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PLoS Genet. 2016 Oct 4;12(10):e1006260. doi: 10.1371/journal.pgen.1006260. eCollection 2016 Oct.

Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis.

Author information

1
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
2
California Pacific Medical Center Research Institute, San Francisco, California, United States of America.
3
Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology. Leiden University Medical Center, Leiden, The Netherlands.
4
Department of Twins Research and Genetic Epidemiology Unit, King's College London, London, United Kingdom.
5
Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, North Carolina, United States of America.
6
Duke Molecular Physiology Institute and Division of Rheumatology. Duke University School of Medicine, Durham, North Carolina, United States of America.
7
Departments of Medicine and Epidemiology & Public Health, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
8
Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, Maryland, United States of America.
9
Health Sciences Research Institute, University of Warwick, Warwick, United Kingdom.
10
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
11
Department of Epidemiology, Harvard T.H. School of Public Health, Boston, Massachusetts, United States of America.
12
School of Medicine, University of Nottingham, Nottingham, United Kingdom.
13
Epidemiology Division, Family Medicine and Public Health Department, University of California, San Diego, La Jolla, California.
14
Respiratory, Inflammation, Autoimmunity Innovative Medicines, AstraZeneca AB, Mölndal, Sweden.
15
Nuffield Department of Orthopaedics, Rheumatology and musculoskeletal sciences, University of Oxford, United Kingdom.
16
Department of Orthopaedics, Leiden University Medical Center, Leiden The Netherlands.
17
Department of Rheumatology and Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
18
University of California at San Francisco, San Francisco, California.
19
University Medical Center Utrecht, Utrecht, The Netherlands.
20
Decode Genetics, Reykjavik, Iceland.
21
Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
22
Department of Hygiene & Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
23
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
24
School of Medicine, University of California, Davis, Sacramento, California.

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.

PMID:
27701424
PMCID:
PMC5049763
DOI:
10.1371/journal.pgen.1006260
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The collection of GOAL samples was funded by Astra Zeneca UK. Dr R. Maciewicz has ownership of stocks or shares in AstraZeneca and has paid employment in AstraZeneca. Dr J. Jordan was funded for genotyping by Algynomics, Inc. and had, but no longer has, stock options in Algynomics. Dr. U. Styrkarsdottir is an employee of deCODE, a biotechnology company that provides genetic testing services. The set-up of the GARP study was partially funded by Pfzer. The GoGo study was funded by GlaxoSmithKline. The rest of the authors have declared that they have no competing interests.

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