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 analysesResearch in context
Summary: 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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-09-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396423003249 |
| _version_ | 1797738965460058112 |
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| author | Benjamin G. Faber Monika Frysz Cindy G. Boer Daniel S. Evans Raja Ebsim Kaitlyn A. Flynn Mischa Lundberg Lorraine Southam April Hartley Fiona R. Saunders Claudia Lindner Jennifer S. Gregory Richard M. Aspden Nancy E. Lane Nicholas C. Harvey David M. Evans Eleftheria Zeggini George Davey Smith Timothy Cootes Joyce Van Meurs John P. Kemp Jonathan H. Tobias |
| author_facet | Benjamin G. Faber Monika Frysz Cindy G. Boer Daniel S. Evans Raja Ebsim Kaitlyn A. Flynn Mischa Lundberg Lorraine Southam April Hartley Fiona R. Saunders Claudia Lindner Jennifer S. Gregory Richard M. Aspden Nancy E. Lane Nicholas C. Harvey David M. Evans Eleftheria Zeggini George Davey Smith Timothy Cootes Joyce Van Meurs John P. Kemp Jonathan H. Tobias |
| author_sort | Benjamin G. Faber |
| collection | DOAJ |
| description | Summary: 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. Funding: Primarily funded by the Medical Research Council and Wellcome Trust. |
| first_indexed | 2024-03-12T13:51:27Z |
| format | Article |
| id | doaj.art-e65b32b807094d3195f523dc966a7bd4 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-03-12T13:51:27Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-e65b32b807094d3195f523dc966a7bd42023-08-23T04:33:28ZengElsevierEBioMedicine2352-39642023-09-0195104759The 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 analysesResearch in contextBenjamin G. Faber0Monika Frysz1Cindy G. Boer2Daniel S. Evans3Raja Ebsim4Kaitlyn A. Flynn5Mischa Lundberg6Lorraine Southam7April Hartley8Fiona R. Saunders9Claudia Lindner10Jennifer S. Gregory11Richard M. Aspden12Nancy E. Lane13Nicholas C. Harvey14David M. Evans15Eleftheria Zeggini16George Davey Smith17Timothy Cootes18Joyce Van Meurs19John P. Kemp20Jonathan H. Tobias21Musculoskeletal Research Unit, University of Bristol, UK; Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UK; Corresponding author. NIHR Academic Clinical Lecturer in Rheumatology Musculoskeletal Research Unit, Learning and Research Building, Level One, Southmead Hospital, Bristol BS10 5NB, UK.Musculoskeletal Research Unit, University of Bristol, UK; Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UKDepartment of Internal Medicine, Erasmus Medical Centre, Rotterdam, the NetherlandsCalifornia Pacific Medical Center Research Institute, San Francisco, USADivision of Informatics, Imaging and Data Sciences, The University of Manchester, UKMater Research Institute, The University of Queensland, Woolloongabba, Australia; Institute for Molecular Bioscience, The University of Queensland, St Lucia, AustraliaUQ Frazer Institute, The University of Queensland, Woolloongabba, AustraliaInstitute of Translational Genomics, Helmholtz Zentrum München – German Research Centre for Environmental Health, Neuherberg, GermanyMedical Research Council Integrative Epidemiology Unit at the University of Bristol, UKCentre for Arthritis and Musculoskeletal Health, University of Aberdeen, UKDivision of Informatics, Imaging and Data Sciences, The University of Manchester, UKCentre for Arthritis and Musculoskeletal Health, University of Aberdeen, UKCentre for Arthritis and Musculoskeletal Health, University of Aberdeen, UKCenter for Musculoskeletal Health, University of California Davis, Sacramento, USAMedical Research Council Lifecourse Epidemiology Centre, University of Southampton, UK; NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, UKMedical Research Council Integrative Epidemiology Unit at the University of Bristol, UK; Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia; UQ Frazer Institute, The University of Queensland, Woolloongabba, AustraliaInstitute of Translational Genomics, Helmholtz Zentrum München – German Research Centre for Environmental Health, Neuherberg, Germany; Technical University of Munich and Klinikum Rechts der Isar, TUM School of Medicine, GermanyMedical Research Council Integrative Epidemiology Unit at the University of Bristol, UKDivision of Informatics, Imaging and Data Sciences, The University of Manchester, UKDepartment of Internal Medicine, Erasmus Medical Centre, Rotterdam, the NetherlandsMedical Research Council Integrative Epidemiology Unit at the University of Bristol, UK; Mater Research Institute, The University of Queensland, Woolloongabba, Australia; Institute for Molecular Bioscience, The University of Queensland, St Lucia, AustraliaMusculoskeletal Research Unit, University of Bristol, UK; Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UKSummary: 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. Funding: Primarily funded by the Medical Research Council and Wellcome Trust.http://www.sciencedirect.com/science/article/pii/S2352396423003249OsteoarthritisGenome-wide association studyMendelian randomisationCartilage |
| spellingShingle | Benjamin G. Faber Monika Frysz Cindy G. Boer Daniel S. Evans Raja Ebsim Kaitlyn A. Flynn Mischa Lundberg Lorraine Southam April Hartley Fiona R. Saunders Claudia Lindner Jennifer S. Gregory Richard M. Aspden Nancy E. Lane Nicholas C. Harvey David M. Evans Eleftheria Zeggini George Davey Smith Timothy Cootes Joyce Van Meurs John P. Kemp Jonathan H. Tobias 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 analysesResearch in context EBioMedicine Osteoarthritis Genome-wide association study Mendelian randomisation Cartilage |
| 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 analysesResearch in context |
| title_full | 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 analysesResearch in context |
| title_fullStr | 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 analysesResearch in context |
| title_full_unstemmed | 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 analysesResearch in context |
| title_short | 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 analysesResearch in context |
| title_sort | 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 analysesresearch in context |
| topic | Osteoarthritis Genome-wide association study Mendelian randomisation Cartilage |
| url | http://www.sciencedirect.com/science/article/pii/S2352396423003249 |
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