Investigation of Association Between Hip Osteoarthritis Susceptibility Loci and Radiographic Proximal Femur Shape

Abstract

ObjectiveTo test whether previously reported hip morphology or osteoarthritis (OA) susceptibility loci are associated with proximal femur shape as represented by statistical shape model (SSM) modes and as univariate or multivariate quantitative traits.MethodsWe used pelvic radiographs and genotype data from 929 subjects with unilateral hip OA who had been recruited previously for the Arthritis Research UK Osteoarthritis Genetics Consortium genome‐wide association study. We built 3 SSMs capturing the shape variation of the OA‐unaffected proximal femur in the entire mixed‐sex cohort and for male/female‐stratified cohorts. We selected 41 candidate single‐nucleotide polymorphisms (SNPs) previously reported as being associated with hip morphology (for replication analysis) or OA (for discovery analysis) and for which genotype data were available. We performed 2 types of analysis for genotype–phenotype associations between these SNPs and the modes of the SSMs: 1) a univariate analysis using individual SSM modes and 2) a multivariate analysis using combinations of SSM modes.ResultsThe univariate analysis identified association between rs4836732 (within the ASTN2 gene) and mode 5 of the female SSM (P = 0.0016) and between rs6976 (within the GLT8D1 gene) and mode 7 of the mixed‐sex SSM (P = 0.0003). The multivariate analysis identified association between rs5009270 (near the IFRD1 gene) and a combination of modes 3, 4, and 9 of the mixed‐sex SSM (P = 0.0004). Evidence of associations remained significant following adjustment for multiple testing. All 3 SNPs had previously been associated with hip OA.ConclusionThese de novo findings suggest that rs4836732, rs6976, and rs5009270 may contribute to hip OA susceptibility by altering proximal femur shape.

Identification of Novel Loci Associated With Hip Shape: A Meta-Analysis of Genomewide Association Studies

“…Table S6). rs4836732, reported to be associated with hip shape by Lindner and colleagues, (6) is in LD (r 2 ¼ 0.49) with rs1885245 ASTN2 SNP we found to be associated with HSM2, both studies observing relationships with femoral head size. Six other SNPs identified across these two SSM studies showed little evidence of association with hip shape in the present study.…”

Radiographic endophenotyping in hip osteoarthritis improves the precision of genetic association analysis

“…However, this approach has been successfully applied to better understand disease biology in related complex traits, including joint shape and pain. [46][47][48][49][50] The results of our analyses show that, if further replication is targeted to the specific OA endophenotypes, study power may improve from nearly 0% in the traditional approach to 80% in a sample size of <5000 cases. We used post hoc power calculations, applying the observed variances from the study population of interest to exemplify the difference in the statistical power of the tests we performed.…”

Investigation of the Relationship Between Susceptibility Loci for Hip Osteoarthritis and Dual X‐Ray Absorptiometry–Derived Hip Shape in a Population‐Based Cohort of Perimenopausal Women

“…An intronic SNP within ASTN2 and a 3′‐untranslated region SNP within GLT8D1 were associated with distinct HSMs in 929 subjects with unilateral hip OA in a model built on the superior femur from the unaffected hip. In the same study, a SNP located near IFRD1 was also associated with a combination of 3 distinct modes in a multivariate canonical correlation analysis (CCA) .…”