Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study
Summary Background Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component...
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| Veröffentlicht in: | The Lancet (British edition) 2012-09, Vol.380 (9844), p.815-823 |
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| creator | Zeggini, Eleftheria Panoutsopoulou, Kalliope Southam, Lorraine Rayner, Nigel W Day-Williams, Aaron G Lopes, Margarida C Boraska, Vesna Esko, Tonu Evangelou, Evangelos Hoffman, Albert Houwing-Duistermaat, Jeanine J Ingvarsson, Thorvaldur Jonsdottir, Ingileif Jonnson, Helgi Kerkhof, Hanneke J Kloppenburg, Margreet Bos, Steffan D Mangino, Massimo Metrustry, Sarah Slagboom, P Eline Thorleifsson, Gudmar Raine, Emma V A Ratnayake, Madhushika Ricketts, Michelle Beazley, Claude Blackburn, Hannah Bumpstead, Suzannah Elliott, Katherine S Hunt, Sarah E Potter, Simon C Shin, So-Youn Yadav, Vijay K Zhai, Guangju Sherburn, Kate Dixon, Kate Arden, Elizabeth Aslam, Nadim Battley, Phillippa-kate Carluke, Ian Doherty, Sally Gordon, Andrew Joseph, John Keen, Richard Koller, Nicola C Mitchell, Sheryl O'Neill, Fiona Paling, Ellen Reed, Mike R Rivadeneira, Fernando Swift, Diane Walker, Kirsten Watkins, Bridget Wheeler, Maggie Birrell, Fraser Ioannidis, John P A Meulenbelt, Ingrid Metspalu, Andres Rai, Ashok Salter, Donald Stefansson, Kari Stykarsdottir, Unnur Uitterlinden, André G van Meurs, Joyce B J Chapman, Kay Deloukas, Panos Ollier, William E R Wallis, Gillian A Arden, Nigel Carr, Andrew Doherty, Michael McCaskie, Andrew Willkinson, J Mark Ralston, Stuart H Valdes, Ana M Spector, Tim D Loughlin, John |
| description | Summary Background Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity. Methods We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11 009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42 938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent. Findings We identified five genome-wide significant loci (binomial test p≤5·0×10−8 ) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 [95% CI 1·08–1·16]; p=7·24×10−11 ), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3 . Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2 , chromosome 6 between FILIP1 and SENP6 , chromosome 12 close to KLHDC5 and PTHLH , and in another region of chromosome 12 close to CHST11 . One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight—a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects. Interpretation Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention. Funding arcOGEN was funded by a special purpose grant from Arthritis Research UK. |
| doi_str_mv | 10.1016/S0140-6736(12)60681-3 |
| format | Article |
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The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity. Methods We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11 009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42 938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent. Findings We identified five genome-wide significant loci (binomial test p≤5·0×10−8 ) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 [95% CI 1·08–1·16]; p=7·24×10−11 ), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3 . Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2 , chromosome 6 between FILIP1 and SENP6 , chromosome 12 close to KLHDC5 and PTHLH , and in another region of chromosome 12 close to CHST11 . One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight—a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects. Interpretation Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention. Funding arcOGEN was funded by a special purpose grant from Arthritis Research UK.</description><identifier>ISSN: 0140-6736</identifier><identifier>EISSN: 1474-547X</identifier><identifier>DOI: 10.1016/S0140-6736(12)60681-3</identifier><identifier>PMID: 22763110</identifier><identifier>CODEN: LANCAO</identifier><language>eng</language><publisher>Kidlington: Elsevier Ltd</publisher><subject>Arthroplasty, Replacement ; Biological and medical sciences ; Case-Control Studies ; chondrocytes ; Diseases of the osteoarticular system ; elderly ; Female ; General aspects ; genes ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Internal Medicine ; Linkage Disequilibrium ; loci ; longevity ; Male ; Medical sciences ; Miscellaneous. Osteoarticular involvement in other diseases ; obesity ; odds ratio ; Osteoarthritis ; Osteoarthritis - genetics ; Osteoarthritis - surgery ; Osteoarthritis, Hip - genetics ; Osteoarthritis, Hip - surgery ; Osteoarthritis, Knee - genetics ; Osteoarthritis, Knee - surgery ; pain ; patients ; people ; phenotype ; Polymorphism, Single Nucleotide ; risk ; risk factors ; single nucleotide polymorphism</subject><ispartof>The Lancet (British edition), 2012-09, Vol.380 (9844), p.815-823</ispartof><rights>Elsevier Ltd</rights><rights>2012 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012 Elsevier Ltd. All rights reserved.</rights><rights>2012 Elsevier Ltd. All rights reserved. 2012 Elsevier Ltd</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c694t-8e7471a9766d41a7252b86a8055ea578bef5afa76f43bbafa6b929fe57e11aec3</citedby><cites>FETCH-LOGICAL-c694t-8e7471a9766d41a7252b86a8055ea578bef5afa76f43bbafa6b929fe57e11aec3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/S0140-6736(12)60681-3$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3536,27903,27904,45974,64364</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26304404$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22763110$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zeggini, Eleftheria</creatorcontrib><creatorcontrib>Panoutsopoulou, Kalliope</creatorcontrib><creatorcontrib>Southam, Lorraine</creatorcontrib><creatorcontrib>Rayner, Nigel W</creatorcontrib><creatorcontrib>Day-Williams, Aaron G</creatorcontrib><creatorcontrib>Lopes, Margarida C</creatorcontrib><creatorcontrib>Boraska, Vesna</creatorcontrib><creatorcontrib>Esko, Tonu</creatorcontrib><creatorcontrib>Evangelou, Evangelos</creatorcontrib><creatorcontrib>Hoffman, Albert</creatorcontrib><creatorcontrib>Houwing-Duistermaat, Jeanine J</creatorcontrib><creatorcontrib>Ingvarsson, Thorvaldur</creatorcontrib><creatorcontrib>Jonsdottir, Ingileif</creatorcontrib><creatorcontrib>Jonnson, Helgi</creatorcontrib><creatorcontrib>Kerkhof, Hanneke J</creatorcontrib><creatorcontrib>Kloppenburg, Margreet</creatorcontrib><creatorcontrib>Bos, Steffan D</creatorcontrib><creatorcontrib>Mangino, Massimo</creatorcontrib><creatorcontrib>Metrustry, Sarah</creatorcontrib><creatorcontrib>Slagboom, P Eline</creatorcontrib><creatorcontrib>Thorleifsson, Gudmar</creatorcontrib><creatorcontrib>Raine, Emma V A</creatorcontrib><creatorcontrib>Ratnayake, Madhushika</creatorcontrib><creatorcontrib>Ricketts, Michelle</creatorcontrib><creatorcontrib>Beazley, Claude</creatorcontrib><creatorcontrib>Blackburn, Hannah</creatorcontrib><creatorcontrib>Bumpstead, Suzannah</creatorcontrib><creatorcontrib>Elliott, Katherine S</creatorcontrib><creatorcontrib>Hunt, Sarah E</creatorcontrib><creatorcontrib>Potter, Simon C</creatorcontrib><creatorcontrib>Shin, So-Youn</creatorcontrib><creatorcontrib>Yadav, Vijay K</creatorcontrib><creatorcontrib>Zhai, Guangju</creatorcontrib><creatorcontrib>Sherburn, Kate</creatorcontrib><creatorcontrib>Dixon, Kate</creatorcontrib><creatorcontrib>Arden, Elizabeth</creatorcontrib><creatorcontrib>Aslam, Nadim</creatorcontrib><creatorcontrib>Battley, Phillippa-kate</creatorcontrib><creatorcontrib>Carluke, Ian</creatorcontrib><creatorcontrib>Doherty, Sally</creatorcontrib><creatorcontrib>Gordon, Andrew</creatorcontrib><creatorcontrib>Joseph, John</creatorcontrib><creatorcontrib>Keen, Richard</creatorcontrib><creatorcontrib>Koller, Nicola C</creatorcontrib><creatorcontrib>Mitchell, Sheryl</creatorcontrib><creatorcontrib>O'Neill, Fiona</creatorcontrib><creatorcontrib>Paling, Ellen</creatorcontrib><creatorcontrib>Reed, Mike R</creatorcontrib><creatorcontrib>Rivadeneira, Fernando</creatorcontrib><creatorcontrib>Swift, Diane</creatorcontrib><creatorcontrib>Walker, Kirsten</creatorcontrib><creatorcontrib>Watkins, Bridget</creatorcontrib><creatorcontrib>Wheeler, Maggie</creatorcontrib><creatorcontrib>Birrell, Fraser</creatorcontrib><creatorcontrib>Ioannidis, John P A</creatorcontrib><creatorcontrib>Meulenbelt, Ingrid</creatorcontrib><creatorcontrib>Metspalu, Andres</creatorcontrib><creatorcontrib>Rai, Ashok</creatorcontrib><creatorcontrib>Salter, Donald</creatorcontrib><creatorcontrib>Stefansson, Kari</creatorcontrib><creatorcontrib>Stykarsdottir, Unnur</creatorcontrib><creatorcontrib>Uitterlinden, André G</creatorcontrib><creatorcontrib>van Meurs, Joyce B J</creatorcontrib><creatorcontrib>Chapman, Kay</creatorcontrib><creatorcontrib>Deloukas, Panos</creatorcontrib><creatorcontrib>Ollier, William E R</creatorcontrib><creatorcontrib>Wallis, Gillian A</creatorcontrib><creatorcontrib>Arden, Nigel</creatorcontrib><creatorcontrib>Carr, Andrew</creatorcontrib><creatorcontrib>Doherty, Michael</creatorcontrib><creatorcontrib>McCaskie, Andrew</creatorcontrib><creatorcontrib>Willkinson, J Mark</creatorcontrib><creatorcontrib>Ralston, Stuart H</creatorcontrib><creatorcontrib>Valdes, Ana M</creatorcontrib><creatorcontrib>Spector, Tim D</creatorcontrib><creatorcontrib>Loughlin, John</creatorcontrib><creatorcontrib>arcOGEN Consortium and arcOGEN Collaborators</creatorcontrib><creatorcontrib>arcOGEN Collaborators</creatorcontrib><creatorcontrib>arcOGEN Consortium</creatorcontrib><title>Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study</title><title>The Lancet (British edition)</title><addtitle>Lancet</addtitle><description>Summary Background Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity. Methods We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11 009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42 938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent. Findings We identified five genome-wide significant loci (binomial test p≤5·0×10−8 ) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 [95% CI 1·08–1·16]; p=7·24×10−11 ), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3 . Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2 , chromosome 6 between FILIP1 and SENP6 , chromosome 12 close to KLHDC5 and PTHLH , and in another region of chromosome 12 close to CHST11 . One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight—a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects. Interpretation Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention. Funding arcOGEN was funded by a special purpose grant from Arthritis Research UK.</description><subject>Arthroplasty, Replacement</subject><subject>Biological and medical sciences</subject><subject>Case-Control Studies</subject><subject>chondrocytes</subject><subject>Diseases of the osteoarticular system</subject><subject>elderly</subject><subject>Female</subject><subject>General aspects</subject><subject>genes</subject><subject>Genetic Predisposition to Disease</subject><subject>Genome-Wide Association Study</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Linkage Disequilibrium</subject><subject>loci</subject><subject>longevity</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Miscellaneous. Osteoarticular involvement in other diseases</subject><subject>obesity</subject><subject>odds ratio</subject><subject>Osteoarthritis</subject><subject>Osteoarthritis - genetics</subject><subject>Osteoarthritis - surgery</subject><subject>Osteoarthritis, Hip - genetics</subject><subject>Osteoarthritis, Hip - surgery</subject><subject>Osteoarthritis, Knee - genetics</subject><subject>Osteoarthritis, Knee - surgery</subject><subject>pain</subject><subject>patients</subject><subject>people</subject><subject>phenotype</subject><subject>Polymorphism, Single Nucleotide</subject><subject>risk</subject><subject>risk factors</subject><subject>single nucleotide polymorphism</subject><issn>0140-6736</issn><issn>1474-547X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFks1u1DAURiMEokPhEYBskKaLFP87YVGEqlIqVXRRKrGzHOd66pKJB9tpNW-PZzIMhQ0rW_K5x9f3c1G8xugYIyzeXyPMUCUkFXNMjgQSNa7ok2KGmWQVZ_L702K2Rw6KFzHeIYSYQPx5cUCIFBRjNCsWFx0MyVlndHJ-KL0tB3go4xgNrJJrXe_Suuy9caX1ofQxgdch3QaXXCznOpir87OvRx9KXS5g8EuoHlwHpY4xl0zKmMZu_bJ4ZnUf4dVuPSxuPp99O_1SXV6dX5x-uqyMaFiqapBMYt1IITqGtSSctLXQNeIcNJd1C5Zrq6WwjLZt3om2IY0FLgFjDYYeFieTdzW2S-hMflzQvVoFt9Rhrbx26u-Twd2qhb9XlDFaN00WzHeC4H-OEJNaujyLvtcD-DEqjKisa8kxySifUBN8jAHs_hqM1CYktQ1JbRJQmKhtSIrmujePe9xX_U4lA-92gI5G9zbowbj4hxMUMYZY5t5OnNVe6UXIzM01QZgjhElTE5mJjxMBeeb3DoKKxsFgoHMBTFKdd_9t9uQfg-ndkL9L_wPWEO_8GIYcqMIqEoUmycaBydZA6S9CYc7R</recordid><startdate>20120901</startdate><enddate>20120901</enddate><creator>Zeggini, Eleftheria</creator><creator>Panoutsopoulou, Kalliope</creator><creator>Southam, Lorraine</creator><creator>Rayner, Nigel W</creator><creator>Day-Williams, Aaron G</creator><creator>Lopes, Margarida C</creator><creator>Boraska, Vesna</creator><creator>Esko, Tonu</creator><creator>Evangelou, Evangelos</creator><creator>Hoffman, Albert</creator><creator>Houwing-Duistermaat, Jeanine J</creator><creator>Ingvarsson, Thorvaldur</creator><creator>Jonsdottir, Ingileif</creator><creator>Jonnson, Helgi</creator><creator>Kerkhof, Hanneke J</creator><creator>Kloppenburg, Margreet</creator><creator>Bos, Steffan D</creator><creator>Mangino, Massimo</creator><creator>Metrustry, Sarah</creator><creator>Slagboom, P Eline</creator><creator>Thorleifsson, Gudmar</creator><creator>Raine, Emma V A</creator><creator>Ratnayake, Madhushika</creator><creator>Ricketts, Michelle</creator><creator>Beazley, Claude</creator><creator>Blackburn, Hannah</creator><creator>Bumpstead, Suzannah</creator><creator>Elliott, Katherine S</creator><creator>Hunt, Sarah E</creator><creator>Potter, Simon C</creator><creator>Shin, So-Youn</creator><creator>Yadav, Vijay K</creator><creator>Zhai, Guangju</creator><creator>Sherburn, Kate</creator><creator>Dixon, Kate</creator><creator>Arden, Elizabeth</creator><creator>Aslam, Nadim</creator><creator>Battley, Phillippa-kate</creator><creator>Carluke, Ian</creator><creator>Doherty, Sally</creator><creator>Gordon, Andrew</creator><creator>Joseph, John</creator><creator>Keen, Richard</creator><creator>Koller, Nicola C</creator><creator>Mitchell, Sheryl</creator><creator>O'Neill, Fiona</creator><creator>Paling, Ellen</creator><creator>Reed, Mike R</creator><creator>Rivadeneira, Fernando</creator><creator>Swift, Diane</creator><creator>Walker, Kirsten</creator><creator>Watkins, Bridget</creator><creator>Wheeler, Maggie</creator><creator>Birrell, Fraser</creator><creator>Ioannidis, John P A</creator><creator>Meulenbelt, Ingrid</creator><creator>Metspalu, Andres</creator><creator>Rai, Ashok</creator><creator>Salter, Donald</creator><creator>Stefansson, Kari</creator><creator>Stykarsdottir, Unnur</creator><creator>Uitterlinden, André G</creator><creator>van Meurs, Joyce B J</creator><creator>Chapman, Kay</creator><creator>Deloukas, Panos</creator><creator>Ollier, William E R</creator><creator>Wallis, Gillian A</creator><creator>Arden, Nigel</creator><creator>Carr, Andrew</creator><creator>Doherty, Michael</creator><creator>McCaskie, Andrew</creator><creator>Willkinson, J Mark</creator><creator>Ralston, Stuart H</creator><creator>Valdes, Ana M</creator><creator>Spector, Tim D</creator><creator>Loughlin, John</creator><general>Elsevier Ltd</general><general>Elsevier</general><general>Lancet Publishing Group</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20120901</creationdate><title>Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study</title><author>Zeggini, Eleftheria ; Panoutsopoulou, Kalliope ; Southam, Lorraine ; Rayner, Nigel W ; Day-Williams, Aaron G ; Lopes, Margarida C ; Boraska, Vesna ; Esko, Tonu ; Evangelou, Evangelos ; Hoffman, Albert ; Houwing-Duistermaat, Jeanine J ; Ingvarsson, Thorvaldur ; Jonsdottir, Ingileif ; Jonnson, Helgi ; Kerkhof, Hanneke J ; Kloppenburg, Margreet ; Bos, Steffan D ; Mangino, Massimo ; Metrustry, Sarah ; Slagboom, P Eline ; Thorleifsson, Gudmar ; Raine, Emma V A ; Ratnayake, Madhushika ; Ricketts, Michelle ; Beazley, Claude ; Blackburn, Hannah ; Bumpstead, Suzannah ; Elliott, Katherine S ; Hunt, Sarah E ; Potter, Simon C ; Shin, So-Youn ; Yadav, Vijay K ; Zhai, Guangju ; Sherburn, Kate ; Dixon, Kate ; Arden, Elizabeth ; Aslam, Nadim ; Battley, Phillippa-kate ; Carluke, Ian ; Doherty, Sally ; Gordon, Andrew ; Joseph, John ; Keen, Richard ; Koller, Nicola C ; Mitchell, Sheryl ; O'Neill, Fiona ; Paling, Ellen ; Reed, Mike R ; Rivadeneira, Fernando ; Swift, Diane ; Walker, Kirsten ; Watkins, Bridget ; Wheeler, Maggie ; Birrell, Fraser ; Ioannidis, John P A ; Meulenbelt, Ingrid ; Metspalu, Andres ; Rai, Ashok ; Salter, Donald ; Stefansson, Kari ; Stykarsdottir, Unnur ; Uitterlinden, André G ; van Meurs, Joyce B J ; Chapman, Kay ; Deloukas, Panos ; Ollier, William E R ; Wallis, Gillian A ; Arden, Nigel ; Carr, Andrew ; Doherty, Michael ; McCaskie, Andrew ; Willkinson, J Mark ; Ralston, Stuart H ; Valdes, Ana M ; Spector, Tim D ; Loughlin, John</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c694t-8e7471a9766d41a7252b86a8055ea578bef5afa76f43bbafa6b929fe57e11aec3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Arthroplasty, Replacement</topic><topic>Biological and medical sciences</topic><topic>Case-Control Studies</topic><topic>chondrocytes</topic><topic>Diseases of the osteoarticular system</topic><topic>elderly</topic><topic>Female</topic><topic>General aspects</topic><topic>genes</topic><topic>Genetic Predisposition to Disease</topic><topic>Genome-Wide Association Study</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Linkage Disequilibrium</topic><topic>loci</topic><topic>longevity</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Miscellaneous. Osteoarticular involvement in other diseases</topic><topic>obesity</topic><topic>odds ratio</topic><topic>Osteoarthritis</topic><topic>Osteoarthritis - genetics</topic><topic>Osteoarthritis - surgery</topic><topic>Osteoarthritis, Hip - genetics</topic><topic>Osteoarthritis, Hip - surgery</topic><topic>Osteoarthritis, Knee - genetics</topic><topic>Osteoarthritis, Knee - surgery</topic><topic>pain</topic><topic>patients</topic><topic>people</topic><topic>phenotype</topic><topic>Polymorphism, Single Nucleotide</topic><topic>risk</topic><topic>risk factors</topic><topic>single nucleotide polymorphism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zeggini, Eleftheria</creatorcontrib><creatorcontrib>Panoutsopoulou, Kalliope</creatorcontrib><creatorcontrib>Southam, Lorraine</creatorcontrib><creatorcontrib>Rayner, Nigel W</creatorcontrib><creatorcontrib>Day-Williams, Aaron G</creatorcontrib><creatorcontrib>Lopes, Margarida C</creatorcontrib><creatorcontrib>Boraska, Vesna</creatorcontrib><creatorcontrib>Esko, Tonu</creatorcontrib><creatorcontrib>Evangelou, Evangelos</creatorcontrib><creatorcontrib>Hoffman, Albert</creatorcontrib><creatorcontrib>Houwing-Duistermaat, Jeanine J</creatorcontrib><creatorcontrib>Ingvarsson, Thorvaldur</creatorcontrib><creatorcontrib>Jonsdottir, Ingileif</creatorcontrib><creatorcontrib>Jonnson, Helgi</creatorcontrib><creatorcontrib>Kerkhof, Hanneke J</creatorcontrib><creatorcontrib>Kloppenburg, Margreet</creatorcontrib><creatorcontrib>Bos, Steffan D</creatorcontrib><creatorcontrib>Mangino, Massimo</creatorcontrib><creatorcontrib>Metrustry, Sarah</creatorcontrib><creatorcontrib>Slagboom, P Eline</creatorcontrib><creatorcontrib>Thorleifsson, Gudmar</creatorcontrib><creatorcontrib>Raine, Emma V A</creatorcontrib><creatorcontrib>Ratnayake, Madhushika</creatorcontrib><creatorcontrib>Ricketts, Michelle</creatorcontrib><creatorcontrib>Beazley, Claude</creatorcontrib><creatorcontrib>Blackburn, Hannah</creatorcontrib><creatorcontrib>Bumpstead, Suzannah</creatorcontrib><creatorcontrib>Elliott, Katherine S</creatorcontrib><creatorcontrib>Hunt, Sarah E</creatorcontrib><creatorcontrib>Potter, Simon C</creatorcontrib><creatorcontrib>Shin, So-Youn</creatorcontrib><creatorcontrib>Yadav, Vijay K</creatorcontrib><creatorcontrib>Zhai, Guangju</creatorcontrib><creatorcontrib>Sherburn, Kate</creatorcontrib><creatorcontrib>Dixon, Kate</creatorcontrib><creatorcontrib>Arden, Elizabeth</creatorcontrib><creatorcontrib>Aslam, Nadim</creatorcontrib><creatorcontrib>Battley, Phillippa-kate</creatorcontrib><creatorcontrib>Carluke, Ian</creatorcontrib><creatorcontrib>Doherty, Sally</creatorcontrib><creatorcontrib>Gordon, Andrew</creatorcontrib><creatorcontrib>Joseph, John</creatorcontrib><creatorcontrib>Keen, Richard</creatorcontrib><creatorcontrib>Koller, Nicola C</creatorcontrib><creatorcontrib>Mitchell, Sheryl</creatorcontrib><creatorcontrib>O'Neill, Fiona</creatorcontrib><creatorcontrib>Paling, Ellen</creatorcontrib><creatorcontrib>Reed, Mike R</creatorcontrib><creatorcontrib>Rivadeneira, Fernando</creatorcontrib><creatorcontrib>Swift, Diane</creatorcontrib><creatorcontrib>Walker, Kirsten</creatorcontrib><creatorcontrib>Watkins, Bridget</creatorcontrib><creatorcontrib>Wheeler, Maggie</creatorcontrib><creatorcontrib>Birrell, Fraser</creatorcontrib><creatorcontrib>Ioannidis, John P A</creatorcontrib><creatorcontrib>Meulenbelt, Ingrid</creatorcontrib><creatorcontrib>Metspalu, Andres</creatorcontrib><creatorcontrib>Rai, Ashok</creatorcontrib><creatorcontrib>Salter, Donald</creatorcontrib><creatorcontrib>Stefansson, Kari</creatorcontrib><creatorcontrib>Stykarsdottir, Unnur</creatorcontrib><creatorcontrib>Uitterlinden, André G</creatorcontrib><creatorcontrib>van Meurs, Joyce B J</creatorcontrib><creatorcontrib>Chapman, Kay</creatorcontrib><creatorcontrib>Deloukas, Panos</creatorcontrib><creatorcontrib>Ollier, William E R</creatorcontrib><creatorcontrib>Wallis, Gillian A</creatorcontrib><creatorcontrib>Arden, Nigel</creatorcontrib><creatorcontrib>Carr, Andrew</creatorcontrib><creatorcontrib>Doherty, Michael</creatorcontrib><creatorcontrib>McCaskie, Andrew</creatorcontrib><creatorcontrib>Willkinson, J Mark</creatorcontrib><creatorcontrib>Ralston, Stuart H</creatorcontrib><creatorcontrib>Valdes, Ana M</creatorcontrib><creatorcontrib>Spector, Tim D</creatorcontrib><creatorcontrib>Loughlin, John</creatorcontrib><creatorcontrib>arcOGEN Consortium and arcOGEN Collaborators</creatorcontrib><creatorcontrib>arcOGEN Collaborators</creatorcontrib><creatorcontrib>arcOGEN Consortium</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>AGRIS</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Lancet (British edition)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zeggini, Eleftheria</au><au>Panoutsopoulou, Kalliope</au><au>Southam, Lorraine</au><au>Rayner, Nigel W</au><au>Day-Williams, Aaron G</au><au>Lopes, Margarida C</au><au>Boraska, Vesna</au><au>Esko, Tonu</au><au>Evangelou, Evangelos</au><au>Hoffman, Albert</au><au>Houwing-Duistermaat, Jeanine J</au><au>Ingvarsson, Thorvaldur</au><au>Jonsdottir, Ingileif</au><au>Jonnson, Helgi</au><au>Kerkhof, Hanneke J</au><au>Kloppenburg, Margreet</au><au>Bos, Steffan D</au><au>Mangino, Massimo</au><au>Metrustry, Sarah</au><au>Slagboom, P Eline</au><au>Thorleifsson, Gudmar</au><au>Raine, Emma V A</au><au>Ratnayake, Madhushika</au><au>Ricketts, Michelle</au><au>Beazley, Claude</au><au>Blackburn, Hannah</au><au>Bumpstead, Suzannah</au><au>Elliott, Katherine S</au><au>Hunt, Sarah E</au><au>Potter, Simon C</au><au>Shin, So-Youn</au><au>Yadav, Vijay K</au><au>Zhai, Guangju</au><au>Sherburn, Kate</au><au>Dixon, Kate</au><au>Arden, Elizabeth</au><au>Aslam, Nadim</au><au>Battley, Phillippa-kate</au><au>Carluke, Ian</au><au>Doherty, Sally</au><au>Gordon, Andrew</au><au>Joseph, John</au><au>Keen, Richard</au><au>Koller, Nicola C</au><au>Mitchell, Sheryl</au><au>O'Neill, Fiona</au><au>Paling, Ellen</au><au>Reed, Mike R</au><au>Rivadeneira, Fernando</au><au>Swift, Diane</au><au>Walker, Kirsten</au><au>Watkins, Bridget</au><au>Wheeler, Maggie</au><au>Birrell, Fraser</au><au>Ioannidis, John P A</au><au>Meulenbelt, Ingrid</au><au>Metspalu, Andres</au><au>Rai, Ashok</au><au>Salter, Donald</au><au>Stefansson, Kari</au><au>Stykarsdottir, Unnur</au><au>Uitterlinden, André G</au><au>van Meurs, Joyce B J</au><au>Chapman, Kay</au><au>Deloukas, Panos</au><au>Ollier, William E R</au><au>Wallis, Gillian A</au><au>Arden, Nigel</au><au>Carr, Andrew</au><au>Doherty, Michael</au><au>McCaskie, Andrew</au><au>Willkinson, J Mark</au><au>Ralston, Stuart H</au><au>Valdes, Ana M</au><au>Spector, Tim D</au><au>Loughlin, John</au><aucorp>arcOGEN Consortium and arcOGEN Collaborators</aucorp><aucorp>arcOGEN Collaborators</aucorp><aucorp>arcOGEN Consortium</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study</atitle><jtitle>The Lancet (British edition)</jtitle><addtitle>Lancet</addtitle><date>2012-09-01</date><risdate>2012</risdate><volume>380</volume><issue>9844</issue><spage>815</spage><epage>823</epage><pages>815-823</pages><issn>0140-6736</issn><eissn>1474-547X</eissn><coden>LANCAO</coden><abstract>Summary Background Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity. Methods We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11 009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42 938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent. Findings We identified five genome-wide significant loci (binomial test p≤5·0×10−8 ) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 [95% CI 1·08–1·16]; p=7·24×10−11 ), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3 . Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2 , chromosome 6 between FILIP1 and SENP6 , chromosome 12 close to KLHDC5 and PTHLH , and in another region of chromosome 12 close to CHST11 . One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight—a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects. Interpretation Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention. Funding arcOGEN was funded by a special purpose grant from Arthritis Research UK.</abstract><cop>Kidlington</cop><pub>Elsevier Ltd</pub><pmid>22763110</pmid><doi>10.1016/S0140-6736(12)60681-3</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0140-6736 |
| ispartof | The Lancet (British edition), 2012-09, Vol.380 (9844), p.815-823 |
| issn | 0140-6736 1474-547X |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3443899 |
| source | MEDLINE; Elsevier ScienceDirect Journals; ProQuest Central UK/Ireland |
| subjects | Arthroplasty, Replacement Biological and medical sciences Case-Control Studies chondrocytes Diseases of the osteoarticular system elderly Female General aspects genes Genetic Predisposition to Disease Genome-Wide Association Study Humans Internal Medicine Linkage Disequilibrium loci longevity Male Medical sciences Miscellaneous. Osteoarticular involvement in other diseases obesity odds ratio Osteoarthritis Osteoarthritis - genetics Osteoarthritis - surgery Osteoarthritis, Hip - genetics Osteoarthritis, Hip - surgery Osteoarthritis, Knee - genetics Osteoarthritis, Knee - surgery pain patients people phenotype Polymorphism, Single Nucleotide risk risk factors single nucleotide polymorphism |
| title | Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study |
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