The identification of distinct protective and susceptibility mechanisms for hip osteoarthritis: findings from a genome-wide association study meta-analysis of minimum joint space width and Mendelian randomisation cluster analyses

Benjamin G Faber; Monika Frysz; Cindy G.  Boer; Daniel S. Evans; Raja  Ebsim; Kaitlyn A.  Flynn; Mischa  Lundberg; Lorraine Southam; April E. Hartley; Fiona Saunders; Claudia  Lindner; Jenny Gregory; Richard Malcolm Aspden; Nancy E. Lane; Nicholas C Harvey; David M. Evans; Eleftheria Zeggini; George Davey Smith; Timothy F. Cootes; Joyce B. van Meurs; John P. Kemp; Jonathan H. Tobias

doi:10.1016/j.ebiom.2023.104759

The identification of distinct protective and susceptibility mechanisms for hip osteoarthritis: findings from a genome-wide association study meta-analysis of minimum joint space width and Mendelian randomisation cluster analyses

Benjamin G Faber^* (Corresponding Author), Monika Frysz, Cindy G. Boer, Daniel S. Evans, Raja Ebsim, Kaitlyn A. Flynn, Mischa Lundberg, Lorraine Southam, April E. Hartley, Fiona Saunders, Claudia Lindner, Jenny Gregory, Richard Malcolm Aspden, Nancy E. Lane, Nicholas C Harvey, David M. Evans, Eleftheria Zeggini, George Davey Smith, Timothy F. Cootes, Joyce B. van MeursJohn P. Kemp, Jonathan H. Tobias

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

Abstract

Background
Hip minimum joint space width (mJSW) provides a proxy for cartilage thickness. This study aimed to conduct a genome-wide association study (GWAS) of mJSW to (i) identify new genetic determinants of mJSW and (ii) identify which mJSW loci convey hip osteoarthritis (HOA) risk and would therefore be of therapeutic interest.
Methods
GWAS meta-analysis of hip mJSW derived from plain X-rays and DXA was performed, stratified by sex and adjusted for age and ancestry principal components. Mendelian randomisation (MR) and cluster analyses were used to examine causal effect of mJSW on HOA.
Findings
50,745 individuals were included in the meta-analysis. 42 SNPs, which mapped to 39 loci, were identified. Mendelian randomisation (MR) revealed little evidence of a causal effect of mJSW on HOA (𝑂𝑅𝐼𝑉𝑊 0.98 [95% CI 0.82-1.18]). However, MR-Clust analysis suggested the null MR estimates reflected the net effect of two distinct causal mechanisms cancelling each other out, one of which was protective, whereas the other increased HOA susceptibility. For the latter mechanism, all loci were positively associated with height, suggesting mechanisms leading to greater height and mJSW increase the risk of HOA in later life.
Interpretations
One group of mJSW loci reduce HOA risk via increased mJSW, suggesting possible utility as targets for chondroprotective therapies. The second group of mJSW loci increased HOA risk, despite increasing mJSW, but were also positively related to height, suggesting they contribute to HOA risk via a growth-related mechanism.

Original language	English
Article number	104759
Number of pages	11
Journal	EBioMedicine
Volume	95
Early online date	22 Aug 2023
DOIs	https://doi.org/10.1016/j.ebiom.2023.104759
Publication status	Published - 1 Sept 2023

Bibliographical note

Funding
Primarily funded by the Medical Research Council and Wellcome Trust.
Acknowledgements
This work has been conducted using the UK Biobank resource (application number 17295).The authors would like to thank the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study (RSI & RSII) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The authors would like to thank Pascal Arp, Mila
Jhamai, Marijn Verkerk, and Carolina Medina-Gomez, MSc, for their help in creating the GWAS database, and Linda Broer PhD, for the creation of the imputed data.
No funders had any role in study design or manuscript writing. BGF is a National Institute of Health and Care Research Academic Clinical Lecturer and was previously supported by a Medical Research Council (MRC) clinical research training fellowship (MR/S021280/1). MF, RE, FS are supported, and this work is funded by a Wellcome Trust collaborative award (reference number 209233). ML is supported by a University of Queensland Research Training Scholarship from The University of Queensland (UQ). ML thanks the Commonwealth Scientific and Industrial Research Organisation for the support through a Postgraduate Top-Up
Scholarship. CL was funded by the MRC (MR/S00405X/1) as well as a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (223267/Z/21/Z). This research was funded in whole, or in part, by the Wellcome Trust [Grant numbers 080280/Z/06/Z, 20378/Z/16/Z, 223267/Z/21/Z]. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. NCH acknowledges support from the MRC (MC_PC_21003; MC_PC_21001) and NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton. BGF, MF, AEH, GDS, JHT work in the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the MRC (MC_UU_00011/1). JPK is funded by a National Health and Medical Research Council (Australia) Investigator grant (GNT1177938), and by the Lions Medical Research Foundation (2020 Lions Dunning-Orlich Investigator Award). DSE acknowledges funding from NIH/NIA U24AG051129. The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institute of Health funding from the following institutes: the National Institute on Aging (NIA),
the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: R01 AR052000, K24 AR048841, U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute
on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01AG027576.

Data Availability Statement

Data sharing statement
The summary minimum joint space width summary statistics have been uploaded to the GWAS Catalog (https://www.ebi.ac.uk/gwas/). The UK Biobank mJSW data from this study will be available in a forthcoming data release. Users must be registered with UK Biobank to access their resources (https://bbams.ndph.ox.ac.uk/ams/).

Keywords

Osteoarthritis
Genome-Wide Association Study
Mendelian Randomisation
CARTILAGE DESTRUCTION

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Faber, B. G., Frysz, M., Boer, C. G., Evans, D. S., Ebsim, R., Flynn, K. A., Lundberg, M., Southam, L., Hartley, A. E., Saunders, F., Lindner, C., Gregory, J., Aspden, R. M., Lane, N. E., Harvey, N. C., Evans, D. M., Zeggini, E., Smith, G. D., Cootes, T. F., ... Tobias, J. H. (2023). The identification of distinct protective and susceptibility mechanisms for hip osteoarthritis: findings from a genome-wide association study meta-analysis of minimum joint space width and Mendelian randomisation cluster analyses. EBioMedicine, 95, Article 104759. https://doi.org/10.1016/j.ebiom.2023.104759

The identification of distinct protective and susceptibility mechanisms for hip osteoarthritis: findings from a genome-wide association study meta-analysis of minimum joint space width and Mendelian randomisation cluster analyses. / Faber, Benjamin G (Corresponding Author); Frysz, Monika; Boer, Cindy G. et al.
In: EBioMedicine, Vol. 95, 104759, 01.09.2023.

Research output: Contribution to journal › Article › peer-review

Faber, BG, Frysz, M, Boer, CG, Evans, DS, Ebsim, R, Flynn, KA, Lundberg, M, Southam, L, Hartley, AE, Saunders, F, Lindner, C, Gregory, J , Aspden, RM, Lane, NE, Harvey, NC, Evans, DM, Zeggini, E, Smith, GD, Cootes, TF, van Meurs, JB, Kemp, JP & Tobias, JH 2023, 'The identification of distinct protective and susceptibility mechanisms for hip osteoarthritis: findings from a genome-wide association study meta-analysis of minimum joint space width and Mendelian randomisation cluster analyses', EBioMedicine, vol. 95, 104759. https://doi.org/10.1016/j.ebiom.2023.104759

Faber BG, Frysz M, Boer CG, Evans DS, Ebsim R, Flynn KA et al. The identification of distinct protective and susceptibility mechanisms for hip osteoarthritis: findings from a genome-wide association study meta-analysis of minimum joint space width and Mendelian randomisation cluster analyses. EBioMedicine. 2023 Sept 1;95:104759. Epub 2023 Aug 22. doi: 10.1016/j.ebiom.2023.104759

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title = "The identification of distinct protective and susceptibility mechanisms for hip osteoarthritis: findings from a genome-wide association study meta-analysis of minimum joint space width and Mendelian randomisation cluster analyses",

abstract = "BackgroundHip minimum joint space width (mJSW) provides a proxy for cartilage thickness. This study aimed to conduct a genome-wide association study (GWAS) of mJSW to (i) identify new genetic determinants of mJSW and (ii) identify which mJSW loci convey hip osteoarthritis (HOA) risk and would therefore be of therapeutic interest.MethodsGWAS meta-analysis of hip mJSW derived from plain X-rays and DXA was performed, stratified by sex and adjusted for age and ancestry principal components. Mendelian randomisation (MR) and cluster analyses were used to examine causal effect of mJSW on HOA.Findings50,745 individuals were included in the meta-analysis. 42 SNPs, which mapped to 39 loci, were identified. Mendelian randomisation (MR) revealed little evidence of a causal effect of mJSW on HOA (푂푅퐼푉푊 0.98 [95% CI 0.82-1.18]). However, MR-Clust analysis suggested the null MR estimates reflected the net effect of two distinct causal mechanisms cancelling each other out, one of which was protective, whereas the other increased HOA susceptibility. For the latter mechanism, all loci were positively associated with height, suggesting mechanisms leading to greater height and mJSW increase the risk of HOA in later life.InterpretationsOne group of mJSW loci reduce HOA risk via increased mJSW, suggesting possible utility as targets for chondroprotective therapies. The second group of mJSW loci increased HOA risk, despite increasing mJSW, but were also positively related to height, suggesting they contribute to HOA risk via a growth-related mechanism.",

keywords = "Osteoarthritis, Genome-Wide Association Study, Mendelian Randomisation, CARTILAGE DESTRUCTION",

author = "Faber, {Benjamin G} and Monika Frysz and Boer, {Cindy G.} and Evans, {Daniel S.} and Raja Ebsim and Flynn, {Kaitlyn A.} and Mischa Lundberg and Lorraine Southam and Hartley, {April E.} and Fiona Saunders and Claudia Lindner and Jenny Gregory and Aspden, {Richard Malcolm} and Lane, {Nancy E.} and Harvey, {Nicholas C} and Evans, {David M.} and Eleftheria Zeggini and Smith, {George Davey} and Cootes, {Timothy F.} and {van Meurs}, {Joyce B.} and Kemp, {John P.} and Tobias, {Jonathan H.}",

note = "Funding Primarily funded by the Medical Research Council and Wellcome Trust. Acknowledgements This work has been conducted using the UK Biobank resource (application number 17295).The authors would like to thank the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study (RSI & RSII) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The authors would like to thank Pascal Arp, Mila Jhamai, Marijn Verkerk, and Carolina Medina-Gomez, MSc, for their help in creating the GWAS database, and Linda Broer PhD, for the creation of the imputed data. No funders had any role in study design or manuscript writing. BGF is a National Institute of Health and Care Research Academic Clinical Lecturer and was previously supported by a Medical Research Council (MRC) clinical research training fellowship (MR/S021280/1). MF, RE, FS are supported, and this work is funded by a Wellcome Trust collaborative award (reference number 209233). ML is supported by a University of Queensland Research Training Scholarship from The University of Queensland (UQ). ML thanks the Commonwealth Scientific and Industrial Research Organisation for the support through a Postgraduate Top-Up Scholarship. CL was funded by the MRC (MR/S00405X/1) as well as a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (223267/Z/21/Z). This research was funded in whole, or in part, by the Wellcome Trust [Grant numbers 080280/Z/06/Z, 20378/Z/16/Z, 223267/Z/21/Z]. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. NCH acknowledges support from the MRC (MC_PC_21003; MC_PC_21001) and NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton. BGF, MF, AEH, GDS, JHT work in the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the MRC (MC_UU_00011/1). JPK is funded by a National Health and Medical Research Council (Australia) Investigator grant (GNT1177938), and by the Lions Medical Research Foundation (2020 Lions Dunning-Orlich Investigator Award). DSE acknowledges funding from NIH/NIA U24AG051129. The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institute of Health funding from the following institutes: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: R01 AR052000, K24 AR048841, U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01AG027576. ",

year = "2023",

month = sep,

day = "1",

doi = "10.1016/j.ebiom.2023.104759",

language = "English",

volume = "95",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier BV",

}

TY - JOUR

T1 - The identification of distinct protective and susceptibility mechanisms for hip osteoarthritis

T2 - findings from a genome-wide association study meta-analysis of minimum joint space width and Mendelian randomisation cluster analyses

AU - Faber, Benjamin G

AU - Frysz, Monika

AU - Boer, Cindy G.

AU - Evans, Daniel S.

AU - Ebsim, Raja

AU - Flynn, Kaitlyn A.

AU - Lundberg, Mischa

AU - Southam, Lorraine

AU - Hartley, April E.

AU - Saunders, Fiona

AU - Lindner, Claudia

AU - Gregory, Jenny

AU - Aspden, Richard Malcolm

AU - Lane, Nancy E.

AU - Harvey, Nicholas C

AU - Evans, David M.

AU - Zeggini, Eleftheria

AU - Smith, George Davey

AU - Cootes, Timothy F.

AU - van Meurs, Joyce B.

AU - Kemp, John P.

AU - Tobias, Jonathan H.

N1 - Funding Primarily funded by the Medical Research Council and Wellcome Trust. Acknowledgements This work has been conducted using the UK Biobank resource (application number 17295).The authors would like to thank the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study (RSI & RSII) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The authors would like to thank Pascal Arp, Mila Jhamai, Marijn Verkerk, and Carolina Medina-Gomez, MSc, for their help in creating the GWAS database, and Linda Broer PhD, for the creation of the imputed data. No funders had any role in study design or manuscript writing. BGF is a National Institute of Health and Care Research Academic Clinical Lecturer and was previously supported by a Medical Research Council (MRC) clinical research training fellowship (MR/S021280/1). MF, RE, FS are supported, and this work is funded by a Wellcome Trust collaborative award (reference number 209233). ML is supported by a University of Queensland Research Training Scholarship from The University of Queensland (UQ). ML thanks the Commonwealth Scientific and Industrial Research Organisation for the support through a Postgraduate Top-Up Scholarship. CL was funded by the MRC (MR/S00405X/1) as well as a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (223267/Z/21/Z). This research was funded in whole, or in part, by the Wellcome Trust [Grant numbers 080280/Z/06/Z, 20378/Z/16/Z, 223267/Z/21/Z]. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. NCH acknowledges support from the MRC (MC_PC_21003; MC_PC_21001) and NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton. BGF, MF, AEH, GDS, JHT work in the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the MRC (MC_UU_00011/1). JPK is funded by a National Health and Medical Research Council (Australia) Investigator grant (GNT1177938), and by the Lions Medical Research Foundation (2020 Lions Dunning-Orlich Investigator Award). DSE acknowledges funding from NIH/NIA U24AG051129. The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institute of Health funding from the following institutes: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: R01 AR052000, K24 AR048841, U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01AG027576.

PY - 2023/9/1

Y1 - 2023/9/1

N2 - BackgroundHip minimum joint space width (mJSW) provides a proxy for cartilage thickness. This study aimed to conduct a genome-wide association study (GWAS) of mJSW to (i) identify new genetic determinants of mJSW and (ii) identify which mJSW loci convey hip osteoarthritis (HOA) risk and would therefore be of therapeutic interest.MethodsGWAS meta-analysis of hip mJSW derived from plain X-rays and DXA was performed, stratified by sex and adjusted for age and ancestry principal components. Mendelian randomisation (MR) and cluster analyses were used to examine causal effect of mJSW on HOA.Findings50,745 individuals were included in the meta-analysis. 42 SNPs, which mapped to 39 loci, were identified. Mendelian randomisation (MR) revealed little evidence of a causal effect of mJSW on HOA (푂푅퐼푉푊 0.98 [95% CI 0.82-1.18]). However, MR-Clust analysis suggested the null MR estimates reflected the net effect of two distinct causal mechanisms cancelling each other out, one of which was protective, whereas the other increased HOA susceptibility. For the latter mechanism, all loci were positively associated with height, suggesting mechanisms leading to greater height and mJSW increase the risk of HOA in later life.InterpretationsOne group of mJSW loci reduce HOA risk via increased mJSW, suggesting possible utility as targets for chondroprotective therapies. The second group of mJSW loci increased HOA risk, despite increasing mJSW, but were also positively related to height, suggesting they contribute to HOA risk via a growth-related mechanism.

AB - BackgroundHip minimum joint space width (mJSW) provides a proxy for cartilage thickness. This study aimed to conduct a genome-wide association study (GWAS) of mJSW to (i) identify new genetic determinants of mJSW and (ii) identify which mJSW loci convey hip osteoarthritis (HOA) risk and would therefore be of therapeutic interest.MethodsGWAS meta-analysis of hip mJSW derived from plain X-rays and DXA was performed, stratified by sex and adjusted for age and ancestry principal components. Mendelian randomisation (MR) and cluster analyses were used to examine causal effect of mJSW on HOA.Findings50,745 individuals were included in the meta-analysis. 42 SNPs, which mapped to 39 loci, were identified. Mendelian randomisation (MR) revealed little evidence of a causal effect of mJSW on HOA (푂푅퐼푉푊 0.98 [95% CI 0.82-1.18]). However, MR-Clust analysis suggested the null MR estimates reflected the net effect of two distinct causal mechanisms cancelling each other out, one of which was protective, whereas the other increased HOA susceptibility. For the latter mechanism, all loci were positively associated with height, suggesting mechanisms leading to greater height and mJSW increase the risk of HOA in later life.InterpretationsOne group of mJSW loci reduce HOA risk via increased mJSW, suggesting possible utility as targets for chondroprotective therapies. The second group of mJSW loci increased HOA risk, despite increasing mJSW, but were also positively related to height, suggesting they contribute to HOA risk via a growth-related mechanism.

KW - Osteoarthritis

KW - Genome-Wide Association Study

KW - Mendelian Randomisation

KW - CARTILAGE DESTRUCTION

U2 - 10.1016/j.ebiom.2023.104759

DO - 10.1016/j.ebiom.2023.104759

M3 - Article

C2 - 37619450

SN - 2352-3964

VL - 95

JO - EBioMedicine

JF - EBioMedicine

M1 - 104759

ER -