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dc.contributor.authorHackinger, Sophie
dc.contributor.authorTrajanoska, Katerina
dc.contributor.authorStyrkarsdottir, Unnur
dc.contributor.authorZengini, Eleni
dc.contributor.authorSteinberg, Julia
dc.contributor.authorRitchie, Graham R S
dc.contributor.authorHatzikotoulas, Konstantinos
dc.contributor.authorGilly, Arthur
dc.contributor.authorEvangelou, Evangelos
dc.contributor.authorKemp, John P
dc.contributor.authorEvans, David
dc.contributor.authorIngvarsson, Thorvaldur
dc.contributor.authorJonsson, Helgi
dc.contributor.authorThorsteinsdottir, Unnur
dc.contributor.authorStefansson, Kari
dc.contributor.authorMcCaskie, Andrew W
dc.contributor.authorBrooks, Roger A
dc.contributor.authorWilkinson, Jeremy M
dc.contributor.authorRivadeneira, Fernando
dc.contributor.authorZeggini, Eleftheria
dc.date.accessioned2018-03-05T14:46:52Z
dc.date.available2018-03-05T14:46:52Z
dc.date.issued2017
dc.date.submitted2018
dc.identifier.citationEvaluation of shared genetic aetiology between osteoarthritis and bone mineral density identifies SMAD3 as a novel osteoarthritis risk locus. 2017, 26 (19):3850-3858 Hum. Mol. Genet.en
dc.identifier.issn1460-2083
dc.identifier.pmid28934396
dc.identifier.doi10.1093/hmg/ddx285
dc.identifier.urihttp://hdl.handle.net/2336/620493
dc.descriptionTo access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Filesen
dc.description.abstractOsteoarthritis (OA) is a common complex disease with high public health burden and no curative therapy. High bone mineral density (BMD) is associated with an increased risk of developing OA, suggesting a shared underlying biology. Here, we performed the first systematic overlap analysis of OA and BMD on a genome wide scale. We used summary statistics from the GEFOS consortium for lumbar spine (n = 31,800) and femoral neck (n = 32,961) BMD, and from the arcOGEN consortium for three OA phenotypes (hip, ncases=3,498; knee, ncases=3,266; hip and/or knee, ncases=7,410; ncontrols=11,009). Performing LD score regression we found a significant genetic correlation between the combined OA phenotype (hip and/or knee) and lumbar spine BMD (rg=0.18, P = 2.23 × 10-2), which may be driven by the presence of spinal osteophytes. We identified 143 variants with evidence for cross-phenotype association which we took forward for replication in independent large-scale OA datasets, and subsequent meta-analysis with arcOGEN for a total sample size of up to 23,425 cases and 236,814 controls. We found robustly replicating evidence for association with OA at rs12901071 (OR 1.08 95% CI 1.05-1.11, Pmeta=3.12 × 10-10), an intronic variant in the SMAD3 gene, which is known to play a role in bone remodeling and cartilage maintenance. We were able to confirm expression of SMAD3 in intact and degraded cartilage of the knee and hip. Our findings provide the first systematic evaluation of pleiotropy between OA and BMD, highlight genes with biological relevance to both traits, and establish a robust new OA genetic risk locus at SMAD3.
dc.description.sponsorshipWellcome Trusten
dc.language.isoenen
dc.publisherOxford University Pressen
dc.relation.urlhttps://academic.oup.com/hmg/article/26/19/3850/3979366en
dc.rightsArchived with thanks to Human molecular geneticsen
dc.subjectSlitgigten
dc.subjectBeinþynningen
dc.subjectGenen
dc.subjectRHE12en
dc.subject.meshBone Densityen
dc.subject.meshDatabases, Nucleic Aciden
dc.subject.meshFemur Necken
dc.subject.meshGenetic Association Studiesen
dc.subject.meshGenetic Pleiotropyen
dc.subject.meshHumansen
dc.subject.meshLumbar Vertebraeen
dc.subject.meshOsteoarthritisen
dc.subject.meshOsteoarthritis, Hipen
dc.subject.meshOsteoarthritis, Kneeen
dc.subject.meshRisk Factorsen
dc.subject.meshSmad3 Proteinen
dc.titleEvaluation of shared genetic aetiology between osteoarthritis and bone mineral density identifies SMAD3 as a novel osteoarthritis risk locus.en
dc.typeArticleen
dc.contributor.department[ 1 ] Wellcome Trust Sanger Inst, Human Genet, Hinxton CB10 1HH, England Show more [ 2 ] Erasmus Univ, Dept Internal Med, Med Ctr, NL-3000 CA Rotterdam, Netherlands Show more [ 3 ] Erasmus Univ, Dept Epidemiol, Med Ctr, NL-3000 CA Rotterdam, Netherlands [ 4 ] deCODE Genet, Sturlugata 8, IS-101 Reykjavik, Iceland Show more [ 5 ] Univ Sheffield, Dept Oncol & Metab, Sheffield S10 2RX, S Yorkshire, England [ 6 ] Dromokaiteio Psychiat Hosp, Dept 5, Athens 12461, Greece Show more [ 7 ] Univ Ioannina, Med Sch, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece Show more [ 8 ] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England Show more [ 9 ] Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England Show more [ 10 ] Univ Queensland, Translat Res Inst, Diamantina Inst, Brisbane, Qld, Australia [ 11 ] Akureyri Hosp, Dept Orthoped Surg, IS-600 Akureyri, Iceland Show more [ 12 ] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland [ 13 ] Univ Akureyri, Inst Hlth Sci, IS-600 Akureyri, Iceland [ 14 ] Natl Univ Hosp Iceland, Dept Med, Landspitali, IS-101 Reykjavik, Iceland Show more [ 15 ] Univ Cambridge, Div Trauma & Orthopaed Surg, Addenbrookes Hosp, Box 180, Cambridge CB2 0QQ, Englanden
dc.identifier.journalHuman molecular geneticsen
dc.rights.accessOpen Access - Opinn aðganguren
dc.departmentcodeRHE12
refterms.dateFOA2018-09-12T17:05:02Z
html.description.abstractOsteoarthritis (OA) is a common complex disease with high public health burden and no curative therapy. High bone mineral density (BMD) is associated with an increased risk of developing OA, suggesting a shared underlying biology. Here, we performed the first systematic overlap analysis of OA and BMD on a genome wide scale. We used summary statistics from the GEFOS consortium for lumbar spine (n = 31,800) and femoral neck (n = 32,961) BMD, and from the arcOGEN consortium for three OA phenotypes (hip, ncases=3,498; knee, ncases=3,266; hip and/or knee, ncases=7,410; ncontrols=11,009). Performing LD score regression we found a significant genetic correlation between the combined OA phenotype (hip and/or knee) and lumbar spine BMD (rg=0.18, P = 2.23 × 10-2), which may be driven by the presence of spinal osteophytes. We identified 143 variants with evidence for cross-phenotype association which we took forward for replication in independent large-scale OA datasets, and subsequent meta-analysis with arcOGEN for a total sample size of up to 23,425 cases and 236,814 controls. We found robustly replicating evidence for association with OA at rs12901071 (OR 1.08 95% CI 1.05-1.11, Pmeta=3.12 × 10-10), an intronic variant in the SMAD3 gene, which is known to play a role in bone remodeling and cartilage maintenance. We were able to confirm expression of SMAD3 in intact and degraded cartilage of the knee and hip. Our findings provide the first systematic evaluation of pleiotropy between OA and BMD, highlight genes with biological relevance to both traits, and establish a robust new OA genetic risk locus at SMAD3.


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