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Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand

Hollander, Wouter den; Boer, Cindy G.; Hart, Deborah J.; Yau, Michelle S.; Ramos, Yolande F.M.; Metrustry, Sarah; Broer, Linda; Deelen, Joris; Cupples, L. Adrienne; Rivadeneira, Fernando; Kloppenburg, Margreet; Peters, Marjolein; Spector, Tim D.; Hofman, Albert; Slagboom, P. Eline; Nelissen, Rob G.H.H.; Uitterlinden, André G.; Felson, David T.; Valdes, Ana M.; Meulenbelt, Ingrid; van Meurs, Joyce J.B.

Authors

Wouter den Hollander

Cindy G. Boer

Deborah J. Hart

Michelle S. Yau

Yolande F.M. Ramos

Sarah Metrustry

Linda Broer

Joris Deelen

L. Adrienne Cupples

Fernando Rivadeneira

Margreet Kloppenburg

Marjolein Peters

Tim D. Spector

Albert Hofman

P. Eline Slagboom

Rob G.H.H. Nelissen

André G. Uitterlinden

David T. Felson

Ana M. Valdes

Ingrid Meulenbelt

Joyce J.B. van Meurs



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

Journal Article Type Article
Publication Date Sep 19, 2017
Journal Annals of the Rheumatic Diseases
Print ISSN 0003-4967
Electronic ISSN 1468-2060
Publisher BMJ Publishing Group
Peer Reviewed Peer Reviewed
APA6 Citation Hollander, W. D., Boer, C. G., Hart, D. J., Yau, M. S., Ramos, Y. F., Metrustry, S., …van Meurs, J. J. (2017). Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand. Annals of the Rheumatic Diseases, doi:10.1136/annrheumdis-2017-211214
DOI https://doi.org/10.1136/annrheumdis-2017-211214
Publisher URL http://ard.bmj.com/content/early/2017/09/19/annrheumdis-2017-211214
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf


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Copyright Statement
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Supplementary.Materials.final.version.pdf (685 Kb)
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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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