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

Kemp, John P., Morris, John A., Medina-Gomez, 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, Changjiang, Harvey, Nicholas C., Cooper, Cyrus, Adams, David J., Greenwood, Celia M. T., Maurano, Matthew T., Kaptoge, Stephen, 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

Author Kemp, John P.
Morris, John A.
Medina-Gomez, 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, Changjiang
Harvey, Nicholas C.
Cooper, Cyrus
Adams, David J.
Greenwood, Celia M. T.
Maurano, Matthew T.
Kaptoge, Stephen
Rivadeneira, Fernando
Tobias, Jonathan H.
Croucher, Peter I.
Ackert-Bicknell, Cheryl L.
Bassett, J. H. Duncan
Williams, Graham R.
Richards, J. Brent
Evans, David M.
Title Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis
Journal name Nature Genetics   Check publisher's open access policy
ISSN 1546-1718
Publication date 2017-09-04
Year available 2017
Sub-type Article (original research)
DOI 10.1038/ng.3949
Open Access Status Not yet assessed
Volume 49
Issue 10
Start page 1468
End page 1475
Total pages 8
Place of publication New York, NY United States
Publisher Nature Publishing Group
Language eng
Subject 1311 Genetics
Abstract Osteoporosis is a common disease diagnosed primarily by measurement of bone mineral density (BMD). We undertook a genomewide 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.
Keyword Genome-Wide Association
High-Trauma Fractures
Ld Score Regression
Quantitative Ultrasound
Mendelian Randomization
Older Women
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
UQ Diamantina Institute Publications
Version Filter Type
Citation counts: Scopus Citation Count Cited 3 times in Scopus Article | Citations
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Created: Fri, 03 Nov 2017, 09:15:39 EST