Meta-analysis of genome-wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women

Daniel L. Koller; Hou-Feng Zheng; David Karasik; Laura Yerges-Armstrong; Ching-Ti Liu; Fiona McGuigan; John P. Kemp; Sylvie Giroux; Dongbing Lai; Howard J. Edenberg; Munro Peacock; Stefan A. Czerwinski; Audrey C. Choh; George McMahon; Beate St Pourcain; Nicholas J. Timpson; Debbie A. Lawlor; David M. Evans; Bradford Towne; John Blangero; Melanie A. Carless; Candace Kammerer; David Goltzman; Christopher S. Kovacs; Jerilynn C. Prior; Tim D. Spector; Francois Rousseau; Jonathan H Tobias; Kristina Akesson; Michael J. Econs; Braxton D. Mitchell; J. Brent Richards; Douglas P. Kiel; Tatiana Foroud

doi:10.1002/jbmr.1796

Meta-analysis of genome-wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women

Daniel L. Koller^*, Hou-Feng Zheng, David Karasik, Laura Yerges-Armstrong, Ching-Ti Liu, Fiona McGuigan, John P. Kemp, Sylvie Giroux, Dongbing Lai, Howard J. Edenberg, Munro Peacock, Stefan A. Czerwinski, Audrey C. Choh, George McMahon, Beate St Pourcain, Nicholas J. Timpson, Debbie A. Lawlor, David M. Evans, Bradford Towne, John BlangeroMelanie A. Carless, Candace Kammerer, David Goltzman, Christopher S. Kovacs, Jerilynn C. Prior, Tim D. Spector, Francois Rousseau, Jonathan H Tobias, Kristina Akesson, Michael J. Econs, Braxton D. Mitchell, J. Brent Richards, Douglas P. Kiel, Tatiana Foroud

^*Corresponding author for this work

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

80 Citations (Scopus)

Abstract

Previous genome-wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta-analyses of these results have identified numerous SNPs of modest effect at genome-wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta-analysis restricted to premenopausal white women from four cohorts (n= 4,061 women, ages 20 to 45) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. Following imputation, age- and weight-adjusted BMD values were tested for association with each SNP. Association of a SNP in the WNT16 gene (rs3801387; p=1.7 x 10(-9) ) and multiple SNPs in the ESR1/C6orf97 (rs4870044; p=1.3 x 10(-8) ) achieved genome-wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven Replication cohorts that included premenopausal women of European, Hispanic-American, and African-American descent (combined n=5,597 for femoral neck; 4,744 for lumbar spine). When the data from the Discovery and Replication cohorts were analyzed jointly, the evidence was more significant (WNT16 joint p=1.3 x 10(-11) ; ESR1/C6orf97 joint p= 1.4 x 10(-10) ). Multiple independent association signals were observed with spine BMD at the ESR1 region after conditioning on the primary signal. Analyses of femoral neck BMD also supported association with SNPs in WNT16 and ESR1/C6orf97 (p<1 x 10(-5) ). Our results confirm that several of the genes contributing to BMD variation across a broad age range in both sexes have effects of similar magnitude on BMD of the spine in premenopausal women. These data support the hypothesis that variants in these genes of known skeletal function also affect BMD during the premenopausal period. © 2012 American Society for Bone and Mineral Research.

Original language	English
Pages (from-to)	547-558
Number of pages	12
Journal	Journal of Bone and Mineral Research
Volume	28
Issue number	3
DOIs	https://doi.org/10.1002/jbmr.1796
Publication status	Published - Mar 2013

Keywords

BONE MINERAL DENSITY
GWAS
PREMENOPAUSAL
META-ANALYSIS
GENETICS
AGE
FRACTURES
VARIANTS
LOCI
MASS

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MRC UoB UNITE Unit - programme 3
Timpson, N. J. (Principal Investigator) & Timpson, N. J. (Principal Investigator)
1/06/13 → 31/03/18
Project: Research
MRC UoB UNITE Unit - Programme 5
Lawlor, D. A. (Principal Investigator) & Lawlor, D. A. (Principal Investigator)
1/06/13 → 31/03/18
Project: Research
B603 THE EFFECT OF COMMON DISEASE ASSOCIATED GENETIC VARIANTS ON TRANSCRIPTOMIC AND EARLY LIFE PHENOTYPES
Evans, D. (Principal Investigator)
1/09/08 → 1/09/11
Project: Research

Cite this

Koller, D. L., Zheng, H.-F., Karasik, D., Yerges-Armstrong, L., Liu, C.-T., McGuigan, F., Kemp, J. P., Giroux, S., Lai, D., Edenberg, H. J., Peacock, M., Czerwinski, S. A., Choh, A. C., McMahon, G., St Pourcain, B., Timpson, N. J., Lawlor, D. A., Evans, D. M., Towne, B., ... Foroud, T. (2013). Meta-analysis of genome-wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women. Journal of Bone and Mineral Research, 28(3), 547-558. https://doi.org/10.1002/jbmr.1796

@article{b7f055abfcd0421d939ba9449fc1705b,

title = "Meta-analysis of genome-wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women",

abstract = "Previous genome-wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta-analyses of these results have identified numerous SNPs of modest effect at genome-wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta-analysis restricted to premenopausal white women from four cohorts (n= 4,061 women, ages 20 to 45) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. Following imputation, age- and weight-adjusted BMD values were tested for association with each SNP. Association of a SNP in the WNT16 gene (rs3801387; p=1.7 x 10(-9) ) and multiple SNPs in the ESR1/C6orf97 (rs4870044; p=1.3 x 10(-8) ) achieved genome-wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven Replication cohorts that included premenopausal women of European, Hispanic-American, and African-American descent (combined n=5,597 for femoral neck; 4,744 for lumbar spine). When the data from the Discovery and Replication cohorts were analyzed jointly, the evidence was more significant (WNT16 joint p=1.3 x 10(-11) ; ESR1/C6orf97 joint p= 1.4 x 10(-10) ). Multiple independent association signals were observed with spine BMD at the ESR1 region after conditioning on the primary signal. Analyses of femoral neck BMD also supported association with SNPs in WNT16 and ESR1/C6orf97 (p<1 x 10(-5) ). Our results confirm that several of the genes contributing to BMD variation across a broad age range in both sexes have effects of similar magnitude on BMD of the spine in premenopausal women. These data support the hypothesis that variants in these genes of known skeletal function also affect BMD during the premenopausal period. {\textcopyright} 2012 American Society for Bone and Mineral Research.",

keywords = "BONE MINERAL DENSITY, GWAS, PREMENOPAUSAL, META-ANALYSIS, GENETICS, AGE, FRACTURES, VARIANTS, LOCI, MASS",

author = "Koller, {Daniel L.} and Hou-Feng Zheng and David Karasik and Laura Yerges-Armstrong and Ching-Ti Liu and Fiona McGuigan and Kemp, {John P.} and Sylvie Giroux and Dongbing Lai and Edenberg, {Howard J.} and Munro Peacock and Czerwinski, {Stefan A.} and Choh, {Audrey C.} and George McMahon and {St Pourcain}, Beate and Timpson, {Nicholas J.} and Lawlor, {Debbie A.} and Evans, {David M.} and Bradford Towne and John Blangero and Carless, {Melanie A.} and Candace Kammerer and David Goltzman and Kovacs, {Christopher S.} and Prior, {Jerilynn C.} and Spector, {Tim D.} and Francois Rousseau and Tobias, {Jonathan H} and Kristina Akesson and Econs, {Michael J.} and Mitchell, {Braxton D.} and Richards, {J. Brent} and Kiel, {Douglas P.} and Tatiana Foroud",

note = "Copyright {\textcopyright} 2012 American Society for Bone and Mineral Research.",

year = "2013",

month = mar,

doi = "10.1002/jbmr.1796",

language = "English",

volume = "28",

pages = "547--558",

journal = "Journal of Bone and Mineral Research",

issn = "1523-4681",

publisher = "Wiley",

number = "3",

}

Koller, DL, Zheng, H-F, Karasik, D, Yerges-Armstrong, L, Liu, C-T, McGuigan, F, Kemp, JP, Giroux, S, Lai, D, Edenberg, HJ, Peacock, M, Czerwinski, SA, Choh, AC, McMahon, G, St Pourcain, B , Timpson, NJ , Lawlor, DA, Evans, DM, Towne, B, Blangero, J, Carless, MA, Kammerer, C, Goltzman, D, Kovacs, CS, Prior, JC, Spector, TD, Rousseau, F, Tobias, JH, Akesson, K, Econs, MJ, Mitchell, BD, Richards, JB, Kiel, DP & Foroud, T 2013, 'Meta-analysis of genome-wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women', Journal of Bone and Mineral Research, vol. 28, no. 3, pp. 547-558. https://doi.org/10.1002/jbmr.1796

TY - JOUR

T1 - Meta-analysis of genome-wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women

AU - Koller, Daniel L.

AU - Zheng, Hou-Feng

AU - Karasik, David

AU - Yerges-Armstrong, Laura

AU - Liu, Ching-Ti

AU - McGuigan, Fiona

AU - Kemp, John P.

AU - Giroux, Sylvie

AU - Lai, Dongbing

AU - Edenberg, Howard J.

AU - Peacock, Munro

AU - Czerwinski, Stefan A.

AU - Choh, Audrey C.

AU - McMahon, George

AU - St Pourcain, Beate

AU - Timpson, Nicholas J.

AU - Lawlor, Debbie A.

AU - Evans, David M.

AU - Towne, Bradford

AU - Blangero, John

AU - Carless, Melanie A.

AU - Kammerer, Candace

AU - Goltzman, David

AU - Kovacs, Christopher S.

AU - Prior, Jerilynn C.

AU - Spector, Tim D.

AU - Rousseau, Francois

AU - Tobias, Jonathan H

AU - Akesson, Kristina

AU - Econs, Michael J.

AU - Mitchell, Braxton D.

AU - Richards, J. Brent

AU - Kiel, Douglas P.

AU - Foroud, Tatiana

PY - 2013/3

Y1 - 2013/3

N2 - Previous genome-wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta-analyses of these results have identified numerous SNPs of modest effect at genome-wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta-analysis restricted to premenopausal white women from four cohorts (n= 4,061 women, ages 20 to 45) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. Following imputation, age- and weight-adjusted BMD values were tested for association with each SNP. Association of a SNP in the WNT16 gene (rs3801387; p=1.7 x 10(-9) ) and multiple SNPs in the ESR1/C6orf97 (rs4870044; p=1.3 x 10(-8) ) achieved genome-wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven Replication cohorts that included premenopausal women of European, Hispanic-American, and African-American descent (combined n=5,597 for femoral neck; 4,744 for lumbar spine). When the data from the Discovery and Replication cohorts were analyzed jointly, the evidence was more significant (WNT16 joint p=1.3 x 10(-11) ; ESR1/C6orf97 joint p= 1.4 x 10(-10) ). Multiple independent association signals were observed with spine BMD at the ESR1 region after conditioning on the primary signal. Analyses of femoral neck BMD also supported association with SNPs in WNT16 and ESR1/C6orf97 (p<1 x 10(-5) ). Our results confirm that several of the genes contributing to BMD variation across a broad age range in both sexes have effects of similar magnitude on BMD of the spine in premenopausal women. These data support the hypothesis that variants in these genes of known skeletal function also affect BMD during the premenopausal period. © 2012 American Society for Bone and Mineral Research.

AB - Previous genome-wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta-analyses of these results have identified numerous SNPs of modest effect at genome-wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta-analysis restricted to premenopausal white women from four cohorts (n= 4,061 women, ages 20 to 45) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. Following imputation, age- and weight-adjusted BMD values were tested for association with each SNP. Association of a SNP in the WNT16 gene (rs3801387; p=1.7 x 10(-9) ) and multiple SNPs in the ESR1/C6orf97 (rs4870044; p=1.3 x 10(-8) ) achieved genome-wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven Replication cohorts that included premenopausal women of European, Hispanic-American, and African-American descent (combined n=5,597 for femoral neck; 4,744 for lumbar spine). When the data from the Discovery and Replication cohorts were analyzed jointly, the evidence was more significant (WNT16 joint p=1.3 x 10(-11) ; ESR1/C6orf97 joint p= 1.4 x 10(-10) ). Multiple independent association signals were observed with spine BMD at the ESR1 region after conditioning on the primary signal. Analyses of femoral neck BMD also supported association with SNPs in WNT16 and ESR1/C6orf97 (p<1 x 10(-5) ). Our results confirm that several of the genes contributing to BMD variation across a broad age range in both sexes have effects of similar magnitude on BMD of the spine in premenopausal women. These data support the hypothesis that variants in these genes of known skeletal function also affect BMD during the premenopausal period. © 2012 American Society for Bone and Mineral Research.

KW - BONE MINERAL DENSITY

KW - GWAS

KW - PREMENOPAUSAL

KW - META-ANALYSIS

KW - GENETICS

KW - AGE

KW - FRACTURES

KW - VARIANTS

KW - LOCI

KW - MASS

U2 - 10.1002/jbmr.1796

DO - 10.1002/jbmr.1796

M3 - Article (Academic Journal)

C2 - 23074152

SN - 1523-4681

VL - 28

SP - 547

EP - 558

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

IS - 3

ER -

Meta-analysis of genome-wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women

Abstract

Keywords

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Projects

MRC UoB UNITE Unit - programme 3

MRC UoB UNITE Unit - Programme 5

B603 THE EFFECT OF COMMON DISEASE ASSOCIATED GENETIC VARIANTS ON TRANSCRIPTOMIC AND EARLY LIFE PHENOTYPES

Cite this