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Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis.

Publication ,  Journal Article
Castaño-Betancourt, MC; Evans, DS; Ramos, YFM; Boer, CG; Metrustry, S; Liu, Y; den Hollander, W; van Rooij, J; Kraus, VB; Yau, MS; Mitchell, BD ...
Published in: PLoS Genet
October 2016

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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Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

October 2016

Volume

12

Issue

10

Start / End Page

e1006260

Location

United States

Related Subject Headings

  • Trehalase
  • Transforming Growth Factor alpha
  • Regulatory Sequences, Nucleic Acid
  • Receptor, Fibroblast Growth Factor, Type 3
  • Polymorphism, Single Nucleotide
  • Phosphatidylinositol 3-Kinases
  • Osteoarthritis, Hip
  • Middle Aged
  • Male
  • Humans
 

Citation

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Castaño-Betancourt, M. C., Evans, D. S., Ramos, Y. F. M., Boer, C. G., Metrustry, S., Liu, Y., … van Meurs, J. B. J. (2016). Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis. PLoS Genet, 12(10), e1006260. https://doi.org/10.1371/journal.pgen.1006260
Castaño-Betancourt, Martha C., Dan S. Evans, Yolande F. M. Ramos, Cindy G. Boer, Sarah Metrustry, Youfang Liu, Wouter den Hollander, et al. “Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis.PLoS Genet 12, no. 10 (October 2016): e1006260. https://doi.org/10.1371/journal.pgen.1006260.
Castaño-Betancourt MC, Evans DS, Ramos YFM, Boer CG, Metrustry S, Liu Y, et al. Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis. PLoS Genet. 2016 Oct;12(10):e1006260.
Castaño-Betancourt, Martha C., et al. “Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis.PLoS Genet, vol. 12, no. 10, Oct. 2016, p. e1006260. Pubmed, doi:10.1371/journal.pgen.1006260.
Castaño-Betancourt MC, Evans DS, Ramos YFM, Boer CG, Metrustry S, Liu Y, den Hollander W, van Rooij J, Kraus VB, Yau MS, Mitchell BD, Muir K, Hofman A, Doherty M, Doherty S, Zhang W, Kraaij R, Rivadeneira F, Barrett-Connor E, Maciewicz RA, Arden N, Nelissen RGHH, Kloppenburg M, Jordan JM, Nevitt MC, Slagboom EP, Hart DJ, Lafeber F, Styrkarsdottir U, Zeggini E, Evangelou E, Spector TD, Uitterlinden AG, Lane NE, Meulenbelt I, Valdes AM, van Meurs JBJ. Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis. PLoS Genet. 2016 Oct;12(10):e1006260.

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

October 2016

Volume

12

Issue

10

Start / End Page

e1006260

Location

United States

Related Subject Headings

  • Trehalase
  • Transforming Growth Factor alpha
  • Regulatory Sequences, Nucleic Acid
  • Receptor, Fibroblast Growth Factor, Type 3
  • Polymorphism, Single Nucleotide
  • Phosphatidylinositol 3-Kinases
  • Osteoarthritis, Hip
  • Middle Aged
  • Male
  • Humans