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Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand
  1. Wouter den Hollander1,
  2. Cindy G Boer2,
  3. Deborah J Hart3,
  4. Michelle S Yau4,5,
  5. Yolande F M Ramos1,
  6. Sarah Metrustry3,
  7. Linda Broer2,
  8. Joris Deelen1,6,
  9. L Adrienne Cupples7,
  10. Fernando Rivadeneira2,
  11. Margreet Kloppenburg8,
  12. Marjolein Peters2,
  13. Tim D Spector3,
  14. Albert Hofman9,10,
  15. P Eline Slagboom1,
  16. Rob G H H Nelissen11,
  17. André G Uitterlinden2,9,
  18. David T Felson12,
  19. Ana M Valdes13,
  20. Ingrid Meulenbelt1,
  21. Joyce J B van Meurs2
  1. 1Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2Department of Internal Medicine, Genetic Laboratory, Erasmus Medical Center, Rotterdam, The Netherlands
  3. 3Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK
  4. 4Institute for Aging Research, Hebrew SeniorLife, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
  5. 5Clinical Epidemiology Research and Training Unit, Boston University School of Medicine, Boston, Massachusetts, USA
  6. 6Max Planck Institute for Biology of Ageing, Cologne, Germany
  7. 7Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA
  8. 8Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  9. 9Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
  10. 10Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
  11. 11Department of Orthopedics, Leiden University Medical Center, Leiden, The Netherlands
  12. 12Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester, UK
  13. 13School of Medicine, University of Nottingham, Nottingham, UK
  1. Correspondence to Dr Joyce J B van Meurs, Department of Internal Medicine, Erasmus MC, Dr Molewaterplein 50, Room Ee571, Rotterdam 3000DR, The Netherlands; j.vanmeurs{at}erasmusmc.nl

Abstract

Objective Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in the elderly. Of all the joints, genetic predisposition is strongest for OA of the hand; however, only few genetic risk loci for hand OA have been identified. Our aim was to identify novel genes associated with hand OA and examine the underlying mechanism.

Methods We performed a genome-wide association study of a quantitative measure of hand OA in 12 784 individuals (discovery: 8743, replication: 4011). Genome-wide significant signals were followed up by analysing gene and allele-specific expression in a RNA sequencing dataset (n=96) of human articular cartilage.

Results We found two significantly associated loci in the discovery set: at chr12 (p=3.5 × 10−10) near the matrix Gla protein (MGP) gene and at chr12 (p=6.1×10−9) near the CCDC91 gene. The DNA variant near the MGP gene was validated in three additional studies, which resulted in a highly significant association between the MGP variant and hand OA (rs4764133, Betameta=0.83, Pmeta=1.8*10−15). This variant is high linkage disequilibrium with a coding variant in MGP, a vitamin K-dependent inhibitor of cartilage calcification. Using RNA sequencing data from human primary cartilage tissue (n=96), we observed that the MGP RNA expression of the hand OA risk allele was significantly lowercompared with the MGP RNA expression of the reference allele (40.7%, p<5*10−16).

Conclusions Our results indicate that the association between the MGP variant and increased risk for hand OA is caused by a lower expression of MGP, which may increase the burden of hand OA by decreased inhibition of cartilage calcification.

  • genetics
  • hand osteoarthritis
  • genome-wide association study
  • functional study
  • Matrix-Gla protein

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Footnotes

  • IM and JJBM contributed equally,

  • WH and CGB contributed equally.

  • Handling editor Tore K Kvien

  • Contributors WdH and CGB contributed equally to this work. DJH, MSY, YFMR and SM performed replication analysis for this work, and LB provided analysis help. LAC and FR provided data. MK provided phenotypic contribution to the GARP study. MP provided data and analyses. TDS contributed data for replication. AH contributed data of the RS cohorts. JD, and PES contributed to genotyping data and analyses of LLS cohort. RGHHN provided contribution to the RAAK study. AGU contributed genotype data of RS cohorts. DTF and AMV contributed replication data for this work. IM and JJBvM jointly supervised this work.

  • Funding This study was funded by The Netherlands Society for Scientific Research (NWO) VIDI Grant 917103521. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. The generation and management of GWAS genotype data for the Rotterdam Study (RS I, RS II and RS III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for HealthyAging (NCHA), project nr. 050-060-810. The Leiden University Medical Centre, the Dutch Arthritis Association and Pfizer Inc., Groton, CT, USA, support the GARP study, while the LLS was supported by the Netherlands Organization of Scientific Research (MW 904-61-095, 911-03-016, 917-66-344 and 911-03-012), Leiden University Medical Centre and by the ’Centre of Medical System Biology' and the ’Netherlands Consortium of Healthy Aging' in the framework of the Netherlands Genomics Initiative (NGI). Furthermore, the research leading to the RAAK biobank and the current results has received funding from the Dutch Arthritis Association (DAA 2010_017) and the European Union’s Seventh Framework Programme (FP7/2007-2011) under grant agreement no. 259679. TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine was supported by the National Institutes of Health (contract no. HHSN268201500001I, N01-HC-25195, AG18393, AR47785) 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. MSY is supported by the National Institutes of Aging (T32AG023480).

  • 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 Ethics committees of the participating studies.

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

  • Author note IM and JJBvM: these authors jointly supervised this work.

  • Correction notice This article has been corrected since it published Online First. The equal contribution statement has been added.

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