Investigation of association between hip osteoarthritis susceptibility loci and radiographic proximal femur shape.
OBJECTIVE
To 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.


METHODS
We 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.


RESULTS
The 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.


CONCLUSIONS
These de novo findings suggest that rs4836732, rs6976, and rs5009270 may contribute to hip OA susceptibility by altering proximal femur shape.
University of Manchester, Manchester, UK.
Claudia
C
Lindner
University of Sheffield, Sheffield, UK.
Shankar
S
Thiagarajah
University of Sheffield, Sheffield, UK.
J Mark
JM
Wilkinson
Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
Kalliope
K
Panoutsopoulou
Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK (current address: Biogen, Cambridge, Massachusetts).
Aaron G
AG
Day-Williams
University of Manchester, Manchester, UK.
Timothy F
TF
Cootes
University of Manchester, Manchester, UK.
Gillian A
GA
Wallis
D000368:Aged; D015331:Cohort Studies; D005260:Female; D005269:Femur / Q000033:anatomy & histology / Q000000981:diagnostic imaging; D005270:Femur Head / Q000033:anatomy & histology / Q000000981:diagnostic imaging*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006023:Glycoproteins / Q000235:genetics; D016695:Glycosyltransferases / Q000235:genetics; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009419:Nerve Tissue Proteins / Q000235:genetics; D015207:Osteoarthritis, Hip / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011859:Radiography
C000593289:ASTN2 protein, human; D006023:Glycoproteins; C490045:IFRD1 protein, human; D017874:Immediate-Early Proteins; D009419:Nerve Tissue Proteins; C000592012:GLT8D1 protein, human; D016695:Glycosyltransferases