A Genome-Wide Association Study Meta-Analysis of Alpha Angle Suggests Cam-Type Morphology May Be a Specific Feature of Hip Osteoarthritis in Older Adults

Benjamin G. Faber; Monika Frysz; April E. Hartley; Raja Ebsim; Cindy G. Boer; Fiona R. Saunders; Jennifer S. Gregory; Richard M. Aspden; Nicholas C. Harvey; Lorraine Southam; William Giles; Christine L. Le Maitre; J. Mark Wilkinson; Joyce B.J. van Meurs; Eleftheria Zeggini; Timothy Cootes; Claudia Lindner; John P. Kemp; George Davey Smith; Jonathan H. Tobias

doi:10.1002/art.42451

A Genome-Wide Association Study Meta-Analysis of Alpha Angle Suggests Cam-Type Morphology May Be a Specific Feature of Hip Osteoarthritis in Older Adults

Benjamin G. Faber^*, Monika Frysz, April E. Hartley, Raja Ebsim, Cindy G. Boer, Fiona R. Saunders, Jennifer S. Gregory, Richard M. Aspden, Nicholas C. Harvey, Lorraine Southam, William Giles, Christine L. Le Maitre, J. Mark Wilkinson, Joyce B.J. van Meurs, Eleftheria Zeggini, Timothy Cootes, Claudia Lindner, John P. Kemp, George Davey Smith, Jonathan H. Tobias

^*Corresponding author for this work

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Abstract

Objective: To examine the genetic architecture of cam morphology using alpha angle (AA) as a proxy measure and conduct an AA genome-wide association study (GWAS) followed by Mendelian randomization (MR) to evaluate its causal relationship with hip osteoarthritis (OA). Methods: Observational analyses examined associations between AA measurements derived from hip dual x-ray absorptiometry (DXA) scans from the UK Biobank study and radiographic hip OA outcomes and subsequent total hip replacement. Following these analyses, an AA GWAS meta-analysis was performed (N = 44,214) using AA measurements previously derived in the Rotterdam Study. Linkage disequilibrium score regression assessed the genetic correlation between AA and hip OA. Genetic associations considered significant (P < 5 × 10⁻⁸) were used as AA genetic instrument for 2-sample MR analysis. Results: DXA-derived AA showed expected associations between AA and radiographic hip OA (adjusted odds ratio [OR] 1.63 [95% confidence interval (95% CI) 1.58, 1.67]) and between AA and total hip replacement (adjusted hazard ratio 1.45 [95% CI 1.33, 1.59]) in the UK Biobank study cohort. The heritability of AA was 10%, and AA had a moderate genetic correlation with hip OA (r_g = 0.26 [95% CI 0.10, 0.43]). Eight independent genetic signals were associated with AA. Two-sample MR provided weak evidence of causal effects of AA on hip OA risk (inverse variance weighted OR 1.84 [95% CI 1.14, 2.96], P = 0.01). In contrast, genetic predisposition for hip OA had stronger evidence of a causal effect on increased AA (inverse variance weighted β = 0.09 [95% CI 0.04, 0.13], P = 4.58 × 10⁻⁵). Conclusion: Expected observational associations between AA and related clinical outcomes provided face validity for the DXA-derived AA measurements. Evidence of bidirectional associations between AA and hip OA, particularly for risk of hip OA on AA, suggests that hip shape modeling secondary to a genetic predisposition to hip OA contributes to the well-established relationship between hip OA and cam morphology in older adults.

Original language	English
Pages (from-to)	900-909
Number of pages	10
Journal	Arthritis and Rheumatology
Volume	75
Issue number	6
DOIs	https://doi.org/10.1002/art.42451
Publication status	Published - Jun 2023

Bibliographical note

Funding Information:
The authors would like to thank the Musculoskeletal Research Unit patient and public involvement group at the University of Bristol for their input into planning our research and Dr. Martin Williams, a consultant musculoskeletal radiologist at North Bristol NHS Trust, who provided substantial training and expertise for this study. The authors would also like to thank the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. The authors acknowledge the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands, for execution of the generation and management of GWAS genotype data for the Rotterdam Study (I, II, and III). Finally, the authors would like to thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, Marjolein Peters, MSc, and Carolina Medina-Gomez, MSc, for their help in creating the GWAS database, and Linda Broer, PhD, for the creation of the imputed data, and Mathijs Versteeg for creating the alpha angle data.

Publisher Copyright:
© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.

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Faber, B. G., Frysz, M., Hartley, A. E., Ebsim, R., Boer, C. G., Saunders, F. R., Gregory, J. S., Aspden, R. M., Harvey, N. C., Southam, L., Giles, W., Le Maitre, C. L., Wilkinson, J. M., van Meurs, J. B. J., Zeggini, E., Cootes, T., Lindner, C., Kemp, J. P., Davey Smith, G., & Tobias, J. H. (2023). A Genome-Wide Association Study Meta-Analysis of Alpha Angle Suggests Cam-Type Morphology May Be a Specific Feature of Hip Osteoarthritis in Older Adults. Arthritis and Rheumatology, 75(6), 900-909. https://doi.org/10.1002/art.42451

@article{f4f37cccdaa0423db2a8fd88b5ebfd61,

title = "A Genome-Wide Association Study Meta-Analysis of Alpha Angle Suggests Cam-Type Morphology May Be a Specific Feature of Hip Osteoarthritis in Older Adults",

abstract = "Objective: To examine the genetic architecture of cam morphology using alpha angle (AA) as a proxy measure and conduct an AA genome-wide association study (GWAS) followed by Mendelian randomization (MR) to evaluate its causal relationship with hip osteoarthritis (OA). Methods: Observational analyses examined associations between AA measurements derived from hip dual x-ray absorptiometry (DXA) scans from the UK Biobank study and radiographic hip OA outcomes and subsequent total hip replacement. Following these analyses, an AA GWAS meta-analysis was performed (N = 44,214) using AA measurements previously derived in the Rotterdam Study. Linkage disequilibrium score regression assessed the genetic correlation between AA and hip OA. Genetic associations considered significant (P < 5 × 10−8) were used as AA genetic instrument for 2-sample MR analysis. Results: DXA-derived AA showed expected associations between AA and radiographic hip OA (adjusted odds ratio [OR] 1.63 [95% confidence interval (95% CI) 1.58, 1.67]) and between AA and total hip replacement (adjusted hazard ratio 1.45 [95% CI 1.33, 1.59]) in the UK Biobank study cohort. The heritability of AA was 10%, and AA had a moderate genetic correlation with hip OA (rg = 0.26 [95% CI 0.10, 0.43]). Eight independent genetic signals were associated with AA. Two-sample MR provided weak evidence of causal effects of AA on hip OA risk (inverse variance weighted OR 1.84 [95% CI 1.14, 2.96], P = 0.01). In contrast, genetic predisposition for hip OA had stronger evidence of a causal effect on increased AA (inverse variance weighted β = 0.09 [95% CI 0.04, 0.13], P = 4.58 × 10−5). Conclusion: Expected observational associations between AA and related clinical outcomes provided face validity for the DXA-derived AA measurements. Evidence of bidirectional associations between AA and hip OA, particularly for risk of hip OA on AA, suggests that hip shape modeling secondary to a genetic predisposition to hip OA contributes to the well-established relationship between hip OA and cam morphology in older adults.",

author = "Faber, {Benjamin G.} and Monika Frysz and Hartley, {April E.} and Raja Ebsim and Boer, {Cindy G.} and Saunders, {Fiona R.} and Gregory, {Jennifer S.} and Aspden, {Richard M.} and Harvey, {Nicholas C.} and Lorraine Southam and William Giles and {Le Maitre}, {Christine L.} and Wilkinson, {J. Mark} and {van Meurs}, {Joyce B.J.} and Eleftheria Zeggini and Timothy Cootes and Claudia Lindner and Kemp, {John P.} and {Davey Smith}, George and Tobias, {Jonathan H.}",

note = "Funding Information: The authors would like to thank the Musculoskeletal Research Unit patient and public involvement group at the University of Bristol for their input into planning our research and Dr. Martin Williams, a consultant musculoskeletal radiologist at North Bristol NHS Trust, who provided substantial training and expertise for this study. The authors would also like to thank the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. The authors acknowledge the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands, for execution of the generation and management of GWAS genotype data for the Rotterdam Study (I, II, and III). Finally, the authors would like to thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, Marjolein Peters, MSc, and Carolina Medina-Gomez, MSc, for their help in creating the GWAS database, and Linda Broer, PhD, for the creation of the imputed data, and Mathijs Versteeg for creating the alpha angle data. Publisher Copyright: {\textcopyright} 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.",

year = "2023",

month = jun,

doi = "10.1002/art.42451",

language = "English",

volume = "75",

pages = "900--909",

journal = "Arthritis and Rheumatology",

issn = "2326-5191",

publisher = "John Wiley & Sons Ltd.",

number = "6",

}

Faber, BG, Frysz, M, Hartley, AE, Ebsim, R, Boer, CG, Saunders, FR, Gregory, JS, Aspden, RM, Harvey, NC, Southam, L, Giles, W, Le Maitre, CL, Wilkinson, JM, van Meurs, JBJ, Zeggini, E, Cootes, T, Lindner, C, Kemp, JP, Davey Smith, G & Tobias, JH 2023, 'A Genome-Wide Association Study Meta-Analysis of Alpha Angle Suggests Cam-Type Morphology May Be a Specific Feature of Hip Osteoarthritis in Older Adults', Arthritis and Rheumatology, vol. 75, no. 6, pp. 900-909. https://doi.org/10.1002/art.42451

TY - JOUR

T1 - A Genome-Wide Association Study Meta-Analysis of Alpha Angle Suggests Cam-Type Morphology May Be a Specific Feature of Hip Osteoarthritis in Older Adults

AU - Faber, Benjamin G.

AU - Frysz, Monika

AU - Hartley, April E.

AU - Ebsim, Raja

AU - Boer, Cindy G.

AU - Saunders, Fiona R.

AU - Gregory, Jennifer S.

AU - Aspden, Richard M.

AU - Harvey, Nicholas C.

AU - Southam, Lorraine

AU - Giles, William

AU - Le Maitre, Christine L.

AU - Wilkinson, J. Mark

AU - van Meurs, Joyce B.J.

AU - Zeggini, Eleftheria

AU - Cootes, Timothy

AU - Lindner, Claudia

AU - Kemp, John P.

AU - Davey Smith, George

AU - Tobias, Jonathan H.

N1 - Funding Information: The authors would like to thank the Musculoskeletal Research Unit patient and public involvement group at the University of Bristol for their input into planning our research and Dr. Martin Williams, a consultant musculoskeletal radiologist at North Bristol NHS Trust, who provided substantial training and expertise for this study. The authors would also like to thank the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. The authors acknowledge the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands, for execution of the generation and management of GWAS genotype data for the Rotterdam Study (I, II, and III). Finally, the authors would like to thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, Marjolein Peters, MSc, and Carolina Medina-Gomez, MSc, for their help in creating the GWAS database, and Linda Broer, PhD, for the creation of the imputed data, and Mathijs Versteeg for creating the alpha angle data. Publisher Copyright: © 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.

PY - 2023/6

Y1 - 2023/6

N2 - Objective: To examine the genetic architecture of cam morphology using alpha angle (AA) as a proxy measure and conduct an AA genome-wide association study (GWAS) followed by Mendelian randomization (MR) to evaluate its causal relationship with hip osteoarthritis (OA). Methods: Observational analyses examined associations between AA measurements derived from hip dual x-ray absorptiometry (DXA) scans from the UK Biobank study and radiographic hip OA outcomes and subsequent total hip replacement. Following these analyses, an AA GWAS meta-analysis was performed (N = 44,214) using AA measurements previously derived in the Rotterdam Study. Linkage disequilibrium score regression assessed the genetic correlation between AA and hip OA. Genetic associations considered significant (P < 5 × 10−8) were used as AA genetic instrument for 2-sample MR analysis. Results: DXA-derived AA showed expected associations between AA and radiographic hip OA (adjusted odds ratio [OR] 1.63 [95% confidence interval (95% CI) 1.58, 1.67]) and between AA and total hip replacement (adjusted hazard ratio 1.45 [95% CI 1.33, 1.59]) in the UK Biobank study cohort. The heritability of AA was 10%, and AA had a moderate genetic correlation with hip OA (rg = 0.26 [95% CI 0.10, 0.43]). Eight independent genetic signals were associated with AA. Two-sample MR provided weak evidence of causal effects of AA on hip OA risk (inverse variance weighted OR 1.84 [95% CI 1.14, 2.96], P = 0.01). In contrast, genetic predisposition for hip OA had stronger evidence of a causal effect on increased AA (inverse variance weighted β = 0.09 [95% CI 0.04, 0.13], P = 4.58 × 10−5). Conclusion: Expected observational associations between AA and related clinical outcomes provided face validity for the DXA-derived AA measurements. Evidence of bidirectional associations between AA and hip OA, particularly for risk of hip OA on AA, suggests that hip shape modeling secondary to a genetic predisposition to hip OA contributes to the well-established relationship between hip OA and cam morphology in older adults.

AB - Objective: To examine the genetic architecture of cam morphology using alpha angle (AA) as a proxy measure and conduct an AA genome-wide association study (GWAS) followed by Mendelian randomization (MR) to evaluate its causal relationship with hip osteoarthritis (OA). Methods: Observational analyses examined associations between AA measurements derived from hip dual x-ray absorptiometry (DXA) scans from the UK Biobank study and radiographic hip OA outcomes and subsequent total hip replacement. Following these analyses, an AA GWAS meta-analysis was performed (N = 44,214) using AA measurements previously derived in the Rotterdam Study. Linkage disequilibrium score regression assessed the genetic correlation between AA and hip OA. Genetic associations considered significant (P < 5 × 10−8) were used as AA genetic instrument for 2-sample MR analysis. Results: DXA-derived AA showed expected associations between AA and radiographic hip OA (adjusted odds ratio [OR] 1.63 [95% confidence interval (95% CI) 1.58, 1.67]) and between AA and total hip replacement (adjusted hazard ratio 1.45 [95% CI 1.33, 1.59]) in the UK Biobank study cohort. The heritability of AA was 10%, and AA had a moderate genetic correlation with hip OA (rg = 0.26 [95% CI 0.10, 0.43]). Eight independent genetic signals were associated with AA. Two-sample MR provided weak evidence of causal effects of AA on hip OA risk (inverse variance weighted OR 1.84 [95% CI 1.14, 2.96], P = 0.01). In contrast, genetic predisposition for hip OA had stronger evidence of a causal effect on increased AA (inverse variance weighted β = 0.09 [95% CI 0.04, 0.13], P = 4.58 × 10−5). Conclusion: Expected observational associations between AA and related clinical outcomes provided face validity for the DXA-derived AA measurements. Evidence of bidirectional associations between AA and hip OA, particularly for risk of hip OA on AA, suggests that hip shape modeling secondary to a genetic predisposition to hip OA contributes to the well-established relationship between hip OA and cam morphology in older adults.

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U2 - 10.1002/art.42451

DO - 10.1002/art.42451

M3 - Article

C2 - 36662418

AN - SCOPUS:85152126186

SN - 2326-5191

VL - 75

SP - 900

EP - 909

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

IS - 6

ER -

A Genome-Wide Association Study Meta-Analysis of Alpha Angle Suggests Cam-Type Morphology May Be a Specific Feature of Hip Osteoarthritis in Older Adults

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