Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk

Duncan, Emma L., Danoy, Patrick, Kemp, John P., Leo, Paul J., McCloskey, Eugene, Nicholson, Geoffrey C., Eastell, Richard, Prince, Richard L., Eisman, John A., Jones, Graeme, Sambrook, Philip N., Reid, Ian R., Dennison, Elaine M., Wark, John, Richards, J. Brent, Uitterlinden, Andre G., Spector, Tim D., Esapa, Chris, Cox, Roger D., Brown, Steve D. M., Thakker, Rajesh V., Addison, Kathryn A., Bradbury, Linda A., Center, Jacqueline R., Cooper, Cyrus, Cremin, Catherine, Estrada, Karol, Felsenberg, Dieter, Glueer, Claus-C., Hadler, Johanna, Henry, Margaret J., Hofman, Albert, Kotowicz, Mark A., Makovey, Joanna, Nguyen, Sing C., Nguyen, Tuan V., Pasco, Julie A., Pryce, Karena, Reid, David M., Rivadeneira, Fernando, Roux, Christian, Stefansson, Kari, Styrkarsdottir, Unnur, Thorleifsson, Gudmar, Tichawangana, Rumbidzai, Evans, David M. and Brown, Matthew A. (2011) Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. PLoS Genetics, 7 4: e1001372.1-e1001372.10. doi:10.1371/journal.pgen.1001372

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Author Duncan, Emma L.
Danoy, Patrick
Kemp, John P.
Leo, Paul J.
McCloskey, Eugene
Nicholson, Geoffrey C.
Eastell, Richard
Prince, Richard L.
Eisman, John A.
Jones, Graeme
Sambrook, Philip N.
Reid, Ian R.
Dennison, Elaine M.
Wark, John
Richards, J. Brent
Uitterlinden, Andre G.
Spector, Tim D.
Esapa, Chris
Cox, Roger D.
Brown, Steve D. M.
Thakker, Rajesh V.
Addison, Kathryn A.
Bradbury, Linda A.
Center, Jacqueline R.
Cooper, Cyrus
Cremin, Catherine
Estrada, Karol
Felsenberg, Dieter
Glueer, Claus-C.
Hadler, Johanna
Henry, Margaret J.
Hofman, Albert
Kotowicz, Mark A.
Makovey, Joanna
Nguyen, Sing C.
Nguyen, Tuan V.
Pasco, Julie A.
Pryce, Karena
Reid, David M.
Rivadeneira, Fernando
Roux, Christian
Stefansson, Kari
Styrkarsdottir, Unnur
Thorleifsson, Gudmar
Tichawangana, Rumbidzai
Evans, David M.
Brown, Matthew A.
Title Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk
Journal name PLoS Genetics   Check publisher's open access policy
ISSN 1553-7390
Publication date 2011-04-01
Year available 2012
Sub-type Article (original research)
DOI 10.1371/journal.pgen.1001372
Open Access Status DOI
Volume 7
Issue 4
Start page e1001372.1
End page e1001372.10
Total pages 10
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Language eng
Abstract 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.
Keyword Osteoporotic fracture
Bone mineral density
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
UQ Diamantina Institute - Open Access Collection
UQ Diamantina Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 104 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 111 times in Scopus Article | Citations
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Created: Mon, 25 Jul 2011, 20:05:59 EST by Matthew Lamb on behalf of UQ Diamantina Institute