Abstract
Objective
Hip 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.
Methods
Hip 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.
Results
Complete genotypic and phenotypic data were available for 3,550 and 3,175 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 x10-8; age 18: -0.05, p=3.3 x10-6) and HSM5 (age 14: beta -0.07, p=1.6 x10-4; age 18: -0.1, p=2.7 x10-6). There was also strong evidence of association between rs10743612 (near PTHLH) and HSM1 (age 14: 0.05, p=1.1 x10-5; 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.
Conclusion
In 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.
Hip 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.
Methods
Hip 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.
Results
Complete genotypic and phenotypic data were available for 3,550 and 3,175 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 x10-8; age 18: -0.05, p=3.3 x10-6) and HSM5 (age 14: beta -0.07, p=1.6 x10-4; age 18: -0.1, p=2.7 x10-6). There was also strong evidence of association between rs10743612 (near PTHLH) and HSM1 (age 14: 0.05, p=1.1 x10-5; 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.
Conclusion
In 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.
| Original language | English |
|---|---|
| Article number | 115792 |
| Number of pages | 7 |
| Journal | Bone |
| Volume | 143 |
| Early online date | 4 Dec 2020 |
| DOIs | |
| Publication status | Published - 1 Feb 2021 |
Bibliographical note
Funding Information:The UK Medical Research Council and the Wellcome Trust (ref: 102215/2/13/2 ) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). GWAS data was generated at Laboratory Corporation of America (LabCorp Holdings, Burlington, NC, USA) by 23andMe and small subset was also performed at Wellcome Sanger Institute to check data quality. MF was supported by a Wellcome Trust PhD studentship (ref: 105504/Z/14/Z). LP works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council and the University of Bristol (MC_UU_00011/1).
Funding Information:
We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The UK Medical Research Council and the Wellcome Trust (ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). GWAS data was generated at Laboratory Corporation of America (LabCorp Holdings, Burlington, NC, USA) by 23andMe and small subset was also performed at Wellcome Sanger Institute to check data quality. MF was supported by a Wellcome Trust PhD studentship (ref: 105504/Z/14/Z). LP works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council and the University of Bristol (MC_UU_00011/1). This publication is the work of the authors and MF will serve as guarantor for the contents of this paper. None of the funders had any influence on data collection, analysis, interpretation of the results, or writing of the paper.
Publisher Copyright:
© 2020 The Author(s)
Keywords
- ALSPAC
- DXA
- hip shape
- Osteoarthritis
- Hip fracture risk
- Genetic association