Phenotypic Dissection of Bone Mineral Density Reveals Skeletal Site Specificity and Facilitates the Identification of Novel Loci in the Genetic Regulation of Bone Mass Attainment

John P. Kemp, Carolina Medina-Gomez, Karol Estrada, Beate St Pourcain, Denise H M Heppe, Nicole M. Warrington, Ling Oei, Susan M. Ring, Claudia J. Kruithof, Nicholas J. Timpson, Lisa E. Wolber, Sjur Reppe, Kaare Gautvik, Elin Grundberg, Bing Ge, Bram van der Eerden, Jeroen van de Peppel, Matthew A. Hibbs, Cheryl L. Ackert-Bicknell, Kwangbom Choi & 13 others Daniel L. Koller, Michael Econs, Frances M K Williams, Tatiana Foroud, M. Carola Zillikens, Claes Ohlsson, Albert Hofman, André G. Uitterlinden, George Davey Smith, Vincent W V Jaddoe, Jonathan H. Tobias, Fernando Rivadeneira, David M. Evans

Research output: Contribution to journalArticle

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Abstract

Heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To quantify the degree to which common genetic variants tag and environmental factors influence BMD, at different sites, we estimated the genetic (rg) and residual (re) correlations between BMD measured at the upper limbs (UL-BMD), lower limbs (LL-BMD) and skull (SK-BMD), using total-body DXA scans of ~4,890 participants recruited by the Avon Longitudinal Study of Parents and their Children (ALSPAC). Point estimates of rg indicated that appendicular sites have a greater proportion of shared genetic architecture (LL-/UL-BMD rg = 0.78) between them, than with the skull (UL-/SK-BMD rg = 0.58 and LL-/SK-BMD rg = 0.43). Likewise, the residual correlation between BMD at appendicular sites (re = 0.55) was higher than the residual correlation between SK-BMD and BMD at appendicular sites (re = 0.20-0.24). To explore the basis for the observed differences in rg and re, genome-wide association meta-analyses were performed (n~9,395), combining data from ALSPAC and the Generation R Study identifying 15 independent signals from 13 loci associated at genome-wide significant level across different skeletal regions. Results suggested that previously identified BMD-associated variants may exert site-specific effects (i.e. differ in the strength of their association and magnitude of effect across different skeletal sites). In particular, variants at CPED1 exerted a larger influence on SK-BMD and UL-BMD when compared to LL-BMD (P = 2.01×10-37), whilst variants at WNT16 influenced UL-BMD to a greater degree when compared to SK- and LL-BMD (P = 2.31×10-14). In addition, we report a novel association between RIN3 (previously associated with Paget's disease) and LL-BMD (rs754388: β = 0.13, SE = 0.02, P = 1.4×10-10). Our results suggest that BMD at different skeletal sites is under a mixture of shared and specific genetic and environmental influences. Allowing for these differences by performing genome-wide association at different skeletal sites may help uncover new genetic influences on BMD.

Original languageEnglish
Article numbere1004423
JournalPLoS Genetics
Volume10
Issue number6
DOIs
StatePublished - 2014

Fingerprint

Genetic Loci
dissection
bone density
Bone Density
Dissection
bone
bones
Bone and Bones
loci
mineral
regulation
genome
longitudinal studies
skull
Skull
Longitudinal Studies
limb
Parents
Genome
Osteitis Deformans

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Phenotypic Dissection of Bone Mineral Density Reveals Skeletal Site Specificity and Facilitates the Identification of Novel Loci in the Genetic Regulation of Bone Mass Attainment. / Kemp, John P.; Medina-Gomez, Carolina; Estrada, Karol; St Pourcain, Beate; Heppe, Denise H M; Warrington, Nicole M.; Oei, Ling; Ring, Susan M.; Kruithof, Claudia J.; Timpson, Nicholas J.; Wolber, Lisa E.; Reppe, Sjur; Gautvik, Kaare; Grundberg, Elin; Ge, Bing; van der Eerden, Bram; van de Peppel, Jeroen; Hibbs, Matthew A.; Ackert-Bicknell, Cheryl L.; Choi, Kwangbom; Koller, Daniel L.; Econs, Michael; Williams, Frances M K; Foroud, Tatiana; Carola Zillikens, M.; Ohlsson, Claes; Hofman, Albert; Uitterlinden, André G.; Davey Smith, George; Jaddoe, Vincent W V; Tobias, Jonathan H.; Rivadeneira, Fernando; Evans, David M.

In: PLoS Genetics, Vol. 10, No. 6, e1004423, 2014.

Research output: Contribution to journalArticle

Kemp, JP, Medina-Gomez, C, Estrada, K, St Pourcain, B, Heppe, DHM, Warrington, NM, Oei, L, Ring, SM, Kruithof, CJ, Timpson, NJ, Wolber, LE, Reppe, S, Gautvik, K, Grundberg, E, Ge, B, van der Eerden, B, van de Peppel, J, Hibbs, MA, Ackert-Bicknell, CL, Choi, K, Koller, DL, Econs, M, Williams, FMK, Foroud, T, Carola Zillikens, M, Ohlsson, C, Hofman, A, Uitterlinden, AG, Davey Smith, G, Jaddoe, VWV, Tobias, JH, Rivadeneira, F & Evans, DM 2014, 'Phenotypic Dissection of Bone Mineral Density Reveals Skeletal Site Specificity and Facilitates the Identification of Novel Loci in the Genetic Regulation of Bone Mass Attainment', PLoS Genetics, vol. 10, no. 6, e1004423. https://doi.org/10.1371/journal.pgen.1004423
Kemp, John P. ; Medina-Gomez, Carolina ; Estrada, Karol ; St Pourcain, Beate ; Heppe, Denise H M ; Warrington, Nicole M. ; Oei, Ling ; Ring, Susan M. ; Kruithof, Claudia J. ; Timpson, Nicholas J. ; Wolber, Lisa E. ; Reppe, Sjur ; Gautvik, Kaare ; Grundberg, Elin ; Ge, Bing ; van der Eerden, Bram ; van de Peppel, Jeroen ; Hibbs, Matthew A. ; Ackert-Bicknell, Cheryl L. ; Choi, Kwangbom ; Koller, Daniel L. ; Econs, Michael ; Williams, Frances M K ; Foroud, Tatiana ; Carola Zillikens, M. ; Ohlsson, Claes ; Hofman, Albert ; Uitterlinden, André G. ; Davey Smith, George ; Jaddoe, Vincent W V ; Tobias, Jonathan H. ; Rivadeneira, Fernando ; Evans, David M. / Phenotypic Dissection of Bone Mineral Density Reveals Skeletal Site Specificity and Facilitates the Identification of Novel Loci in the Genetic Regulation of Bone Mass Attainment. In: PLoS Genetics. 2014 ; Vol. 10, No. 6.
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abstract = "Heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To quantify the degree to which common genetic variants tag and environmental factors influence BMD, at different sites, we estimated the genetic (rg) and residual (re) correlations between BMD measured at the upper limbs (UL-BMD), lower limbs (LL-BMD) and skull (SK-BMD), using total-body DXA scans of ~4,890 participants recruited by the Avon Longitudinal Study of Parents and their Children (ALSPAC). Point estimates of rg indicated that appendicular sites have a greater proportion of shared genetic architecture (LL-/UL-BMD rg = 0.78) between them, than with the skull (UL-/SK-BMD rg = 0.58 and LL-/SK-BMD rg = 0.43). Likewise, the residual correlation between BMD at appendicular sites (re = 0.55) was higher than the residual correlation between SK-BMD and BMD at appendicular sites (re = 0.20-0.24). To explore the basis for the observed differences in rg and re, genome-wide association meta-analyses were performed (n~9,395), combining data from ALSPAC and the Generation R Study identifying 15 independent signals from 13 loci associated at genome-wide significant level across different skeletal regions. Results suggested that previously identified BMD-associated variants may exert site-specific effects (i.e. differ in the strength of their association and magnitude of effect across different skeletal sites). In particular, variants at CPED1 exerted a larger influence on SK-BMD and UL-BMD when compared to LL-BMD (P = 2.01×10-37), whilst variants at WNT16 influenced UL-BMD to a greater degree when compared to SK- and LL-BMD (P = 2.31×10-14). In addition, we report a novel association between RIN3 (previously associated with Paget's disease) and LL-BMD (rs754388: β = 0.13, SE = 0.02, P = 1.4×10-10). Our results suggest that BMD at different skeletal sites is under a mixture of shared and specific genetic and environmental influences. Allowing for these differences by performing genome-wide association at different skeletal sites may help uncover new genetic influences on BMD.",
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T1 - Phenotypic Dissection of Bone Mineral Density Reveals Skeletal Site Specificity and Facilitates the Identification of Novel Loci in the Genetic Regulation of Bone Mass Attainment

AU - Kemp, John P.

AU - Medina-Gomez, Carolina

AU - Estrada, Karol

AU - St Pourcain, Beate

AU - Heppe, Denise H M

AU - Warrington, Nicole M.

AU - Oei, Ling

AU - Ring, Susan M.

AU - Kruithof, Claudia J.

AU - Timpson, Nicholas J.

AU - Wolber, Lisa E.

AU - Reppe, Sjur

AU - Gautvik, Kaare

AU - Grundberg, Elin

AU - Ge, Bing

AU - van der Eerden, Bram

AU - van de Peppel, Jeroen

AU - Hibbs, Matthew A.

AU - Ackert-Bicknell, Cheryl L.

AU - Choi, Kwangbom

AU - Koller, Daniel L.

AU - Econs, Michael

AU - Williams, Frances M K

AU - Foroud, Tatiana

AU - Carola Zillikens, M.

AU - Ohlsson, Claes

AU - Hofman, Albert

AU - Uitterlinden, André G.

AU - Davey Smith, George

AU - Jaddoe, Vincent W V

AU - Tobias, Jonathan H.

AU - Rivadeneira, Fernando

AU - Evans, David M.

PY - 2014

Y1 - 2014

N2 - Heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To quantify the degree to which common genetic variants tag and environmental factors influence BMD, at different sites, we estimated the genetic (rg) and residual (re) correlations between BMD measured at the upper limbs (UL-BMD), lower limbs (LL-BMD) and skull (SK-BMD), using total-body DXA scans of ~4,890 participants recruited by the Avon Longitudinal Study of Parents and their Children (ALSPAC). Point estimates of rg indicated that appendicular sites have a greater proportion of shared genetic architecture (LL-/UL-BMD rg = 0.78) between them, than with the skull (UL-/SK-BMD rg = 0.58 and LL-/SK-BMD rg = 0.43). Likewise, the residual correlation between BMD at appendicular sites (re = 0.55) was higher than the residual correlation between SK-BMD and BMD at appendicular sites (re = 0.20-0.24). To explore the basis for the observed differences in rg and re, genome-wide association meta-analyses were performed (n~9,395), combining data from ALSPAC and the Generation R Study identifying 15 independent signals from 13 loci associated at genome-wide significant level across different skeletal regions. Results suggested that previously identified BMD-associated variants may exert site-specific effects (i.e. differ in the strength of their association and magnitude of effect across different skeletal sites). In particular, variants at CPED1 exerted a larger influence on SK-BMD and UL-BMD when compared to LL-BMD (P = 2.01×10-37), whilst variants at WNT16 influenced UL-BMD to a greater degree when compared to SK- and LL-BMD (P = 2.31×10-14). In addition, we report a novel association between RIN3 (previously associated with Paget's disease) and LL-BMD (rs754388: β = 0.13, SE = 0.02, P = 1.4×10-10). Our results suggest that BMD at different skeletal sites is under a mixture of shared and specific genetic and environmental influences. Allowing for these differences by performing genome-wide association at different skeletal sites may help uncover new genetic influences on BMD.

AB - Heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To quantify the degree to which common genetic variants tag and environmental factors influence BMD, at different sites, we estimated the genetic (rg) and residual (re) correlations between BMD measured at the upper limbs (UL-BMD), lower limbs (LL-BMD) and skull (SK-BMD), using total-body DXA scans of ~4,890 participants recruited by the Avon Longitudinal Study of Parents and their Children (ALSPAC). Point estimates of rg indicated that appendicular sites have a greater proportion of shared genetic architecture (LL-/UL-BMD rg = 0.78) between them, than with the skull (UL-/SK-BMD rg = 0.58 and LL-/SK-BMD rg = 0.43). Likewise, the residual correlation between BMD at appendicular sites (re = 0.55) was higher than the residual correlation between SK-BMD and BMD at appendicular sites (re = 0.20-0.24). To explore the basis for the observed differences in rg and re, genome-wide association meta-analyses were performed (n~9,395), combining data from ALSPAC and the Generation R Study identifying 15 independent signals from 13 loci associated at genome-wide significant level across different skeletal regions. Results suggested that previously identified BMD-associated variants may exert site-specific effects (i.e. differ in the strength of their association and magnitude of effect across different skeletal sites). In particular, variants at CPED1 exerted a larger influence on SK-BMD and UL-BMD when compared to LL-BMD (P = 2.01×10-37), whilst variants at WNT16 influenced UL-BMD to a greater degree when compared to SK- and LL-BMD (P = 2.31×10-14). In addition, we report a novel association between RIN3 (previously associated with Paget's disease) and LL-BMD (rs754388: β = 0.13, SE = 0.02, P = 1.4×10-10). Our results suggest that BMD at different skeletal sites is under a mixture of shared and specific genetic and environmental influences. Allowing for these differences by performing genome-wide association at different skeletal sites may help uncover new genetic influences on BMD.

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