Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk.
Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been...
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Public Library of Science (PLoS)
2011
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oai:doaj.org-article:67487b75c7514774bb6c8bedffb4cbdc2021-11-18T06:17:31ZGenome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk.1553-73901553-740410.1371/journal.pgen.1001372https://doaj.org/article/67487b75c7514774bb6c8bedffb4cbdc2011-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21533022/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55-85 years), with either extreme high or low hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0, n = 1055, or -4.0 to -1.5, n = 900), with replication in cohorts of women drawn from the general population (n = 20,898). The study replicates 21 of 26 known BMD-associated genes. Additionally, we report suggestive association of a further six new genetic associations in or around the genes CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 is also reported, which has high bone mass, supporting the involvement of this gene in BMD determination. In addition to identifying further genes associated with BMD, this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies.Emma L DuncanPatrick DanoyJohn P KempPaul J LeoEugene McCloskeyGeoffrey C NicholsonRichard EastellRichard L PrinceJohn A EismanGraeme JonesPhilip N SambrookIan R ReidElaine M DennisonJohn WarkJ Brent RichardsAndre G UitterlindenTim D SpectorChris EsapaRoger D CoxSteve D M BrownRajesh V ThakkerKathryn A AddisonLinda A BradburyJacqueline R CenterCyrus CooperCatherine CreminKarol EstradaDieter FelsenbergClaus-C GlüerJohanna HadlerMargaret J HenryAlbert HofmanMark A KotowiczJoanna MakoveySing C NguyenTuan V NguyenJulie A PascoKarena PryceDavid M ReidFernando RivadeneiraChristian RouxKari StefanssonUnnur StyrkarsdottirGudmar ThorleifssonRumbidzai TichawanganaDavid M EvansMatthew A BrownPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 7, Iss 4, p e1001372 (2011) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Genetics QH426-470 |
| spellingShingle |
Genetics QH426-470 Emma L Duncan Patrick Danoy John P Kemp Paul J Leo Eugene McCloskey Geoffrey C Nicholson Richard Eastell Richard L Prince John A Eisman Graeme Jones Philip N Sambrook Ian R Reid Elaine M Dennison John Wark J Brent Richards Andre G Uitterlinden Tim D Spector Chris Esapa Roger D Cox Steve D M Brown Rajesh V Thakker Kathryn A Addison Linda A Bradbury Jacqueline R Center Cyrus Cooper Catherine Cremin Karol Estrada Dieter Felsenberg Claus-C Glüer Johanna Hadler Margaret J Henry Albert Hofman Mark A Kotowicz Joanna Makovey Sing C Nguyen Tuan V Nguyen Julie A Pasco Karena Pryce David M Reid Fernando Rivadeneira Christian Roux Kari Stefansson Unnur Styrkarsdottir Gudmar Thorleifsson Rumbidzai Tichawangana David M Evans Matthew A Brown Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. |
| description |
Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55-85 years), with either extreme high or low hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0, n = 1055, or -4.0 to -1.5, n = 900), with replication in cohorts of women drawn from the general population (n = 20,898). The study replicates 21 of 26 known BMD-associated genes. Additionally, we report suggestive association of a further six new genetic associations in or around the genes CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 is also reported, which has high bone mass, supporting the involvement of this gene in BMD determination. In addition to identifying further genes associated with BMD, this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies. |
| format |
article |
| author |
Emma L Duncan Patrick Danoy John P Kemp Paul J Leo Eugene McCloskey Geoffrey C Nicholson Richard Eastell Richard L Prince John A Eisman Graeme Jones Philip N Sambrook Ian R Reid Elaine M Dennison John Wark J Brent Richards Andre G Uitterlinden Tim D Spector Chris Esapa Roger D Cox Steve D M Brown Rajesh V Thakker Kathryn A Addison Linda A Bradbury Jacqueline R Center Cyrus Cooper Catherine Cremin Karol Estrada Dieter Felsenberg Claus-C Glüer Johanna Hadler Margaret J Henry Albert Hofman Mark A Kotowicz Joanna Makovey Sing C Nguyen Tuan V Nguyen Julie A Pasco Karena Pryce David M Reid Fernando Rivadeneira Christian Roux Kari Stefansson Unnur Styrkarsdottir Gudmar Thorleifsson Rumbidzai Tichawangana David M Evans Matthew A Brown |
| author_facet |
Emma L Duncan Patrick Danoy John P Kemp Paul J Leo Eugene McCloskey Geoffrey C Nicholson Richard Eastell Richard L Prince John A Eisman Graeme Jones Philip N Sambrook Ian R Reid Elaine M Dennison John Wark J Brent Richards Andre G Uitterlinden Tim D Spector Chris Esapa Roger D Cox Steve D M Brown Rajesh V Thakker Kathryn A Addison Linda A Bradbury Jacqueline R Center Cyrus Cooper Catherine Cremin Karol Estrada Dieter Felsenberg Claus-C Glüer Johanna Hadler Margaret J Henry Albert Hofman Mark A Kotowicz Joanna Makovey Sing C Nguyen Tuan V Nguyen Julie A Pasco Karena Pryce David M Reid Fernando Rivadeneira Christian Roux Kari Stefansson Unnur Styrkarsdottir Gudmar Thorleifsson Rumbidzai Tichawangana David M Evans Matthew A Brown |
| author_sort |
Emma L Duncan |
| title |
Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. |
| title_short |
Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. |
| title_full |
Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. |
| title_fullStr |
Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. |
| title_full_unstemmed |
Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. |
| title_sort |
genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2011 |
| url |
https://doaj.org/article/67487b75c7514774bb6c8bedffb4cbdc |
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