholar]
  69. Johansen A, Romundstad L, Nielsen CS, Schirmer H, Stubhaug A 2012. Persistent postsurgical pain in a general population: prevalence and predictors in the Tromsø study. Pain 153:1390–96
    [Google Scholar]
  70. Johnston KJA, Adams MJ, Nicholl BI, Ward J, Strawbridge RJ et al. 2019a. Genome-wide association study of multisite chronic pain in UK Biobank. PLOS Genet 15:e1008164
    [Google Scholar]
  71. Johnston KJA, Adams MJ, Nicholl BI, Ward J, Strawbridge RJ et al. 2019b. Identification of novel common variants associated with chronic pain using conditional false discovery rate analysis with major depressive disorder and assessment of pleiotropic effects of LRFN5. Transl. Psychiat 9:310
    [Google Scholar]
  72. Jones AV, Hockley JRF, Hyde C, Gorman D, Sredic-Rhodes A et al. 2016. Genome-wide association analysis of pain severity in dysmenorrhea identifies association at chromosome 1p13.2, near the nerve growth factor locus. Pain 157:2571–81
    [Google Scholar]
  73. Jones GT, Power C, Macfarlane GJ 2009. Adverse events in childhood and chronic widespread pain in adult life: results from the 1958 British Birth Cohort Study. Pain 143:92–96
    [Google Scholar]
  74. Jung BF, Johnson RW, Griffin DRJ, Dworkin RH 2004. Risk factors for postherpetic neuralgia in patients with herpes zoster. Neurology 62:1545–51
    [Google Scholar]
  75. Junqueira DR, Ferreira ML, Refshauge K, Maher CG, Hopper JL et al. 2014. Heritability and lifestyle factors in chronic low back pain: results of the Australian twin low back pain study (The AUTBACK study). Eur. J. Pain 18:1410–18
    [Google Scholar]
  76. Kehlet H, Jensen TS, Woolf CJ 2006. Persistent postsurgical pain: risk factors and prevention. Lancet 367:1618–25
    [Google Scholar]
  77. Keogh E, Cochrane M. 2002. Anxiety sensitivity, cognitive biases, and the experience of pain. J. Pain 3:320–29
    [Google Scholar]
  78. Khan HS, Stroman PW. 2015. Inter-individual differences in pain processing investigated by functional magnetic resonance imaging of the brainstem and spinal cord. Neuroscience 307:231–41
    [Google Scholar]
  79. Kim H, Neubert JK, San Miguel A, Xu K, Krishnaraju RK et al. 2004. Genetic influence on variability in human acute experimental pain sensitivity associated with gender, ethnicity and psychological temperament. Pain 109:488–96
    [Google Scholar]
  80. Kim HJ, Yang GS, Greenspan JD, Downton KD, Griffith KA et al. 2017. Racial and ethnic differences in experimental pain sensitivity: systematic review and meta-analysis. Pain 158:194–211
    [Google Scholar]
  81. Klepstad P, Fladvad T, Skorpen F, Bjordal K, Caraceni A et al. 2011. Influence from genetic variability on opioid use for cancer pain: a European genetic association study of 2294 cancer pain patients. Pain 152:1139–45
    [Google Scholar]
  82. Kringel D, Lippmann C, Parnham MJ, Kalso E, Ultsch A, Lotsch J 2018. A machine-learned analysis of human gene polymorphisms modulating persisting pain points to major roles of neuroimmune processes. Eur. J. Pain 22:1735–56
    [Google Scholar]
  83. LaCroix-Fralish ML, Ledoux JB, Mogil JS 2007. The Pain Genes Database: an interactive web browser of pain-related transgenic knockout studies. Pain 131:3.e1–4
    [Google Scholar]
  84. LaCroix-Fralish ML, Mogil JS. 2009. Progress in genetic studies of pain and analgesia. Annu. Rev. Pharmacol. Toxicol. 49:97–121
    [Google Scholar]
  85. Lander ES, Schork NJ. 1994. Genetic dissection of complex traits. Science 265:2037–48
    [Google Scholar]
  86. Langford DL, Crager SE, Shehzad Z, Smith SB, Sotocinal SG et al. 2006. Social modulation of pain as evidence for empathy in mice. Science 312:1967–70
    [Google Scholar]
  87. Langford DL, Tuttle AH, Briscoe C, Harvey-Lewis C, Baran I et al. 2011. Varying perceived social threat modulates pain behavior in male mice. J. Pain 12:125–32
    [Google Scholar]
  88. Langford DL, Tuttle AH, Brown K, Deschenes S, Fischer DB et al. 2010. Social approach to pain in laboratory mice. Soc. Neurosci. 5:163–70
    [Google Scholar]
  89. Lanier LH. 1943. Variability in the pain threshold. Science 97:49–50
    [Google Scholar]
  90. Lariviere WR, Wilson SG, Laughlin TM, Kokayeff A, West EE et al. 2002. Heritability of nociception. III. Genetic relationships among commonly used assays of nociception and hypersensitivity. Pain 97:75–86
    [Google Scholar]
  91. Lemmela S, Solovieva S, Shiri R, Benner C, Heliovaara M et al. 2016. Genome-wide meta-analysis of sciatica in Finnish population. PLOS ONE 11:e0163877
    [Google Scholar]
  92. Li Z, Chen J, Zhao Y, Wang Y, Xu J et al. 2017. Common variants in ZMIZ1 and near NGF confer risk for primary dysmenorrhoea. Nat. Commun. 8:14900
    [Google Scholar]
  93. Liang D-Y, Zheng M, Sun Y, Sahbaie P, Low SA et al. 2014. The Netrin-1 receptor DCC is a regulator of maladaptive responses to chronic morphine administration. BMC Genom 15:345
    [Google Scholar]
  94. Liebeskind JC. 1991. Pain can kill. Pain 44:3–4
    [Google Scholar]
  95. Liu M-G, Chen J. 2014. Preclinical research on pain comorbidity with affective disorders and cognitive deficits: challenges and perspectives. Prog. Neurobiol. 116:13–32
    [Google Scholar]
  96. Livshits G, MacGregor AJ, Gieger C, Malkin I, Moayyeri A et al. 2015. An omics investigation into chronic widespread musculoskeletal pain reveals epiandrosterone sulfate as a potential biomarker. Pain 156:1845–51
    [Google Scholar]
  97. Loggia ML, Jensen K, Gollub RL, Wasan AD, Edwards RR, Kong J 2011. The catechol-O-methyltransferase (COMT) val158met polymorphism affects brain responses to repeated painful stimuli. PLOS ONE 6:e27764
    [Google Scholar]
  98. Macfarlane GJ, Barnish MS, Jones GT 2017. Persons with chronic widespread pain experience excess mortality: longitudinal results from UK Biobank and meta-analysis. Ann. Rheum. Dis. 76:1815–22
    [Google Scholar]
  99. MacGregor AJ, Griffiths GO, Baker J, Spector TD 1997. Determinants of pressure pain threshold in adult twins: evidence that shared environmental influences predominate. Pain 73:253–57
    [Google Scholar]
  100. Magrangeas F, Kuiper R, Avet-Loiseau H, Gouraud W, Guerin-Charbonnel C et al. 2016. A genome-wide association study identifies a novel locus for bortezomib-induced peripheral neuropathy in European patients with multiple myeloma. Clin. Cancer Res. 22:4350–55
    [Google Scholar]
  101. Malkin I, Williams FMK, LaChance G, Spector T, MacGregor AJ, Livshits G 2014. Low back and common widespread pain share common genetic determinants. Ann. Hum. Genet. 78:357–66
    [Google Scholar]
  102. Mansfield KE, Sim J, Jordan JL, Jordan KP 2016. A systematic review and meta-analysis of the prevalence of chronic widespread pain in the general population. Pain 157:55–64
    [Google Scholar]
  103. Mapplebeck JCS, Beggs S, Salter MW 2015. Sex differences in pain: a tale of two immune cells. Pain 157:S2–6
    [Google Scholar]
  104. Martin LJ, Acland EL, Cho C, Gandhi W, Chen D et al. 2019. Male-specific conditioned pain hypersensitivity in mice and humans. Curr. Biol. 29:191–201.e4
    [Google Scholar]
  105. Martin LJ, Hathaway G, Isbester K, Mirali S, Acland EL et al. 2015. Reducing social stress elicits emotional contagion of pain in mouse and human strangers. Curr. Biol. 25:326–32
    [Google Scholar]
  106. Martinez-Calderon J, Flores-Cortes M, Morales-Asencio JM, Luque-Suarez A 2020. Which psychological factors are involved in the onset and/or persistence of musculoskeletal pain? An umbrella review of systematic reviews and meta-analyses of prospective cohort studies. Clin. J. Pain 36:626–37
    [Google Scholar]
  107. McIntosh AM, Hall LS, Zeng Y, Adams MJ, Gibson J et al. 2016. Genetic and environmental risk for chronic pain and the contribution of risk variants for major depressive disorder: a family-based mixed-model analysis. PLOS Med 13:e1002090
    [Google Scholar]
  108. Meloto CB, Bortsov AV, Bair E, Helgeson E, Ostrom C et al. 2016. Modification of COMT-dependent pain sensitivity by psychological stress and sex. Pain 157:858–67
    [Google Scholar]
  109. Melzack R. 1975. The McGill Pain Questionnaire: major properties and scoring methods. Pain 1:277–99
    [Google Scholar]
  110. Meng W, Adams MJ, Palmer CNA Shi J et al. 2019. Genome-wide association study of knee pain identifies associations with GDF5 and COL27A1 in UK Biobank. Commun. Biol. 2:321
    [Google Scholar]
  111. Meng W, Chan BW, Harris C, Freidin MB, Hebert HL et al. 2020. A genome-wide association study finds genetic variants associated with neck or shoulder pain in UK Biobank. Hum. Mol. Genet. 29:1396–404
    [Google Scholar]
  112. Meng W, Deshmukh HA, Donnelly LA, Wellcome Trust Case Control Consort., SUMMIT Study Group, et al. 2015a. A genome-wide association study provides evidence of sex-specific involvement of Chr1p35.1 (ZSCAN20-TLR12P) and Chr8p23.1 (HMGB1P46) with diabetic neuropathic pain. eBioMedicine 2:1386–93
    [Google Scholar]
  113. Meng W, Deshmukh HA, van Zuydam NR, Liu Y, Donnelly LA et al. 2015b. A genome-wide association study suggests an association of Chr8p21.3 (GFRA2) with diabetic neuropathic pain. Eur. J. Pain 19:392–99
    [Google Scholar]
  114. Mieda T, Nishizawa D, Nakagawa H, Tsujita M, Imanishi H et al. 2016. Genome-wide association study identifies candidate loci associated with postoperative fentanyl requirements after laparoscopic-assisted colectomy. Pharmacogenomics 17:133–45
    [Google Scholar]
  115. Miyamoto Y, Shi D, Nakajima M, Ozaki K, Sudo A et al. 2008. Common variants in DVWA on chromosome 3p24.3 are associated with susceptibility to knee osteoarthritis. Nat. Genet. 40:994–98
    [Google Scholar]
  116. Mogil JS. 1999. The genetic mediation of individual differences in sensitivity to pain and its inhibition. PNAS 96:7744–51
    [Google Scholar]
  117. Mogil JS. 2003. Interaction between sex and genotype in the mediation of pain and pain inhibition. Semin. Pain Med. 1:197–205
    [Google Scholar]
  118. Mogil JS. 2009. Are we getting anywhere in human pain genetics. ? Pain 146:231–32
    [Google Scholar]
  119. Mogil JS. 2012a. Pain genetics: past, present and future. Trends Genet 28:258–66
    [Google Scholar]
  120. Mogil JS. 2012b. Sex differences in pain and pain inhibition: multiple explanations of a controversial phenomenon. Nat. Rev. Neurosci. 13:859–66
    [Google Scholar]
  121. Mogil JS. 2017. Laboratory environmental factors and pain behavior: the relevance of unknown unknowns to reproducibility and translation. Lab. Anim. 46:136–41
    [Google Scholar]
  122. Mogil JS. 2018. Sex-based divergence of mechanisms underlying pain and pain inhibition. Curr. Opin. Behav. Sci. 23:113–17
    [Google Scholar]
  123. Mogil JS. 2020. Qualitative sex differences in pain processing: emerging evidence of a biased literature. Nat. Rev. Neurosci. 21:353–65
    [Google Scholar]
  124. Mogil JS, Bailey AL. 2010. Sex and gender differences in pain and analgesia. Prog. Brain Res. 186:141–57
    [Google Scholar]
  125. Mogil JS, Chanda ML. 2005. The case for the inclusion of female subjects in basic science studies of pain. Pain 117:1–5
    [Google Scholar]
  126. Mogil JS, Grisel JE. 1998. Transgenic studies of pain. Pain 77:107–28
    [Google Scholar]
  127. Mogil JS, McCarson KE. 2000. Finding pain genes: bottom-up and top-down approaches. J. Pain 1:Suppl. 166–80
    [Google Scholar]
  128. Mogil JS, Sorge RE, LaCroix-Fralish ML, Smith SB, Fortin A et al. 2011. Pain sensitivity and vasopressin analgesia are mediated by a gene-sex-environment interaction. Nat. Neurosci. 14:1569–73
    [Google Scholar]
  129. Mogil JS, Sternberg WF, Marek P, Sadowski B, Belknap JK, Liebeskind JC 1996. The genetics of pain and pain inhibition. PNAS 93:3048–55
    [Google Scholar]
  130. Mogil JS, Wilson SG, Bon K, Lee SE, Chung K et al. 1999. Heritability of nociception. I. Responses of eleven inbred mouse strains on twelve measures of nociception. Pain 80:67–82
    [Google Scholar]
  131. Mogil JS, Wilson SG, Chesler EJ, Rankin AL, Nemmani KVS et al. 2003. The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. PNAS 100:4867–72
    [Google Scholar]
  132. Mogil JS, Yu L, Basbaum AI 2000. Pain genes?: natural variation and transgenic mutants. Annu. Rev. Neurosci. 23:777–811
    [Google Scholar]
  133. Momi SK, Fabiane SM, Lachance G, Livshits G, Williams FMK 2015. Neuropathic pain as part of chronic widespread pain: environmental and genetic influences. Pain 156:2100–6
    [Google Scholar]
  134. Muralidharan A, Sotocinal SG, Austin J-S, Mogil JS 2020. The influence of aging and duration of nerve injury on the antiallodynic efficacy of analgesics in laboratory mice. Pain Rep 5:e824
    [Google Scholar]
  135. Nakajima M, Takahashi A, Kou I, Rodriguez-Fontenla C, Gomez-Reino JJ et al. 2010. New sequence variants in HLA class II/III region associated with susceptibility to knee osteoarthritis identified by genome-wide association study. PLOS ONE 5:e9723
    [Google Scholar]
  136. Neziri AY, Scaramozzino P, Andersen OK, Dickenson AH, Arendt-Nielsen L, Curatolo M 2011. Reference values of mechanical and thermal pain tests in a pain-free population. Eur. J. Pain 15:376–83
    [Google Scholar]
  137. Niederberger E, Resch E, Parnham MJ, Geisslinger G 2017. Drugging the pain epigenome. Nat. Rev. Neurol. 13:434–47
    [Google Scholar]
  138. Nielsen C, Knudsen G, Steingrimsdottir O 2012. Twin studies of pain. Clin. Genet. 82:331–40
    [Google Scholar]
  139. Nielsen CS, Price DD, Vassend O, Stubhaug A, Harris JR 2005. Characterizing individual differences in heat-pain sensitivity. Pain 119:65–74
    [Google Scholar]
  140. Nielsen CS, Staud R, Price DD 2009. Individual differences in pain sensitivity: measurement, causation, and consequences. J. Pain 10:231–37
    [Google Scholar]
  141. Nielsen CS, Stubhaug A, Price DD, Vassend O, Czajkowski N, Harris JR 2008. Individual differences in pain sensitivity: genetic and environmental contributions. Pain 136:21–29
    [Google Scholar]
  142. Nishizawa D, Fukuda K, Kasai S, Hasegawa J, Aoki Y et al. 2014. Genome-wide association study identifies a potent locus associated with human opioid sensitivity. Mol. Psychiat. 19:55–62
    [Google Scholar]
  143. Nishizawa D, Mieda T, Tsujita M, Nakagawa H, Yamaguchi S et al. 2018. Genome-wide scan identifies candidate loci related to remifentanil requirements during laparoscopic-assisted colectomy. Pharmacogenomics 19:113–27
    [Google Scholar]
  144. Nissenbaum J, Devor M, Seltzer Z, Gebauer M, Michaelis M et al. 2010. Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2. . Genome Res 20:1180–90
    [Google Scholar]
  145. Norbury TA, MacGregor AJ, Urwin J, Spector TD, McMahon SB 2007. Heritability of responses to painful stimuli in women: a classical twin study. Brain 130:3041–49
    [Google Scholar]
  146. North RY, Li Y, Ray P, Rhines LD, Tatsui CE et al. 2019. Electrophysiological and transcriptomic correlates of neuropathic pain in human dorsal root ganglion neurons. Brain 142:1215–26
    [Google Scholar]
  147. Ogata S, Williams F, Burri A 2017. Genetic factors explain the association between pain catastrophizing and chronic widespread pain. J. Pain 18:1111–16
    [Google Scholar]
  148. Painter JN, Anderson CA, Nyholt DR, Macgregor S, Lin J et al. 2011. Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis. Nat. Genet. 43:51–54
    [Google Scholar]
  149. Parisien M, Khoury S, Chabot-Dore A-J, Sotocinal SG, Slade GD et al. 2017. Effect of human genetic variability on gene transcription in dorsal root ganglia and association with pain phenotypes. Cell Rep 19:1940–52
    [Google Scholar]
  150. Patti GJ, Yanes O, Shriver LP, Courade J-P, Tautenhahn R et al. 2012. Metabolomics implicates altered sphingolipids in chronic pain of neuropathic origin. Nat. Chem. Biol. 8:232–34
    [Google Scholar]
  151. Peters MJ, Broer L, Willemen HL, Eiriksdottir G, Hocking LJ et al. 2013. Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region. Ann. Rheum. Dis. 72:427–36
    [Google Scholar]
  152. Pinheiro MB, Morosoli JJ, Colodro-Conde L, Ferreira PH, Ordonana JR 2018a. Genetic and environmental influences to low back pain and symptoms of depression and anxiety: a population-based twin study. J. Psychosom. Res. 105:92–98
    [Google Scholar]
  153. Pinheiro MB, Morosoli JJ, Ferreira ML, Madrid-Valero JJ, Refshauge K et al. 2018b. Genetic and environmental contributions to sleep quality and low back pain: a population-based twin study. Psychosom. Med. 80:3263–70
    [Google Scholar]
  154. Plenge RM, Seielstad M, Padyukov L, Lee AT, Remmers EF et al. 2007. TRAF1-C5 as a risk locus for rheumatoid arthritis—a genomewide study. N. Engl. J. Med. 357:1199–209
    [Google Scholar]
  155. Polderman TJ, Benyamin B, de Leeuw CA, Sullivan PF, van Bochoven A et al. 2015. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat. Genet. 47:702–9
    [Google Scholar]
  156. Prendergast BJ, Onishi KG, Zucker I 2014. Female mice liberated for inclusion in neuroscience and biomedical research. Neurosci. Biobehav. Rev. 40:1–5
    [Google Scholar]
  157. Price DD, McGrath P, Rafii A, Buckingham B 1983. The validation of visual analogue scales as ratio scale measures for chronic and experimental pain. Pain 17:45–56
    [Google Scholar]
  158. Price RC, Asenjo JF, Christou NV, Backman SB, Schweinhardt P 2013. The role of excess subcutaneous fat in pain and sensory sensitivity in obesity. Eur. J. Pain 17:1316–26
    [Google Scholar]
  159. Rahim-Williams B, Riley JL III, Williams AK, Fillingim RB 2012. A quantitative review of ethnic group differences in experimental pain response: Do biology, psychology, and culture matter. ? Pain Med 13:522–40
    [Google Scholar]
  160. Rahmioglu N, Macgregor S, Drong AW, Hedman AK, Harris HR et al. 2015. Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci. Hum. Mol. Genet. 24:1185–99
    [Google Scholar]
  161. Randall CL, Wright CD, Chernus JM, McNeil DW, Feingold E et al. 2017. A preliminary genome-wide association study of pain-related fear: implications for orofacial pain. Pain Res. Manag. 2017:7375468
    [Google Scholar]
  162. Ray PR, Khan J, Wangzhou A, Tavares-Ferreira D, Akopian AN et al. 2019. Transcriptome analysis of the human tibial nerve identifies sexually dimorphic expression of genes involved in pain, inflammation, and neuro-immunity. Front. Mol. Neurosci. 12:37
    [Google Scholar]
  163. Recla JM, Bubier JA, Gatti DM, Ryan JL, Long KH et al. 2019. Genetic mapping in Diversity Outbred mice identifies a Trpa1 variant influencing late-phase formalin response. Pain 160:1740–53
    [Google Scholar]
  164. Recla JM, Robledo RF, Gatti DM, Bult CJ, Churchill GA, Chelser EJ 2014. Precise genetic mapping and integrative bioinformatics in Diversity Outbred mice reveals Hydin as a novel pain gene. Mamm. Genome 25:211–22
    [Google Scholar]
  165. Reyes-Gibby CC, Shete S, Rakvag T, Bhat SV, Skorpen F et al. 2007. Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene. Pain 130:25–30
    [Google Scholar]
  166. Reyes-Gibby CC, Wang J, Silvas MR, Yu RK, Hanna EY, Shete S 2016. Genome-wide association study suggests common variants within RP11–634B7.4 gene influencing severe pre-treatment pain in head and neck cancer patients. Sci. Rep. 6:34206
    [Google Scholar]
  167. Reyes-Gibby CC, Wang J, Yeung S-CJ, Chaftari P, Yu RK et al. 2018. Genome-wide association study identifies genes associated with neuropathy in patients with head and neck cancer. Sci. Rep. 8:8789
    [Google Scholar]
  168. Riley JL III, Robinson ME, Wise EA, Price DD 1999. A meta-analytic review of pain perception across the menstrual cycle. Pain 81:225–35
    [Google Scholar]
  169. Rosen S, Ham B, Mogil JS 2017a. Sex differences in neuroimmunity and pain. J. Neurosci. Res. 95:500–8
    [Google Scholar]
  170. Rosen SF, Ham B, Drouin S, Boachie N, Chabot-Dore A-J et al. 2017b. T cell mediation of pregnancy analgesia affecting chronic pain in mice. J. Neurosci. 37:9819–27
    [Google Scholar]
  171. Ruau D, Dudley JT, Chen R, Phillips NG, Swan GE et al. 2012. Integrative approach to pain genetics identifies pain sensitivity loci across diseases. PLOS Comput. Biol. 8:e1002538
    [Google Scholar]
  172. Sanders AE, Jain D, Sofer T, Kerr KF, Laurie CC et al. 2017. GWAS identifies new loci for painful temporomandibular disorder: Hispanic Community Health Study/Study of Latinos. J. Dent. Res. 96:277–84
    [Google Scholar]
  173. Sapkota Y, Steinthorsdottir V, Morris AP, Fassbender A, Rahmioglu N et al. 2017. Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism. Nat. Commun. 8:15539
    [Google Scholar]
  174. Schmahl C, Ludascher P, Greffrath W, Kraus A, Valerius G et al. 2012. COMT val158met polymorphism and neural pain processing. PLOS ONE 7:e23658
    [Google Scholar]
  175. Silverwood V, Blagojevic-Bucknall M, Jinks C, Jordan JL, Protheroe J, Jordan KP 2014. Current evidence on risk factors for knee osteoarthritis in older adults: a systematic review and meta-analysis. Osteoarthr. Cartil. 23:507–15
    [Google Scholar]
  176. Smith AH, Jensen KP, Li J, Nunez Y, Farrer LA et al. 2017. Genome-wide association study of therapeutic opioid dosing identifies a novel locus upstream of OPRM1. Mol. . Psychiat 22:346–52
    [Google Scholar]
  177. Smith SB, Parisien M, Bair E, Belfer I, Chabot-Dore A-J et al. 2019. Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males. Pain 160:579–91
    [Google Scholar]
  178. Sobalska-Kwapis M, Smolarz B, Slomka M, Szaflik T, Kepka W et al. 2017. New variants near RHOJ and C2, HLA-DRA region and susceptibility to endometriosis in the Polish population—the genome-wide association study. Eur. J. Obstet. Gynecol. Reprod. Biol. 217:106–12
    [Google Scholar]
  179. Sorge RE, LaCroix-Fralish ML, Tuttle AH, Khoutorsky A, Sotocinal SG et al. 2013. The Yin and Yang of pain: variability in formalin test nociception and morphine analgesia produced by the Yin Yang 1 transcription factor gene. Genes Brain Behav 12:405–13
    [Google Scholar]
  180. Sorge RE, Martin LJ, Isbester KA, Sotocinal SG, Rosen S et al. 2014. Olfactory exposure to males, including men, causes stress and related analgesia in rodents. Nat. Methods 11:629–32
    [Google Scholar]
  181. Sorge RE, Strath LJ. 2018. Sex differences in pain responses. Curr. Opin. Physiol. 6:75–81
    [Google Scholar]
  182. Sorge RE, Trang T, Dorfman R, Smith SB, Beggs S et al. 2012. Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nat. Med. 18:595–99
    [Google Scholar]
  183. St. Sauver JL, Warner DO, Yawn BP, Jacobson DJ, McGree ME et al. 2013. Why patients visit their doctors: assessing the most prevalent conditions in a defined American population. Mayo Clin. Proc. 88:56–67
    [Google Scholar]
  184. Stahl MK, El-Metwally AA, Mikkelsson MK, Salminen JJ, Pulkkinen LR et al. 2013. Genetic and environmental influences on non-specific neck pain in early adolescence: a classical twin study. Eur. J. Pain 17:791–98
    [Google Scholar]
  185. Stewart WF, Lipton RB, Celentano DD, Reed ML 1992. Prevalence of migraine headache in the United States: relation to age, income, race, and other sociodemographic factors. J. Am. Med. Assoc. 267:64–69
    [Google Scholar]
  186. Stoicea N, Costa A, Periel L, Uribe A, Weaver T, Bergese SD 2019. Current perspectives on the opioid crisis in the US healthcare system: a comprehensive literature review. Medicine 98:e15425
    [Google Scholar]
  187. Styrkarsdottir U, Lund SH, Thorleifsson G, Zink F, Stefansson OA et al. 2018. Meta-analysis of Icelandic and UK data sets identifies missense variants in SMO, IL11, COL11A1 and 13 more new loci associated with osteoarthritis. Nat. Genet 50:1681–87
    [Google Scholar]
  188. Styrkarsdottir U, Thorleifsson G, Helgadottir HT, Bomer N, Metrustry S et al. 2014. Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31. Nat. Genet. 46:498–502
    [Google Scholar]
  189. Sullivan MJ, Adams H, Horan S, Maher D, Boland D, Gross R 2008. The role of perceived injustice in the experience of chronic pain and disability: scale development and validation. J. Occup. Rehabil. 18:249–61
    [Google Scholar]
  190. Sullivan MJL, Bishop S, Pivik J 1995. The Pain Catastrophizing scale: development and validation. Psychol. Assess. 7:524–32
    [Google Scholar]
  191. Sullivan MJL, Thorn B, Haythornthwaite JA, Keefe F, Martin M et al. 2001. Theoretical perspectives on the relation between catastrophizing and pain. Clin. J. Pain 17:52–64
    [Google Scholar]
  192. Suri P, Palmer MR, Tsepilov YA, Freidin MB, Boer CG et al. 2018. Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain. PLOS Genet 14:e1007601
    [Google Scholar]
  193. Tabor HK, Risch NJ, Myers RM 2002. Candidate-gene approaches for studying complex genetic traits: practical considerations. Nat. Rev. Genet. 3:391–97
    [Google Scholar]
  194. Takahashi K, Nishizawa D, Kasai S, Koukita Y, Fukuda K et al. 2018. Genome-wide association study identifies polymorphisms associated with the analgesic effect of fentanyl in the preoperative cold pressor-induced pain test. J. Pharmacol. Sci. 136:107–13
    [Google Scholar]
  195. Tan SHS, Lau BPH, Khin LW, Lingaraj K 2016. The importance of patient sex in the outcomes of anterior cruciate ligament reconstructions: a systematic review and meta-analysis. Am. J. Sports Med. 44:242–54
    [Google Scholar]
  196. Tansley SN, Tuttle AH, Wu N, Tohyama S, Dossett K et al. 2019. Modulation of social behavior and dominance status by chronic pain in mice. Genes Brain Behav 18:e12514
    [Google Scholar]
  197. Tashani OA, Astita R, Sharp D, Johnson MI 2017. Body mass index and distribution of body fat can influence sensory detection and pain sensitivity. Eur. J. Pain 21:1186–96
    [Google Scholar]
  198. Tegeder I, Costigan M, Griffin RS, Abele A, Belfer I et al. 2006. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat. Med. 12:1269–77
    [Google Scholar]
  199. Timmerans G, Sternbach RA. 1974. Factors of human chronic pain: an analysis of personality and pain reaction variables. Science 184:806–8
    [Google Scholar]
  200. Trost Z, Strachan E, Sullivan M, Vervoort T, Avery AR, Afari N 2015. Heritability of pain catastrophizing and associations with experimental pain outcomes: a twin study. Pain 156:514–20
    [Google Scholar]
  201. van den Maagdenberg AMJM, Nyholt DR, Anttila V 2019. Novel hypotheses emerging from GWAS in migraine. ? J. Headache Pain 20:5
    [Google Scholar]
  202. Van Reij RRI, Hoofwijk DMN, Rutten BPF, Weinhold L, Leber M et al. 2020. The association between genome-wide polymorphisms and chronic postoperative pain: a prospective observational study. Anaesthesia 75:Suppl. 1e111–20
    [Google Scholar]
  203. VanDenKerkhof EG, Macdonald HM, Jones GT, Power C, Macfarlane GJ 2011. Diet, lifestyle and chronic widespread pain: results from the 1958 British Birth Cohort Study. Pain Res. Manag. 16:87–92
    [Google Scholar]
  204. Vargas-Alarcon G, Fragoso JM, Cruz-Robles D, Vargas A, Vargas A et al. 2007. Catechol-O-methyltransferase gene haplotypes in Mexican and Spanish patients with fibromyalgia. Arthritis Res. Ther. 9:r110
    [Google Scholar]
  205. Vassend O, Roysamb E, Nielsen CS, Czajkowski NO 2017. Musculoskeletal complaints, anxiety-depression symptoms, and neuroticism: a study of middle-aged twins. Health Psychol 36:729–39
    [Google Scholar]
  206. Vassend O, Roysamb E, Nielsen CS, Czajkowski NO 2018. Fatigue symptoms in relation to neuroticism, anxiety-depression, and musculoskeletal pain. A longitudinal twin study. PLOS ONE 13:e0198594
    [Google Scholar]
  207. Vehof J, Zavos HMS, Lachance G, Hammond CJ, Williams FMK 2014. Shared genetic factors underlie chronic pain syndromes. Pain 155:1562–68
    [Google Scholar]
  208. Veluchamy A, Hebert HL, Meng W, Palmer CNA, Smith BH 2018. Systematic review and meta-analysis of genetic risk factors for neuropathic pain. Pain 159:825–48
    [Google Scholar]
  209. Vicuna L, Strochlic DE, Latremoliere A, Bali KK, Simonetti M et al. 2015. The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell–derived leukocyte elastase. Nat. Med. 21:518–23
    [Google Scholar]
  210. Visscher CM, Schouten MJ, Ligthart L, van Houtem CMHH, de Jongh A, Boomsma DI 2018. Shared genetics of temporomandibular disorder pain and neck pain: results of a twin study. J. Oral Facial Pain Headache 32:107–12
    [Google Scholar]
  211. Vlaeyen JW, Linton SJ. 2012. Fear-avoidance model of chronic musculoskeletal pain: 12 years on. Pain 153:1144–47
    [Google Scholar]
  212. Walter C, Lötsch J. 2009. Meta-analysis of the relevance of the OPRM1 118A>G genetic variant for pain treatment. Pain 146:270–75
    [Google Scholar]
  213. Walton DM, MacDermid JC, Giorgianni AA, Mascarenhas JC, West SC, Zammit CA 2013. Risk factors for persistent problems following acute whiplash injury: update of a systematic review and meta-analysis. J. Orthop. Sports Phys. Ther. 43:31–43
    [Google Scholar]
  214. Warner SC, Van Meurs JB, Schiphof D, Bierma-Zeinstra SM, Hofman A et al. 2017. Genome-wide association scan of neuropathic pain symptoms post total joint replacement highlights a variant in the protein-kinase C gene. Eur. J. Hum. Genet. 25:446–51
    [Google Scholar]
  215. Weimer K, Hahn E, Monnikes N, Herr A-K, Stengel A, Enck P 2019. Are individual learning experiences more important than heritable tendencies? A pilot twin study on placebo analgesia. Front. Psychiat. 10:679
    [Google Scholar]
  216. Wieskopf JS, Mathur J, Limapichat W, Post MR, Al-Qazzaz M et al. 2015. The nicotinic α6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors. Sci. Transl. Med. 7:287ra72
    [Google Scholar]
  217. Willemen HLDM, Kavelaars A, Prado J, Maas M, Versteeg S et al. 2018. Identification of FAM173B as a protein methyltransferase promoting chronic pain. PLOS Biol 16:e2003452
    [Google Scholar]
  218. Williams FMK, Scollen S, Cao D, Memari Y, Hyde CL et al. 2012. Genes contributing to pain sensitivity in the normal population: an exome sequencing study. PLOS Genet 8:e1003095
    [Google Scholar]
  219. Wilson CA, Roffey DM, Chow D, Alkherayf F, Wai EK 2016. A systematic review of preoperative predictors for postoperative clinical outcomes following lumbar discectomy. Spine J 16:1413–22
    [Google Scholar]
  220. Wray NR, Wijmenga C, Sullivan PF, Yang J, Visscher PM 2018. Common disease is more complex than implied by the core gene omnigenic model. Cell 173:1573–80
    [Google Scholar]
  221. Yanes T, McInerney-Leo AM, Law M, Cummings S 2020. The emerging field of polygenic risk scores and perspective for use in clinical care. Hum. Mol. Genet. 29(R2):R165–76
    [Google Scholar]
  222. Zeggini E, Panoutsopoulou K, Southam L, Rayner NW, Day-Williams AG et al. 2012. Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study. Lancet 380:815–23
    [Google Scholar]
  223. Zhang Y, Qi G, Park J-H, Chatterjee N 2018. Estimation of complex effect-size distributions using summary-level statistics from genome-wide association studies across 32 complex traits. Nat. Genet. 50:1318–26
    [Google Scholar]
  224. Zorina-Lichtenwalter K, Meloto CB, Khoury S, Diatchenko L 2016. Genetic predictors of human chronic pain conditions. Neuroscience 338:36–62
    [Google Scholar]
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