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A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip

OBJECTIVES: Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. METHODS: We performed a two-stage meta-analysis on more than...

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Autores principales: Evangelou, Evangelos, Kerkhof, Hanneke J, Styrkarsdottir, Unnur, Ntzani, Evangelia E, Bos, Steffan D, Esko, Tonu, Evans, Daniel S, Metrustry, Sarah, Panoutsopoulou, Kalliope, Ramos, Yolande F M, Thorleifsson, Gudmar, Tsilidis, Konstantinos K, Arden, Nigel, Aslam, Nadim, Bellamy, Nicholas, Birrell, Fraser, Blanco, Francisco J, Carr, Andrew, Chapman, Kay, Day-Williams, Aaron G, Deloukas, Panos, Doherty, Michael, Engström, Gunnar, Helgadottir, Hafdis T, Hofman, Albert, Ingvarsson, Thorvaldur, Jonsson, Helgi, Keis, Aime, Keurentjes, J Christiaan, Kloppenburg, Margreet, Lind, Penelope A, McCaskie, Andrew, Martin, Nicholas G, Milani, Lili, Montgomery, Grant W, Nelissen, Rob G H H, Nevitt, Michael C, Nilsson, Peter M, Ollier, William ER, Parimi, Neeta, Rai, Ashok, Ralston, Stuart H, Reed, Mike R, Riancho, Jose A, Rivadeneira, Fernando, Rodriguez-Fontenla, Cristina, Southam, Lorraine, Thorsteinsdottir, Unnur, Tsezou, Aspasia, Wallis, Gillian A, Wilkinson, J Mark, Gonzalez, Antonio, Lane, Nancy E, Lohmander, L Stefan, Loughlin, John, Metspalu, Andres, Uitterlinden, Andre G, Jonsdottir, Ingileif, Stefansson, Kari, Slagboom, P Eline, Zeggini, Eleftheria, Meulenbelt, Ingrid, Ioannidis, John PA, Spector, Tim D, van Meurs, Joyce B J, Valdes, Ana M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251181/
https://www.ncbi.nlm.nih.gov/pubmed/23989986
http://dx.doi.org/10.1136/annrheumdis-2012-203114
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author Evangelou, Evangelos
Kerkhof, Hanneke J
Styrkarsdottir, Unnur
Ntzani, Evangelia E
Bos, Steffan D
Esko, Tonu
Evans, Daniel S
Metrustry, Sarah
Panoutsopoulou, Kalliope
Ramos, Yolande F M
Thorleifsson, Gudmar
Tsilidis, Konstantinos K
Arden, Nigel
Aslam, Nadim
Bellamy, Nicholas
Birrell, Fraser
Blanco, Francisco J
Carr, Andrew
Chapman, Kay
Day-Williams, Aaron G
Deloukas, Panos
Doherty, Michael
Engström, Gunnar
Helgadottir, Hafdis T
Hofman, Albert
Ingvarsson, Thorvaldur
Jonsson, Helgi
Keis, Aime
Keurentjes, J Christiaan
Kloppenburg, Margreet
Lind, Penelope A
McCaskie, Andrew
Martin, Nicholas G
Milani, Lili
Montgomery, Grant W
Nelissen, Rob G H H
Nevitt, Michael C
Nilsson, Peter M
Ollier, William ER
Parimi, Neeta
Rai, Ashok
Ralston, Stuart H
Reed, Mike R
Riancho, Jose A
Rivadeneira, Fernando
Rodriguez-Fontenla, Cristina
Southam, Lorraine
Thorsteinsdottir, Unnur
Tsezou, Aspasia
Wallis, Gillian A
Wilkinson, J Mark
Gonzalez, Antonio
Lane, Nancy E
Lohmander, L Stefan
Loughlin, John
Metspalu, Andres
Uitterlinden, Andre G
Jonsdottir, Ingileif
Stefansson, Kari
Slagboom, P Eline
Zeggini, Eleftheria
Meulenbelt, Ingrid
Ioannidis, John PA
Spector, Tim D
van Meurs, Joyce B J
Valdes, Ana M
author_facet Evangelou, Evangelos
Kerkhof, Hanneke J
Styrkarsdottir, Unnur
Ntzani, Evangelia E
Bos, Steffan D
Esko, Tonu
Evans, Daniel S
Metrustry, Sarah
Panoutsopoulou, Kalliope
Ramos, Yolande F M
Thorleifsson, Gudmar
Tsilidis, Konstantinos K
Arden, Nigel
Aslam, Nadim
Bellamy, Nicholas
Birrell, Fraser
Blanco, Francisco J
Carr, Andrew
Chapman, Kay
Day-Williams, Aaron G
Deloukas, Panos
Doherty, Michael
Engström, Gunnar
Helgadottir, Hafdis T
Hofman, Albert
Ingvarsson, Thorvaldur
Jonsson, Helgi
Keis, Aime
Keurentjes, J Christiaan
Kloppenburg, Margreet
Lind, Penelope A
McCaskie, Andrew
Martin, Nicholas G
Milani, Lili
Montgomery, Grant W
Nelissen, Rob G H H
Nevitt, Michael C
Nilsson, Peter M
Ollier, William ER
Parimi, Neeta
Rai, Ashok
Ralston, Stuart H
Reed, Mike R
Riancho, Jose A
Rivadeneira, Fernando
Rodriguez-Fontenla, Cristina
Southam, Lorraine
Thorsteinsdottir, Unnur
Tsezou, Aspasia
Wallis, Gillian A
Wilkinson, J Mark
Gonzalez, Antonio
Lane, Nancy E
Lohmander, L Stefan
Loughlin, John
Metspalu, Andres
Uitterlinden, Andre G
Jonsdottir, Ingileif
Stefansson, Kari
Slagboom, P Eline
Zeggini, Eleftheria
Meulenbelt, Ingrid
Ioannidis, John PA
Spector, Tim D
van Meurs, Joyce B J
Valdes, Ana M
author_sort Evangelou, Evangelos
collection PubMed
description OBJECTIVES: Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. METHODS: We performed a two-stage meta-analysis on more than 78 000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for ‘in silico’ or ‘de novo’ replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used. RESULTS: We accumulated 11 277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10(−9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10(−8)) and follow-up studies (p=7.3×10(−4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10(−7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10(−6), OR=1.27 in male specific analysis). CONCLUSIONS: Novel genetic loci for hip OA were found in this meta-analysis of GWAS.
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spelling pubmed-42511812014-12-04 A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip Evangelou, Evangelos Kerkhof, Hanneke J Styrkarsdottir, Unnur Ntzani, Evangelia E Bos, Steffan D Esko, Tonu Evans, Daniel S Metrustry, Sarah Panoutsopoulou, Kalliope Ramos, Yolande F M Thorleifsson, Gudmar Tsilidis, Konstantinos K Arden, Nigel Aslam, Nadim Bellamy, Nicholas Birrell, Fraser Blanco, Francisco J Carr, Andrew Chapman, Kay Day-Williams, Aaron G Deloukas, Panos Doherty, Michael Engström, Gunnar Helgadottir, Hafdis T Hofman, Albert Ingvarsson, Thorvaldur Jonsson, Helgi Keis, Aime Keurentjes, J Christiaan Kloppenburg, Margreet Lind, Penelope A McCaskie, Andrew Martin, Nicholas G Milani, Lili Montgomery, Grant W Nelissen, Rob G H H Nevitt, Michael C Nilsson, Peter M Ollier, William ER Parimi, Neeta Rai, Ashok Ralston, Stuart H Reed, Mike R Riancho, Jose A Rivadeneira, Fernando Rodriguez-Fontenla, Cristina Southam, Lorraine Thorsteinsdottir, Unnur Tsezou, Aspasia Wallis, Gillian A Wilkinson, J Mark Gonzalez, Antonio Lane, Nancy E Lohmander, L Stefan Loughlin, John Metspalu, Andres Uitterlinden, Andre G Jonsdottir, Ingileif Stefansson, Kari Slagboom, P Eline Zeggini, Eleftheria Meulenbelt, Ingrid Ioannidis, John PA Spector, Tim D van Meurs, Joyce B J Valdes, Ana M Ann Rheum Dis Clinical and Epidemiological Research OBJECTIVES: Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. METHODS: We performed a two-stage meta-analysis on more than 78 000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for ‘in silico’ or ‘de novo’ replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used. RESULTS: We accumulated 11 277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10(−9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10(−8)) and follow-up studies (p=7.3×10(−4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10(−7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10(−6), OR=1.27 in male specific analysis). CONCLUSIONS: Novel genetic loci for hip OA were found in this meta-analysis of GWAS. BMJ Publishing Group 2014-12 2013-08-29 /pmc/articles/PMC4251181/ /pubmed/23989986 http://dx.doi.org/10.1136/annrheumdis-2012-203114 Text en Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Clinical and Epidemiological Research
Evangelou, Evangelos
Kerkhof, Hanneke J
Styrkarsdottir, Unnur
Ntzani, Evangelia E
Bos, Steffan D
Esko, Tonu
Evans, Daniel S
Metrustry, Sarah
Panoutsopoulou, Kalliope
Ramos, Yolande F M
Thorleifsson, Gudmar
Tsilidis, Konstantinos K
Arden, Nigel
Aslam, Nadim
Bellamy, Nicholas
Birrell, Fraser
Blanco, Francisco J
Carr, Andrew
Chapman, Kay
Day-Williams, Aaron G
Deloukas, Panos
Doherty, Michael
Engström, Gunnar
Helgadottir, Hafdis T
Hofman, Albert
Ingvarsson, Thorvaldur
Jonsson, Helgi
Keis, Aime
Keurentjes, J Christiaan
Kloppenburg, Margreet
Lind, Penelope A
McCaskie, Andrew
Martin, Nicholas G
Milani, Lili
Montgomery, Grant W
Nelissen, Rob G H H
Nevitt, Michael C
Nilsson, Peter M
Ollier, William ER
Parimi, Neeta
Rai, Ashok
Ralston, Stuart H
Reed, Mike R
Riancho, Jose A
Rivadeneira, Fernando
Rodriguez-Fontenla, Cristina
Southam, Lorraine
Thorsteinsdottir, Unnur
Tsezou, Aspasia
Wallis, Gillian A
Wilkinson, J Mark
Gonzalez, Antonio
Lane, Nancy E
Lohmander, L Stefan
Loughlin, John
Metspalu, Andres
Uitterlinden, Andre G
Jonsdottir, Ingileif
Stefansson, Kari
Slagboom, P Eline
Zeggini, Eleftheria
Meulenbelt, Ingrid
Ioannidis, John PA
Spector, Tim D
van Meurs, Joyce B J
Valdes, Ana M
A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip
title A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip
title_full A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip
title_fullStr A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip
title_full_unstemmed A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip
title_short A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip
title_sort meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip
topic Clinical and Epidemiological Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251181/
https://www.ncbi.nlm.nih.gov/pubmed/23989986
http://dx.doi.org/10.1136/annrheumdis-2012-203114
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AT stefanssonkari metaanalysisofgenomewideassociationstudiesidentifiesnovelvariantsassociatedwithosteoarthritisofthehip
AT slagboompeline metaanalysisofgenomewideassociationstudiesidentifiesnovelvariantsassociatedwithosteoarthritisofthehip
AT zegginieleftheria metaanalysisofgenomewideassociationstudiesidentifiesnovelvariantsassociatedwithosteoarthritisofthehip
AT meulenbeltingrid metaanalysisofgenomewideassociationstudiesidentifiesnovelvariantsassociatedwithosteoarthritisofthehip
AT ioannidisjohnpa metaanalysisofgenomewideassociationstudiesidentifiesnovelvariantsassociatedwithosteoarthritisofthehip
AT spectortimd metaanalysisofgenomewideassociationstudiesidentifiesnovelvariantsassociatedwithosteoarthritisofthehip
AT vanmeursjoycebj metaanalysisofgenomewideassociationstudiesidentifiesnovelvariantsassociatedwithosteoarthritisofthehip
AT valdesanam metaanalysisofgenomewideassociationstudiesidentifiesnovelvariantsassociatedwithosteoarthritisofthehip