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Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis

Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis
Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis
Osteoporosis is a common disease diagnosed primarily by measurement of bone mineral density (BMD). We undertook a genome-wide association study (GWAS) in 142,487 individuals from the UK Biobank to identify loci associated with BMD as estimated by quantitative ultrasound of the heel. We identified 307 conditionally independent single-nucleotide polymorphisms (SNPs) that attained genome-wide significance at 203 loci, explaining approximately 12% of the phenotypic variance. These included 153 previously unreported loci, and several rare variants with large effect sizes. To investigate the underlying mechanisms, we undertook (1) bioinformatic, functional genomic annotation and human osteoblast expression studies; (2) gene-function prediction; (3) skeletal phenotyping of 120 knockout mice with deletions of genes adjacent to lead independent SNPs; and (4) analysis of gene expression in mouse osteoblasts, osteocytes and osteoclasts. The results implicate GPC6 as a novel determinant of BMD, and also identify abnormal skeletal phenotypes in knockout mice associated with a further 100 prioritized genes.
1061-4036
1468-1475
Kemp, John P.
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Morris, John A.
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Medina-Gómez, Carolina
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Forgetta, Vincenzo
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Warrington, Nicole M.
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Youlten, Scott E.
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Zheng, Jie
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Gregson, Celia L.
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Grundberg, Elin
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Logan, John G.
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Pollard, Andrea S.
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Sparkes, Penny C.
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Ghirardello, Elena J.
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Allen, Rebecca
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Leitch, Victoria D.
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Butterfield, Natalie C.
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Komla-Ebri, Davide
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Adoum, Anne-Tounsia
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Curry, Katharine F.
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White, Jacqueline K
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Kussy, Fiona
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Greenlaw, Keelin M.
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Xu, Changjang
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Harvey, Nicholas C.
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Cooper, Cyrus
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Adams, David J.
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Greenwood, Celia M.T.
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Maurano, Matthew T.
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Kaptoge, Stephen K.
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Tobias, Jonathan H.
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Croucher, Peter I.
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Ackert-Bicknell, Cheryl L.
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Bassett, J.H. Duncan
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Williams, Graham R.
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Richards, J. Brent
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Evans, David M.
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Kemp, John P.
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Morris, John A.
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Medina-Gómez, Carolina
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Forgetta, Vincenzo
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Warrington, Nicole M.
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Youlten, Scott E.
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Zheng, Jie
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Gregson, Celia L.
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Grundberg, Elin
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Trajanoska, Katerina
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Logan, John G.
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Pollard, Andrea S.
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Sparkes, Penny C.
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Ghirardello, Elena J.
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Allen, Rebecca
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Leitch, Victoria D.
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Butterfield, Natalie C.
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Komla-Ebri, Davide
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Adoum, Anne-Tounsia
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Curry, Katharine F.
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White, Jacqueline K
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Kussy, Fiona
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Greenlaw, Keelin M.
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Xu, Changjang
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Harvey, Nicholas C.
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Cooper, Cyrus
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Adams, David J.
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Greenwood, Celia M.T.
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Maurano, Matthew T.
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Kaptoge, Stephen K.
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Rivadeneira, Fernando
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Tobias, Jonathan H.
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Croucher, Peter I.
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Ackert-Bicknell, Cheryl L.
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Bassett, J.H. Duncan
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Williams, Graham R.
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Richards, J. Brent
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Evans, David M.
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Kemp, John P., Morris, John A., Medina-Gómez, Carolina, Forgetta, Vincenzo, Warrington, Nicole M., Youlten, Scott E., Zheng, Jie, Gregson, Celia L., Grundberg, Elin, Trajanoska, Katerina, Logan, John G., Pollard, Andrea S., Sparkes, Penny C., Ghirardello, Elena J., Allen, Rebecca, Leitch, Victoria D., Butterfield, Natalie C., Komla-Ebri, Davide, Adoum, Anne-Tounsia, Curry, Katharine F., White, Jacqueline K, Kussy, Fiona, Greenlaw, Keelin M., Xu, Changjang, Harvey, Nicholas C., Cooper, Cyrus, Adams, David J., Greenwood, Celia M.T., Maurano, Matthew T., Kaptoge, Stephen K., Rivadeneira, Fernando, Tobias, Jonathan H., Croucher, Peter I., Ackert-Bicknell, Cheryl L., Bassett, J.H. Duncan, Williams, Graham R., Richards, J. Brent and Evans, David M. (2017) Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis. Nature Genetics, 49 (10), 1468-1475. (doi:10.1038/ng.3949).

Record type: Article

Abstract

Osteoporosis is a common disease diagnosed primarily by measurement of bone mineral density (BMD). We undertook a genome-wide association study (GWAS) in 142,487 individuals from the UK Biobank to identify loci associated with BMD as estimated by quantitative ultrasound of the heel. We identified 307 conditionally independent single-nucleotide polymorphisms (SNPs) that attained genome-wide significance at 203 loci, explaining approximately 12% of the phenotypic variance. These included 153 previously unreported loci, and several rare variants with large effect sizes. To investigate the underlying mechanisms, we undertook (1) bioinformatic, functional genomic annotation and human osteoblast expression studies; (2) gene-function prediction; (3) skeletal phenotyping of 120 knockout mice with deletions of genes adjacent to lead independent SNPs; and (4) analysis of gene expression in mouse osteoblasts, osteocytes and osteoclasts. The results implicate GPC6 as a novel determinant of BMD, and also identify abnormal skeletal phenotypes in knockout mice associated with a further 100 prioritized genes.

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Accepted/In Press date: 11 August 2017
e-pub ahead of print date: 4 September 2017
Published date: October 2017

Identifiers

Local EPrints ID: 413885
URI: http://eprints.soton.ac.uk/id/eprint/413885
ISSN: 1061-4036
PURE UUID: b4db1b4e-b83b-41a5-85da-1badf08157dc
ORCID for Nicholas C. Harvey: ORCID iD orcid.org/0000-0002-8194-2512
ORCID for Cyrus Cooper: ORCID iD orcid.org/0000-0003-3510-0709

Catalogue record

Date deposited: 08 Sep 2017 16:30
Last modified: 18 Mar 2024 05:05

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Contributors

Author: John P. Kemp
Author: John A. Morris
Author: Carolina Medina-Gómez
Author: Vincenzo Forgetta
Author: Nicole M. Warrington
Author: Scott E. Youlten
Author: Jie Zheng
Author: Celia L. Gregson
Author: Elin Grundberg
Author: Katerina Trajanoska
Author: John G. Logan
Author: Andrea S. Pollard
Author: Penny C. Sparkes
Author: Elena J. Ghirardello
Author: Rebecca Allen
Author: Victoria D. Leitch
Author: Natalie C. Butterfield
Author: Davide Komla-Ebri
Author: Anne-Tounsia Adoum
Author: Katharine F. Curry
Author: Jacqueline K White
Author: Fiona Kussy
Author: Keelin M. Greenlaw
Author: Changjang Xu
Author: Cyrus Cooper ORCID iD
Author: David J. Adams
Author: Celia M.T. Greenwood
Author: Matthew T. Maurano
Author: Stephen K. Kaptoge
Author: Fernando Rivadeneira
Author: Jonathan H. Tobias
Author: Peter I. Croucher
Author: Cheryl L. Ackert-Bicknell
Author: J.H. Duncan Bassett
Author: Graham R. Williams
Author: J. Brent Richards
Author: David M. Evans

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