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

Baird, Denis; Paternoster, Lavinia; Gregory, Jennifer S.; Faber, Benjamin G; Saunders, Fiona; Giuraniuc, Claudiu V.; Barr, Rebecca; Lawlor, Deborah A; Aspden, Richard M.; Tobias, Jonathan H

doi:10.1002/art.40584

Cited by 26 publications

(27 citation statements)

References 36 publications

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“…S6). (26) Therefore, using the hypothesis-free GWAS approach, the present study has advanced understanding of the genetic influence on hip shape through identification of six new associated loci.…”

Section: Astn2mentioning

confidence: 99%

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

Baird

Evans

Kamanu

et al. 2018

Journal of Bone and Mineral Research

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We aimed to report the first genomewide association study (GWAS) meta‐analysis of dual‐energy X‐ray absorptiometry (DXA)‐derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant ( p < 5 × 10 −9 , adjusted for 10 independent outcomes) single‐nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look‐up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9 , PTHrP , RUNX1 , NKX3‐2 , FGFR4 , DICER1 , and HHIP . The SNP adjacent to DICER1 also showed osteoblast cis‐regulatory activity of GSC , in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD ( r 2 > 0.5) were identified, which intersected with open chromatin sites as detected by ATAC‐seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

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Section: Astn2mentioning

confidence: 99%

“…rs13148031 and rs4837613, previously suggested to be associated with increased and decreased joint space width, respectively, are in high LD (r 2 > 0.8) with minor alleles of 4q31.21 and ASTN2 reported here. (26) Hip fracture…”

Section: Hip Oamentioning

confidence: 99%

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

Baird

Evans

Kamanu

et al. 2018

Journal of Bone and Mineral Research

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“…This was demonstrated recently when exploring the genetic influences on hip shape with the gene for disruptor of telomeric silencing 1-like (DOT1L) protein. Investigators reported that this polymorphism was associated with a reduced superior joint space seen on subregional modelling, and this result was not evident when looking at whole hip shape models 16 .…”

Section: Introductionmentioning

confidence: 99%

Subregional statistical shape modelling identifies lesser trochanter size as a possible risk factor for radiographic hip osteoarthritis, a cross-sectional analysis from the Osteoporotic Fractures in Men Study

Faber

Bredbenner

Baird

et al. 2020

Osteoarthritis and Cartilage

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Objective: Statistical shape modelling (SSM) of hip dual-energy X-ray absorptiometry (DXA) scans has identified relationships between hip shape and radiographic hip OA (rHOA). We aimed to further elucidate shape characteristics related to rHOA by focusing on subregions identified from whole-hip shape models. Method: SSM was applied to hip DXAs obtained in the Osteoporotic Fractures in Men Study. Whole-hip shape modes (HSMs) associated with rHOA were combined to form a composite at-risk-shape. Subsequently, subregional HSMs (cam-type and lesser trochanter modes) were built, and associations with rHOA were examined by logistic regression. Subregional HSMs were further characterised, by examining associations with 3D-HSMs derived from concurrent hip CT scans. Results: 4,098 participants were identified with hip DXAs and radiographs. Composite shapes from whole-hip HSMs revealed that lesser trochanter size and cam-type femoral head are related to rHOA. From sub-regional models, lesser trochanter mode (LTM)1 [OR 0.74; 95%CI 0.63.0.87] and cam-type mode (CTM)3 [OR 1.27; 1.13.1.42] were associated with rHOA, associations being similar to those for whole hip HSMs. 515 MrOS participants had hip DXAs and 3D-HSMs derived from hip CT scans. LTM1 was associated with 3D-HSMs that also represented a larger lesser trochanter [3D-HSM7 (beta (b)-0.23;-0.33,-0.14) and 3D-HSM9 (b0.36; 0.27.0.45)], and CTM3 with 3D-HSMs describing cam morphology [3D-HSM3 (b-0.16;-0.25,-0.07) and 3D-HSM6 (b 0.19; 0.10.0.28)]. Conclusion: Subregional SSM of hip DXA scans suggested larger lesser trochanter and cam morphology underlie associations between overall hip shape and rHOA. 3D hip modelling suggests our subregional SSMs represent true anatomical variations in hip shape, warranting further investigation.

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“…It is also increasingly well understood that subtle changes to skeletal morphology and joint shape can increase susceptibility to joint conditions such as OA later in life [ 24 ]. A recent large genome-wide association study on hip shape identified COL11A1 as a contributor to hip shape [ 25 ]. Joint shapes seen in development and disease have been shown to have significant impact on the biomechanical performance of joints [ 24 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

The mechanical impact of col11a2 loss on joints; col11a2 mutant zebrafish show changes to joint development and function, which leads to early-onset osteoarthritis

Lawrence

Kague

Aggleton

et al. 2018

Phil. Trans. R. Soc. B

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Collagen is the major structural component of cartilage, and mutations in the genes encoding type XI collagen are associated with severe skeletal dysplasias (fibrochondrogenesis and Stickler syndrome) and early-onset osteoarthritis (OA). The impact of the lack of type XI collagen on cell behaviour and mechanical performance during skeleton development is unknown. We studied a zebrafish mutant for col11a2 and evaluated cartilage, bone development and mechanical properties to address this. We show that in col11a2 mutants, type II collagen is made but is prematurely degraded in maturing cartilage and ectopically expressed in the joint. These changes are correlated with increased stiffness of both bone and cartilage; quantified using atomic force microscopy. In the mutants, the skeletal rudiment terminal region in the jaw joint is broader and the interzone smaller. These differences in shape and material properties impact on joint function and mechanical performance, which we modelled using finite element analyses. Finally, we show that col11a2 heterozygous carriers reach adulthood but show signs of severe early-onset OA. Taken together, our data demonstrate a key role for type XI collagen in maintaining the properties of cartilage matrix; which when lost leads to alterations to cell behaviour that give rise to joint pathologies.This article is part of the Theo Murphy meeting issue ‘Mechanics of development’.

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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

Abstract: Hip OA susceptibility loci were associated with shape in this study, suggesting that these loci (and potentially yet-to-be-identified hip OA loci) could contribute to hip OA in later life via perturbing biologic pathways that mediate morphology development.

Cited by 26 publications

References 36 publications

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

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

Subregional statistical shape modelling identifies lesser trochanter size as a possible risk factor for radiographic hip osteoarthritis, a cross-sectional analysis from the Osteoporotic Fractures in Men Study

The mechanical impact of col11a2 loss on joints; col11a2 mutant zebrafish show changes to joint development and function, which leads to early-onset osteoarthritis

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