Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis.

Castaño-Betancourt, Martha C

Evans, Dan S

Ramos, Yolande FM

Boer, Cindy G

Metrustry, Sarah

Liu, Youfang

den Hollander, Wouter

van Rooij, Jeroen

Kraus, Virginia B

Yau, Michelle S

Mitchell, Braxton D

Muir, Kenneth

Hofman, Albert

Doherty, Michael

Doherty, Sally

Zhang, Weiya

Kraaij, Robert

Rivadeneira, Fernando

Barrett-Connor, Elizabeth

Maciewicz, Rose A

Arden, Nigel

Nelissen, Rob GHH

Kloppenburg, Margreet

Jordan, Joanne M

Nevitt, Michael C

Slagboom, Eline P

Hart, Deborah J

Lafeber, Floris

Styrkarsdottir, Unnur

Zeggini, Eleftheria

Evangelou, Evangelos

Spector, Tim D

Uitterlinden, Andre G

Lane, Nancy E

Meulenbelt, Ingrid

Valdes, Ana M

van Meurs, Joyce BJ

Barsh, Gregory S

United States

2017-10-01T21:51:10Z

2017-10-01T21:51:10Z

2016-10

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.

https://www.ncbi.nlm.nih.gov/pubmed/27701424

PGENETICS-D-16-00520

1553-7404

https://hdl.handle.net/10161/15604

eng

Public Library of Science (PLoS)

PLoS Genet

10.1371/journal.pgen.1006260

Aged

Aged, 80 and over

Cartilage

Female

Genetic Heterogeneity

Genetic Predisposition to Disease

Genome-Wide Association Study

Hip Joint

Humans

Male

Middle Aged

Osteoarthritis, Hip

Phosphatidylinositol 3-Kinases

Polymorphism, Single Nucleotide

Receptor, Fibroblast Growth Factor, Type 3

Regulatory Sequences, Nucleic Acid

Transforming Growth Factor alpha

Trehalase

Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis.

Journal article

Kraus, Virginia B|0000-0001-8173-8258

https://www.ncbi.nlm.nih.gov/pubmed/27701424

e1006260

10

Clinical Science Departments

Duke

Duke Molecular Physiology Institute

Institutes and Centers

Medicine

Medicine, Rheumatology and Immunology

Orthopaedics

Pathology

School of Medicine

Published online

12