RT Journal Article
SR Electronic
T1 Radiographic endophenotyping in hip osteoarthritis improves the precision of genetic association analysis
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 1199
OP 1206
DO 10.1136/annrheumdis-2016-210373
VO 76
IS 7
A1 Kalliope Panoutsopoulou
A1 Shankar Thiagarajah
A1 Eleni Zengini
A1 Aaron G Day-Williams
A1 Yolande FM Ramos
A1 Jennifer MTA Meessen
A1 Kasper Huetink
A1 Rob GHH Nelissen
A1 Lorraine Southam
A1 N William Rayner
A1 arcOGEN Consortium
A1 Michael Doherty
A1 Ingrid Meulenbelt
A1 Eleftheria Zeggini
A1 J Mark Wilkinson
YR 2017
UL http://ard.bmj.com/content/76/7/1199.abstract
AB Objective Osteoarthritis (OA) has a strong genetic component but the success of previous genome-wide association studies (GWAS) has been restricted due to insufficient sample sizes and phenotype heterogeneity. Our aim was to examine the effect of clinically relevant endophenotyping according to site of maximal joint space narrowing (maxJSN) and bone remodelling response on GWAS signal detection in hip OA.Methods A stratified GWAS meta-analysis was conducted in 2118 radiographically defined hip OA cases and 6500 population-based controls. Signals were followed up by analysing differential expression of proximal genes for bone remodelling endophenotypes in 33 pairs of macroscopically intact and OA-affected cartilage.Results We report suggestive evidence (p<5×10−6) of association at 6 variants with OA endophenotypes that would have been missed by using presence of hip OA as the disease end point. For example, in the analysis of hip OA cases with superior maxJSN versus cases with non-superior maxJSN we detected association with a variant in the LRCH1 gene (rs754106, p=1.49×10−7, OR (95% CIs) 0.70 (0.61 to 0.80)). In the comparison of hypertrophic with non-hypertrophic OA the most significant variant was located between STT3B and GADL1 (rs6766414, p=3.13×10−6, OR (95% CIs) 1.45 (1.24 to 1.69)). Both of these associations were fully attenuated in non-stratified analyses of all hip OA cases versus population controls (p>0.05). STT3B was significantly upregulated in OA-affected versus intact cartilage, particularly in the analysis of hypertrophic and normotrophic compared with atrophic bone remodelling pattern (p=4.2×10−4).Conclusions Our findings demonstrate that stratification of OA cases into more homogeneous endophenotypes can identify genes of potential functional importance otherwise obscured by disease heterogeneity.