Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis

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  • Castaño-Betancourt, Martha C.
    • Other Affiliation: Department of Internal Medicine; Erasmus Medical Center
  • Evans, Dan S.
    • Other Affiliation: California Pacific Medical Center Research Institute
  • Ramos, Yolande F. M.
    • Other Affiliation: Department of Medical Statistics and Bioinformatics; Section Molecular Epidemiology; Leiden University Medical Center
  • Boer, Cindy G.
    • ORCID: 0000-0003-4809-0044
    • Other Affiliation: Department of Internal Medicine; Erasmus Medical Center
  • Metrustry, Sarah
    • Other Affiliation: Department of Twins Research and Genetic Epidemiology Unit; King’s College London
  • Liu, Youfang
    • Affiliation: School of Medicine, Thurston Arthritis Research Center
  • den Hollander, Wouter
    • Other Affiliation: Department of Medical Statistics and Bioinformatics; Section Molecular Epidemiology; Leiden University Medical Center
  • van Rooij, Jeroen
    • ORCID: 0000-0001-9754-073X
    • Other Affiliation: Department of Internal Medicine; Erasmus Medical Center
  • Kraus, Virginia B.
    • Other Affiliation: Duke Molecular Physiology Institute and Division of Rheumatology; Duke University School of Medicine
  • Yau, Michelle S.
    • Other Affiliation: Departments of Medicine and Epidemiology & Public Health; University of Maryland School of Medicine
  • Mitchell, Braxton D.
    • Other Affiliation: Departments of Medicine and Epidemiology & Public Health; University of Maryland School of Medicine
  • Muir, Kenneth
    • Other Affiliation: Health Sciences Research Institute; University of Warwick
  • Hofman, Albert
    • Other Affiliation: Department of Epidemiology; Erasmus Medical Center
  • Doherty, Michael
    • Other Affiliation: School of Medicine; University of Nottingham
  • Doherty, Sally
    • Other Affiliation: School of Medicine; University of Nottingham
  • Zhang, Weiya
    • Other Affiliation: School of Medicine; University of Nottingham
  • Kraaij, Robert
    • Other Affiliation: Department of Internal Medicine; Erasmus Medical Center
  • Rivadeneira, Fernando
    • Other Affiliation: Department of Internal Medicine; Erasmus Medical Center
  • Barrett-Connor, Elizabeth
    • Other Affiliation: Epidemiology Division; Family Medicine and Public Health Department; University of California
  • Maciewicz, Rose A.
    • Other Affiliation: Respiratory; Inflammation; Autoimmunity Innovative Medicines
  • Arden, Nigel
    • Other Affiliation: Nuffield Department of Orthopaedics; Rheumatology and musculoskeletal sciences; University of Oxford
  • Nelissen, Rob G. H. H.
    • Other Affiliation: Department of Orthopaedics; Leiden University Medical Center
  • Kloppenburg, Margreet
    • Other Affiliation: Department of Rheumatology and Department of Clinical Epidemiology; Leiden University Medical Center
  • Jordan, Joanne M.
    • Affiliation: School of Medicine, Thurston Arthritis Research Center
  • Nevitt, Michael C.
    • Other Affiliation: University of California at San Francisco
  • Slagboom, Eline P.
    • Other Affiliation: Department of Medical Statistics and Bioinformatics; Section Molecular Epidemiology; Leiden University Medical Center
  • Hart, Deborah J.
    • Other Affiliation: Department of Twins Research and Genetic Epidemiology Unit; King’s College London
  • Lafeber, Floris
    • Other Affiliation: University Medical Center Utrecht
  • Styrkarsdottir, Unnur
    • Other Affiliation: Decode Genetics
  • Zeggini, Eleftheria
    • Other Affiliation: Wellcome Trust Sanger Institute
  • Evangelou, Evangelos
    • Other Affiliation: Department of Epidemiology and Biostatistics; School of Public Health; Imperial College London
  • Spector, Tim D.
    • Other Affiliation: Department of Twins Research and Genetic Epidemiology Unit; King’s College London
  • Uitterlinden, Andre G.
    • Other Affiliation: Department of Epidemiology; Erasmus Medical Center
  • Lane, Nancy E.
    • Other Affiliation: School of Medicine; University of California
  • Meulenbelt, Ingrid
    • Other Affiliation: Department of Medical Statistics and Bioinformatics; Section Molecular Epidemiology; Leiden University Medical Center
  • Valdes, Ana M.
    • Other Affiliation: School of Medicine; University of Nottingham
  • van Meurs, Joyce B. J.
    • Other Affiliation: Department of Internal Medicine; Erasmus Medical Center
Abstract
  • Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10−8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.
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Resource type
  • Article
Rights statement
  • In Copyright
Journal title
  • PLoS Genetics
Journal volume
  • 12
Journal issue
  • 10
Page start
  • e1006260
Language
  • English
ISSN
  • 1553-7390
  • 1553-7404

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