Genome-Wide Association Study Using Extreme Truncate Selection Identifies Novel Genes Affecting Bone Mineral Density and Fracture Risk

Emma L. Duncan; Patrick A. Danoy; John P. Kemp; Paul J. Leo; Eugene V. 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. Glueer; 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

doi:10.1371/journal.pgen.1001372

Genome-Wide Association Study Using Extreme Truncate Selection Identifies Novel Genes Affecting Bone Mineral Density and Fracture Risk

Emma L. Duncan^*, Patrick A. Danoy, John P. Kemp, Paul J. Leo, Eugene V. 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. BrownRajesh V. Thakker, Kathryn A. Addison, Linda A. Bradbury, Jacqueline R. Center, Cyrus Cooper, Catherine Cremin, Karol Estrada, Dieter Felsenberg, Claus-C. Glueer, 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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	e1001372
Journal	Plos Genetics
Volume	7
Issue number	4
DOIs	https://doi.org/10.1371/journal.pgen.1001372
Publication status	Published - Apr 2011

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Duncan, E. L., Danoy, P. A., Kemp, J. P., Leo, P. J., McCloskey, E. V., Nicholson, G. C., Eastell, R., Prince, R. L., Eisman, J. A., Jones, G., Sambrook, P. N., Reid, I. R., Dennison, E. M., Wark, J., Richards, J. B., Uitterlinden, A. G., Spector, T. D., Esapa, C., Cox, R. D., ... Brown, M. A. (2011). Genome-Wide Association Study Using Extreme Truncate Selection Identifies Novel Genes Affecting Bone Mineral Density and Fracture Risk. Plos Genetics, 7(4), Article e1001372. https://doi.org/10.1371/journal.pgen.1001372

@article{f71109021f0a4d699a30785477d1e582,

title = "Genome-Wide Association Study Using Extreme Truncate Selection Identifies Novel Genes Affecting Bone Mineral Density and Fracture Risk",

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.",

author = "Duncan, {Emma L.} and Danoy, {Patrick A.} and Kemp, {John P.} and Leo, {Paul J.} and McCloskey, {Eugene V.} and Nicholson, {Geoffrey C.} and Richard Eastell and Prince, {Richard L.} and Eisman, {John A.} and Graeme Jones and Sambrook, {Philip N.} and Reid, {Ian R.} and Dennison, {Elaine M.} and John Wark and Richards, {J. Brent} and Uitterlinden, {Andre G.} and Spector, {Tim D.} and Chris Esapa and Cox, {Roger D.} and Brown, {Steve D. M.} and Thakker, {Rajesh V.} and Addison, {Kathryn A.} and Bradbury, {Linda A.} and Center, {Jacqueline R.} and Cyrus Cooper and Catherine Cremin and Karol Estrada and Dieter Felsenberg and Claus-C. Glueer and Johanna Hadler and Henry, {Margaret J.} and Albert Hofman and Kotowicz, {Mark A.} and Joanna Makovey and Nguyen, {Sing C.} and Nguyen, {Tuan V.} and Pasco, {Julie A.} and Karena Pryce and Reid, {David M.} and Fernando Rivadeneira and Christian Roux and Kari Stefansson and Unnur Styrkarsdottir and Gudmar Thorleifsson and Rumbidzai Tichawangana and Evans, {David M.} and Brown, {Matthew A.}",

year = "2011",

month = apr,

doi = "10.1371/journal.pgen.1001372",

language = "English",

volume = "7",

journal = "Plos Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "4",

}

Duncan, EL, Danoy, PA, Kemp, JP, Leo, PJ, McCloskey, EV, Nicholson, GC, Eastell, R, Prince, RL, Eisman, JA, Jones, G, Sambrook, PN, Reid, IR, Dennison, EM, Wark, J, Richards, JB, Uitterlinden, AG, Spector, TD, Esapa, C, Cox, RD, Brown, SDM, Thakker, RV, Addison, KA, Bradbury, LA, Center, JR, Cooper, C, Cremin, C, Estrada, K, Felsenberg, D, Glueer, C-C, Hadler, J, Henry, MJ, Hofman, A, Kotowicz, MA, Makovey, J, Nguyen, SC, Nguyen, TV, Pasco, JA, Pryce, K, Reid, DM, Rivadeneira, F, Roux, C, Stefansson, K, Styrkarsdottir, U, Thorleifsson, G, Tichawangana, R, Evans, DM & Brown, MA 2011, 'Genome-Wide Association Study Using Extreme Truncate Selection Identifies Novel Genes Affecting Bone Mineral Density and Fracture Risk', Plos Genetics, vol. 7, no. 4, e1001372. https://doi.org/10.1371/journal.pgen.1001372

TY - JOUR

T1 - Genome-Wide Association Study Using Extreme Truncate Selection Identifies Novel Genes Affecting Bone Mineral Density and Fracture Risk

AU - Duncan, Emma L.

AU - Danoy, Patrick A.

AU - Kemp, John P.

AU - Leo, Paul J.

AU - McCloskey, Eugene V.

AU - Nicholson, Geoffrey C.

AU - Eastell, Richard

AU - Prince, Richard L.

AU - Eisman, John A.

AU - Jones, Graeme

AU - Sambrook, Philip N.

AU - Reid, Ian R.

AU - Dennison, Elaine M.

AU - Wark, John

AU - Richards, J. Brent

AU - Uitterlinden, Andre G.

AU - Spector, Tim D.

AU - Esapa, Chris

AU - Cox, Roger D.

AU - Brown, Steve D. M.

AU - Thakker, Rajesh V.

AU - Addison, Kathryn A.

AU - Bradbury, Linda A.

AU - Center, Jacqueline R.

AU - Cooper, Cyrus

AU - Cremin, Catherine

AU - Estrada, Karol

AU - Felsenberg, Dieter

AU - Glueer, Claus-C.

AU - Hadler, Johanna

AU - Henry, Margaret J.

AU - Hofman, Albert

AU - Kotowicz, Mark A.

AU - Makovey, Joanna

AU - Nguyen, Sing C.

AU - Nguyen, Tuan V.

AU - Pasco, Julie A.

AU - Pryce, Karena

AU - Reid, David M.

AU - Rivadeneira, Fernando

AU - Roux, Christian

AU - Stefansson, Kari

AU - Styrkarsdottir, Unnur

AU - Thorleifsson, Gudmar

AU - Tichawangana, Rumbidzai

AU - Evans, David M.

AU - Brown, Matthew A.

PY - 2011/4

Y1 - 2011/4

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pgen.1001372

DO - 10.1371/journal.pgen.1001372

M3 - Article

SN - 1553-7390

VL - 7

JO - Plos Genetics

JF - Plos Genetics

IS - 4

M1 - e1001372

ER -

Genome-Wide Association Study Using Extreme Truncate Selection Identifies Novel Genes Affecting Bone Mineral Density and Fracture Risk

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