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Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region
  1. Marjolein J Peters1,2,
  2. Linda Broer3,
  3. Hanneke L D M Willemen4,
  4. Gudny Eiriksdottir5,
  5. Lynne J Hocking6,
  6. Kate L Holliday7,
  7. Michael A Horan8,
  8. Ingrid Meulenbelt9,
  9. Tuhina Neogi10,
  10. Maria Popham11,
  11. Carsten O Schmidt12,
  12. Anushka Soni13,
  13. Ana M Valdes11,
  14. Najaf Amin3,
  15. Elaine M Dennison14,15,
  16. Niels Eijkelkamp16,
  17. Tamara B Harris17,
  18. Deborah J Hart11,
  19. Albert Hofman3,
  20. Frank J P M Huygen18,
  21. Karen A Jameson14,
  22. Gareth T Jones19,
  23. Lenore J Launer17,
  24. Hanneke J M Kerkhof1,2,
  25. Marjolein de Kruijf1,2,18,
  26. John McBeth7,
  27. Margreet Kloppenburg20,21,
  28. William E Ollier22,
  29. Ben Oostra23,
  30. Antony Payton22,
  31. Fernando Rivadeneira1,2,3,
  32. Blair H Smith24,
  33. Albert V Smith5,25,
  34. Lisette Stolk1,2,
  35. Alexander Teumer26,
  36. Wendy Thomson7,
  37. André G Uitterlinden1,2,3,
  38. Ke Wang10,
  39. Sophie H van Wingerden3,
  40. Nigel K Arden14,27,
  41. Cyrus Cooper14,27,
  42. David Felson10,
  43. Vilmundur Gudnason5,25,
  44. Gary J Macfarlane19,
  45. Neil Pendleton8,
  46. P Eline Slagboom2,9,
  47. Tim D Spector11,
  48. Henry Völzke12,
  49. Annemieke Kavelaars4,
  50. Cornelia M van Duijn3,
  51. Frances M K Williams11,
  52. Joyce B J van Meurs1,2
  1. 1Department of Internal Medicine, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
  2. 2The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, The Netherlands
  3. 3Department of Epidemiology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
  4. 4Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, The Netherlands
  5. 5Icelandic Heart Association Research Institute, Kopavogur, Iceland
  6. 6Aberdeen Pain Research Collaboration (Musculoskeletal Research), University of Aberdeen, Aberdeen, UK
  7. 7Arthritis Research UK Epidemiology Unit, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
  8. 8Mental Health and Neurodegeneration Group, School Community Based Medicine, University of Manchester, Manchester, UK
  9. 9Department of Medical Statistics and Bioinformatics, Section of Molecular Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands
  10. 10Clinical Epidemiology Unit, Boston University School of Medicine, Boston, Massachusetts, USA
  11. 11Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
  12. 12Institute for Community Medicine, University of Greifswald, Greifswald, Germany
  13. 13NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK
  14. 14MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, UK
  15. 15School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand
  16. 16Molecular Nociception Group, University College London, London, UK
  17. 17Intramural Research Program, Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, Maryland, USA
  18. 18Department of Anaesthesiology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
  19. 19Aberdeen Pain Research Collaboration (Epidemiology Group), University of Aberdeen, Aberdeen, UK
  20. 20Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  21. 21Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
  22. 22Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK
  23. 23Department of Clinical Genetics, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
  24. 24Medical Research Institute, University of Dundee, Dundee, UK
  25. 25Department of Medicine, University of Iceland, Reykjavik, Iceland
  26. 26Institute of Functional Genomics, Ernst Moritz Arndt University Greifswald, University of Greifswald, Greifswald, Germany
  27. 27NIHR Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
  1. Correspondence to Dr Joyce B J van Meurs, Genetic Laboratory Department of Internal Medicine, Erasmus Medical Center Rotterdam, Room Ee579b, Erasmus MC, PO Box 2040, Rotterdam 3000 CA, The Netherlands; j.vanmeurs{at}erasmusmc.nl

Abstract

Background and objectives Chronic widespread pain (CWP) is a common disorder affecting ∼10% of the general population and has an estimated heritability of 48–52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP.

Methods We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain.

Results The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10−8). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10−7) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10−8, I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10−4).

Conclusions We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.

  • Gene Polymorphism
  • Fibromyalgis/Pain Syndromes
  • Epidemiology

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