Abstract
ObjectiveHip shape is a well-recognized risk factor for hip osteoarthritis (OA) and hip fracture. We aimed to investigate whether the genetic variants known to be associated with adult hip shape were also associated with adolescent hip shape.MethodsHip DXA scans, obtained in offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC) at two time points (mean ages 13.8 and 17.8 years), were used to quantify hip morphology using a 53-point Statistical Shape Model (SSM). Principal component analysis was used to generate hip shape modes (HSMs). Genetic variants which had previously shown genome-wide significant association with specific HSMs in adults were tested for association with the same HSMs in adolescents (at each timepoint separately) using SNPTEST v2.ResultsComplete genotypic and phenotypic data were available for 3550 and 3175 individuals at 14 and 18 years, respectively. The strongest evidence for association with adolescent hip shape was for a variant located near SOX9 (rs2158915) with consistent effects across both time points for HSM1 (age 14: beta −0.05, p = 9.9 × 10−8; age 18: −0.05, p = 3.3 × 10−6) and HSM5 (age 14: beta −0.07, p = 1.6 × 10−4; age 18: −0.1, p = 2.7 × 10−6). There was also strong evidence of association between rs10743612 (near PTHLH) and HSM1 (age 14: 0.05, p = 1.1 × 10−5; age 18: 0.04, p = 0.003) and between rs6537291 (near HHIP) and HSM2 (age 14: −0.06, p = 0.001; age 18: −0.07, p = 0.001) across both time points. The genes with the strongest associations with hip shape in adolescents, (SOX9, PTHLH and HHIP) are known to be involved in endochondral bone formation. HSM1 indicates narrower aspect ratio of the upper femur, whereas both HSM2 and HSM5 reflect variation in the femoral head size and femoral neck width, features previously found to be related to the risk of OA in later life. The SOX9 locus has previously been found to associate with increased risk of hip fracture.ConclusionIn conclusion, variants implicated in endochondral bone formation appear to consistently influence hip shape between adolescence and adulthood, including those aspects related to risk of hip OA and/or fracture in later life.
Highlights
Hip shape is thought to be one of the most important risk factors for hip osteoarthritis (OA) [1], and has been found to be associated with the risk of osteoporotic hip fracture [2]
Further genetic evidence for the involvement of joint shape in the development of OA comes from a recent genome-wide association study (GWAS) of 770 cases with developmental dysplasia of the hip (DDH) and 3364 healthy controls, in the Na tional Joint Registry for England, Wales, Northern Ireland and the Isle of Man (NJR), which identified rs143383 variant in GDF5 to be robustly associated with DDH case status [13]; the same variant has been re ported to be associated with increased risk of OA [14]
In order to bridge this knowledge gap, we investigated if the eight genetic variants associated with adult dual-energy X-ray absorpti ometry (DXA)-derived hip shape in the previous adult GWAS [10] are associated with hip shape in adolescence
Summary
Hip shape is thought to be one of the most important risk factors for hip osteoarthritis (OA) [1], and has been found to be associated with the risk of osteoporotic hip fracture [2]. Further genetic evidence for the involvement of joint shape in the development of OA comes from a recent genome-wide association study (GWAS) of 770 cases with DDH and 3364 healthy controls, in the Na tional Joint Registry for England, Wales, Northern Ireland and the Isle of Man (NJR), which identified rs143383 variant in GDF5 to be robustly associated with DDH case status [13]; the same variant has been re ported to be associated with increased risk of OA [14]
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