Novel genetic variants for cartilage thickness and hip osteoarthritis
| Autor: | Weiya Zhang, Michael C. Nevitt, Fernando Rivadeneira, Martha C. Castaño-Betancourt, Elizabeth Barrett-Connor, Yolande F. M. Ramos, Margreet Kloppenburg, Jeroen van Rooij, Deborah J. Hart, Ingrid Meulenbelt, Sarah Metrustry, Michelle S. Yau, Joanne M. Jordan, Evangelos Evangelou, André G. Uitterlinden, Rose A. Maciewicz, Sally Doherty, Unnur Styrkarsdottir, Youfang Liu, Michael Doherty, Robert Kraaij, Ana M. Valdes, Daniel S. Evans, Virginia B. Kraus, Tim D. Spector, Wouter den Hollander, Braxton D. Mitchell, Kenneth Muir, Albert Hofman, Eleftheria Zeggini, Cindy G. Boer, Rob G H H Nelissen, Eline Slagboom, Nigel K Arden, Floris P J G Lafeber, Nancy E Lane, Joyce B. J. van Meurs |
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| Přispěvatelé: | Barsh, Gregory S, Internal Medicine, Epidemiology |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Aging Cancer Research Fibroblast Growth Factor Gene Expression Genome-wide association study Osteoarthritis Regulatory Sequences Nucleic Acid Osteoarthritis Hip Phosphatidylinositol 3-Kinases Medicine and Health Sciences 80 and over 2.1 Biological and endogenous factors Genetics(clinical) Trehalase Aetiology Musculoskeletal System Genetics (clinical) Exome sequencing Genetics Aged 80 and over Ecology Genomics Single Nucleotide Middle Aged 3. Good health Class Ia Phosphatidylinositol 3-Kinase Phenotypes medicine.anatomical_structure Connective Tissue Hip Joint Female Anatomy Type 3 Research Article Receptor lcsh:QH426-470 Evolution Single-nucleotide polymorphism and over Biology Polymorphism Single Nucleotide Pelvis 03 medical and health sciences Genetic Heterogeneity Rheumatology Behavior and Systematics Clinical Research Genome-Wide Association Studies medicine Receptor Fibroblast Growth Factor Type 3 Humans Genetic Predisposition to Disease Polymorphism Molecular Biology Ecology Evolution Behavior and Systematics Aged 0604 Genetics Hip Nucleic Acid Genetic heterogeneity Cartilage Arthritis Human Genome Biology and Life Sciences Computational Biology Human Genetics Transforming Growth Factor alpha Genome Analysis medicine.disease Human genetics lcsh:Genetics Joints (Anatomy) Biological Tissue 030104 developmental biology Genetic Loci Musculoskeletal Regulatory Sequences Genome-Wide Association Study Developmental Biology |
| Zdroj: | PLoS Genetics, 12(10). Public Library of Science PLoS genetics, vol 12, iss 10 Castaño-Betancourt, MC; Evans, DS; Ramos, YFM; Boer, CG; Metrustry, S; Liu, Y; et al.(2016). Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis. PLoS Genetics, 12(10), e1006260. doi: 10.1371/journal.pgen.1006260. UC Davis: Retrieved from: http://www.escholarship.org/uc/item/89m303gq Castaño-Betancourt, M C, Evans, D S, Ramos, Y F M, Boer, C G, Metrustry, S, Liu, Y, den Hollander, W, van Rooij, J, Kraus, V B, Yau, M S, Mitchell, B D, Muir, K, Hofman, A, Doherty, M, Doherty, S, Zhang, W, Kraaij, R, Rivadeneira, F, Barrett-Connor, E, Maciewicz, R A, Arden, N, Nelissen, R G H H, Kloppenburg, M, Jordan, J M, Nevitt, M C, Slagboom, E P, Hart, D J, Lafeber, F, Styrkarsdottir, U, Zeggini, E, Evangelou, E, Spector, T D, Uitterlinden, A G, Lane, N E, Meulenbelt, I, Valdes, A M & van Meurs, J B J 2016, ' Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis ', PL o S Genetics, vol. 12, no. 10, e1006260 . https://doi.org/10.1371/journal.pgen.1006260 PLoS Genetics PLoS Genetics, Vol 12, Iss 10, p e1006260 (2016) PLoS Genetics (online), 12(10):e1006260. Public Library of Science PLoS Genetics, 12(10) |
| ISSN: | 1553-7404 1553-7390 |
| DOI: | 10.1371/journal.pgen.1006260. |
| Popis: | 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. Author Summary Osteoarthritis (OA) is the most common form of arthritis and a leading cause of chronic disability in the western society affecting millions of people. OA is a degenerative joint disease characterized by changes in all joint tissues, including cartilage, bone and synovium, causing chronic pain and loss of function. There are no effective therapeutic treatments available for OA and therefore finding novel biological pathways through genetic association studies can open up new treatment options. The number of known DNA variants associated with OA-risk is limited. To identify new loci, we have performed a Genome Wide Association Study meta-analysis on cartilage thickness, one of the joint tissues affected in OA in a total sample of more than 20,000 individuals from twelve cohorts. This analysis revealed six variants associated with cartilage thickness, four of these being novel associations, including TGFA as the most prominent one. A systematic prioritization for underlying causal genes, using diverse lines of evidence, highlighted genes underlying the disease associations, including TGFA, RUNX2 and PIK3R1. Large scale exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies |
| Databáze: | OpenAIRE |
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