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

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

doi:10.1038/ng.3949

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

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

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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.

Original language	English
Pages (from-to)	1468-1475
Number of pages	8
Journal	Nature Genetics
Volume	49
Issue number	10
DOIs	https://doi.org/10.1038/ng.3949
Publication status	Published - Oct 2017

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621629/

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Kemp, J. P., Morris, J. A., Medina-Gomez, C., Forgetta, V., Warrington, N. M., Youlten, S. E., Zheng, J., Gregson, C. L., Grundberg, E., Trajanoska, K., Logan, J. G., Pollard, A. S., Sparkes, P. C., Ghirardello, E. J., Allen, R., Leitch, V. D., Butterfield, N. C., Komla-Ebri, D., Adoum, A.-T., ... Evans, D. 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. https://doi.org/10.1038/ng.3949

@article{ba07f581e366435cb53eefe12b13fb14,

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

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.",

keywords = "GENOME-WIDE ASSOCIATION, HIGH-TRAUMA FRACTURES, LD SCORE REGRESSION, QUANTITATIVE ULTRASOUND, MENDELIAN RANDOMIZATION, GENE-FUNCTION, OLDER WOMEN, METAANALYSIS, MOUSE, RISK",

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

year = "2017",

month = oct,

doi = "10.1038/ng.3949",

language = "English",

volume = "49",

pages = "1468--1475",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group - Macmillan Publishers",

number = "10",

}

Kemp, JP, Morris, JA, Medina-Gomez, C, Forgetta, V, Warrington, NM, Youlten, SE, Zheng, J, Gregson, CL, Grundberg, E, Trajanoska, K, Logan, JG, Pollard, AS, Sparkes, PC, Ghirardello, EJ, Allen, R, Leitch, VD, Butterfield, NC, Komla-Ebri, D, Adoum, A-T, Curry, KF, White, JK, Kussy, F, Greenlaw, KM, Xu, C, Harvey, NC, Cooper, C, Adams, DJ, Greenwood, CMT, Maurano, MT, Kaptoge, S, Rivadeneira, F, Tobias, JH, Croucher, PI, Ackert-Bicknell, CL, Bassett, JHD, Williams, GR, Richards, JB & Evans, DM 2017, 'Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis', Nature Genetics, vol. 49, no. 10, pp. 1468-1475. https://doi.org/10.1038/ng.3949

TY - JOUR

T1 - Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis

AU - Kemp, John P.

AU - Morris, John A.

AU - Medina-Gomez, Carolina

AU - Forgetta, Vincenzo

AU - Warrington, Nicole M.

AU - Youlten, Scott E.

AU - Zheng, Jie

AU - Gregson, Celia L.

AU - Grundberg, Elin

AU - Trajanoska, Katerina

AU - Logan, John G.

AU - Pollard, Andrea S.

AU - Sparkes, Penny C.

AU - Ghirardello, Elena J.

AU - Allen, Rebecca

AU - Leitch, Victoria D.

AU - Butterfield, Natalie C.

AU - Komla-Ebri, Davide

AU - Adoum, Anne-Tounsia

AU - Curry, Katharine F.

AU - White, Jacqueline K.

AU - Kussy, Fiona

AU - Greenlaw, Keelin M.

AU - Xu, Changjiang

AU - Harvey, Nicholas C.

AU - Cooper, Cyrus

AU - Adams, David J.

AU - Greenwood, Celia M. T.

AU - Maurano, Matthew T.

AU - Kaptoge, Stephen

AU - Rivadeneira, Fernando

AU - Tobias, Jonathan H.

AU - Croucher, Peter I.

AU - Ackert-Bicknell, Cheryl L.

AU - Bassett, J. H. Duncan

AU - Williams, Graham R.

AU - Richards, J. Brent

AU - Evans, David M.

PY - 2017/10

Y1 - 2017/10

N2 - 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.

AB - 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.

KW - GENOME-WIDE ASSOCIATION

KW - HIGH-TRAUMA FRACTURES

KW - LD SCORE REGRESSION

KW - QUANTITATIVE ULTRASOUND

KW - MENDELIAN RANDOMIZATION

KW - GENE-FUNCTION

KW - OLDER WOMEN

KW - METAANALYSIS

KW - MOUSE

KW - RISK

U2 - 10.1038/ng.3949

DO - 10.1038/ng.3949

M3 - Article

C2 - 28869591

SN - 1061-4036

VL - 49

SP - 1468

EP - 1475

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

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

Abstract

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