Article Text

Download PDFPDF
Extended report
Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density
  1. Nerea Alonso1,
  2. Karol Estrada2,
  3. Omar M E Albagha1,3,
  4. Lizbeth Herrera2,
  5. Sjur Reppe4,5,6,
  6. Ole K Olstad4,
  7. Kaare M Gautvik5,6,
  8. Niamh M Ryan7,
  9. Kathryn L Evans7,8,
  10. Carrie M Nielson9,
  11. Yi-Hsiang Hsu10,11,12,
  12. Douglas P Kiel11,12,13,
  13. George Markozannes14,
  14. Evangelia E Ntzani14,15,
  15. Evangelos Evangelou14,16,
  16. Bjarke Feenstra17,
  17. Xueping Liu17,
  18. Mads Melbye17,18,19,
  19. Laura Masi20,
  20. Maria Luisa Brandi20,
  21. Philip Riches1,
  22. Anna Daroszewska1,21,
  23. José Manuel Olmos22,
  24. Carmen Valero22,
  25. Jesús Castillo22,
  26. José A Riancho22,
  27. Lise B Husted23,
  28. Bente L Langdahl23,
  29. Matthew A Brown24,
  30. Emma L Duncan24,25,26,
  31. Stephen Kaptoge27,
  32. Kay-Tee Khaw28,
  33. Ricardo Usategui-Martín29,
  34. Javier Del Pino-Montes29,
  35. Rogelio González-Sarmiento29,
  36. Joshua R Lewis30,31,32,
  37. Richard L Prince30,33,
  38. Patrizia D’Amelio34,
  39. Natalia García-Giralt35,
  40. Xavier Nogués35,
  41. Simona Mencej-Bedrac36,
  42. Janja Marc36,
  43. Orit Wolstein37,
  44. John A Eisman37,
  45. Ling Oei2,
  46. Carolina Medina-Gómez2,
  47. Katharina E Schraut38,39,
  48. Pau Navarro40,
  49. James F Wilson38,40,
  50. Gail Davies8,
  51. John Starr8,
  52. Ian Deary8,
  53. Toshiko Tanaka41,
  54. Luigi Ferrucci41,
  55. Fernando Gianfrancesco42,
  56. Luigi Gennari43,
  57. Gavin Lucas44,
  58. Roberto Elosua44,
  59. André G Uitterlinden2,
  60. Fernando Rivadeneira2,
  61. Stuart H Ralston1
  1. 1 Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
  2. 2 Departments of Internal Medicine and Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands
  3. 3 Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar
  4. 4 Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
  5. 5 Department of Clinical Biochemistry, Lovisenberg Diakonale Hospital, Oslo, Norway
  6. 6 Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
  7. 7 Centre for Genomic and Experimental Medicine, IGMM, University of Edinburgh, Edinburgh, UK
  8. 8 Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
  9. 9 Department of Public Health and Preventive Medicine, Oregon Health and Science University, Portland, Oregon, USA
  10. 10 Department of Medicine Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
  11. 11 BROAD Institute of MIT and Harvard, Cambridge, Massachusetts, USA
  12. 12 Musculoskeletal Research Center, Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts, USA
  13. 13 Harvard Medical School, Boston, Massachusetts, USA
  14. 14 Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
  15. 15 Centre for Evidence Synthesis in Health, Department of Health Services, Policy and Practice, School of Public Health, Brown University, Rhode Island, USA
  16. 16 Department of Epidemiology and Biostatistics, Imperial College London, London, UK
  17. 17 Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
  18. 18 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  19. 19 Department of Medicine, Stanford School of Medicine, Stanford, California, USA
  20. 20 Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
  21. 21 Institute of Ageing and Chronic Disease, The MRC-Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing, University of Liverpool, Liverpool, UK
  22. 22 Department of Internal Medicine, Hospital UM Valdecilla, University of Cantabria, IDIVAL, RETICEF, Santander, Spain
  23. 23 Department of Endocrinology and Internal Medicine THG, Aarhus University Hospital, Aarhus, Denmark
  24. 24 Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia
  25. 25 Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
  26. 26 Department of Endocrinology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
  27. 27 Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  28. 28 Department of Public Health and Primary Care, School of Medicine, University of Cambridge, Cambridge, UK
  29. 29 Molecular Medicine Unit, Department of Medicine and Biomedical Research Institute of Salamanca (IBSAL), University Hospital of Salamanca, University of Salamanca – CSIC, Salamanca, Spain
  30. 30 School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia
  31. 31 Centre for Kidney Research, School of Public Health, University of Sydney, Sydney, New South Wales, Australia
  32. 32 School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia
  33. 33 Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
  34. 34 Gerontology and Bone Metabolic Diseases Unit, Department of Medical Science, University of Torino, Torino, Italy
  35. 35 Department of Internal Medicine, Hospital del Mar-IMIM, RETICEF, Universitat Autonoma de Barcelona, Barcelona, Spain
  36. 36 Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
  37. 37 Osteoporosis and Bone Biology Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
  38. 38 Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK
  39. 39 Edinburgh/British Heart Foundation Centre for Cardiovascular Science, QMRI, University of Edinburgh, Edinburgh, UK
  40. 40 MRC Human Genetics Unit, MRC, IGMM, University of Edinburgh, Edinburgh, UK
  41. 41 Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA
  42. 42 Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council of Italy, Naples, Italy
  43. 43 Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
  44. 44 Grup de Recerca en Genètica i Epidemiologia Cardiovascular, IMIM, Barcelona, Spain
  1. Correspondence to Professor Stuart H Ralston, Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, IGMM University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK; stuart.ralston{at}ed.ac.uk

Abstract

Objectives To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis.

Methods Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies.

Results A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10−9) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures.

Conclusion We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism.

  • osteoporosis
  • gene polymorphism
  • bone mineral density

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Footnotes

  • Handling editor Tore K Kvien

  • Contributors Study conception: SHR, NA, AGU and FR; data collection: NA, OMEA, LM, MLB, PR, AD, JMO, CV, JC, JAR, LBH, BLL, MAB, ELD, SK, K-TK, RU-M, JdP-M, RG-S, JRL, RLP, PD, NG-G, XN, SM-B, JM, OW, JAE, BF, MM, KES, PN, JFW, GD, JS, ID, TT, LF, FG, LG, GL and RE; genotyping: AGU and FR; data analysis: NA, OMEA, SR, OKO, KMG, NMR, KLE, CMN, Y-HH, DPK, GM, EEN, EE, XL, BF, MM, KES, LH, LO and CMG; drafting of the manuscript: NA and SHR; all authors contributed to critically review the article and approved the final manuscript. NA, SR, CMN, EEN and NMR takes responsibility for the data analysis.

  • Funding ORCADES was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK and the European Union framework programme 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We would like to acknowledge the invaluable contributions of Lorraine Anderson and the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. CABRIO was supported by the Instituto de Salud Carlos III and Fondos FEDER from the EU (PI 11/1092 and PI12/615). The AOGC study was funded by the Australian National Health and Medical Research Council (Project grant 511132). Lothian Birth Cohort 1921 phenotype collection was supported by the UK’s Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Age UK (The Disconnected Mind project). Genotyping of the cohorts was funded by the BBSRC. The work was undertaken by the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the BBSRC and Medical Research Council (MRC) is gratefully acknowledged. Research work on Slovenian case and control samples was funded by Slovenian Research Agency (project no. P3-0298 and J3-2330). The Danish National Birth Cohort (DNBC) is a result of major grants from the Danish National Research Foundation, the Danish Pharmacists’ Fund, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation and the Health Fund of the Danish Health Insurance Societies. The DNBC biobank is a part of the Danish National Biobank resource, which is supported by the Novo Nordisk Foundation. Dr Bjarke Feenstra is supported by an Oak Foundation Fellowship. The Framingham Study was funded by grants from the US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Aging (R01 AR 41398 and R01 AR061162; DPK and R01 AR 050066; DK). The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute’s Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA‐II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This research was performed within the Genetic Factors for Osteoporosis (GEFOS) consortium, funded by the European Commission (HEALTH-F2-2008-201865-GEFOS).

  • Competing interests None declared.

  • Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.

  • Ethics approval Each study received local ethical approval by the relevant ethics committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement There is not any additional unpublished data from the study.