TY - JOUR
T1 - Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis
AU - Castaño-Betancourt, Martha C
AU - Evans, Dan S
AU - Ramos, Yolande F M
AU - Boer, Cindy G
AU - Metrustry, Sarah
AU - Liu, Youfang
AU - den Hollander, Wouter
AU - van Rooij, Jeroen
AU - Kraus, Virginia B
AU - Yau, Michelle S
AU - Mitchell, Braxton D
AU - Muir, Kenneth
AU - Hofman, Albert
AU - Doherty, Michael
AU - Doherty, Sally
AU - Zhang, Weiya
AU - Kraaij, Robert
AU - Rivadeneira, Fernando
AU - Barrett-Connor, Elizabeth
AU - Maciewicz, Rose A
AU - Arden, Nigel
AU - Nelissen, Rob G H H
AU - Kloppenburg, Margreet
AU - Jordan, Joanne M
AU - Nevitt, Michael C
AU - Slagboom, Eline P
AU - Hart, Deborah J
AU - Lafeber, Floris
AU - Styrkarsdottir, Unnur
AU - Zeggini, Eleftheria
AU - Evangelou, Evangelos
AU - Spector, Tim D
AU - Uitterlinden, Andre G
AU - Lane, Nancy E
AU - Meulenbelt, Ingrid
AU - Valdes, Ana M
AU - van Meurs, Joyce B J
PY - 2016/10/4
Y1 - 2016/10/4
N2 - 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.
AB - 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.
U2 - 10.1371/journal.pgen.1006260
DO - 10.1371/journal.pgen.1006260
M3 - Article
C2 - 27701424
SN - 1553-7390
VL - 12
JO - PL o S Genetics
JF - PL o S Genetics
IS - 10
M1 - e1006260
ER -