Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus

Carolina Medina-Gomez; John P Kemp; Niki L Dimou; Eskil Kreiner; Alessandra Chesi; Babette S Zemel; Klaus Bønnelykke; Cindy G Boer; Tarunveer S Ahluwalia; Hans Bisgaard; Evangelos Evangelou; Denise H M Heppe; Lynda F Bonewald; Jeffrey P Gorski; Mohsen Ghanbari; Serkalem Demissie; Gustavo Duque; Matthew T Maurano; Douglas P Kiel; Yi-Hsiang Hsu; Bram C J van der Eerden; Cheryl Ackert-Bicknell; Sjur Reppe; Kaare M Gautvik; Truls Raastad; David Karasik; Jeroen van de Peppel; Vincent W V Jaddoe; André G Uitterlinden; Jonathan H Tobias; Struan F A Grant; Pantelis G Bagos; David M Evans; Fernando Rivadeneira

doi:10.1038/s41467-017-00108-3

Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus

Carolina Medina-Gomez, John P Kemp, Niki L Dimou, Eskil Kreiner, Alessandra Chesi, Babette S Zemel, Klaus Bønnelykke, Cindy G Boer, Tarunveer S Ahluwalia, Hans Bisgaard, Evangelos Evangelou, Denise H M Heppe, Lynda F Bonewald, Jeffrey P Gorski, Mohsen Ghanbari, Serkalem Demissie, Gustavo Duque, Matthew T Maurano, Douglas P Kiel, Yi-Hsiang HsuBram C J van der Eerden, Cheryl Ackert-Bicknell, Sjur Reppe, Kaare M Gautvik, Truls Raastad, David Karasik, Jeroen van de Peppel, Vincent W V Jaddoe, André G Uitterlinden, Jonathan H Tobias, Struan F A Grant, Pantelis G Bagos, David M Evans, Fernando Rivadeneira

Department of Clinical Medicine

40 Citations (Scopus)

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Abstract

Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% (95% CI: 34-52%) for TBLH-BMD, and 39% (95% CI: 30-48%) for TB-LM, with a shared genetic component of 43% (95% CI: 29-56%). We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5. Variants in the TOM1L2/SREBF1 locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that SREBF1 is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass.

Original language	English
Article number	121
Journal	Nature Communications
Volume	8
Number of pages	11
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-017-00108-3
Publication status	Published - 1 Dec 2017

Keywords

Body Weight
Bone Density
Carrier Proteins/genetics
Child
Female
Gene Expression
Genetic Pleiotropy
Genome-Wide Association Study/methods
Humans
Male
Meta-Analysis as Topic
Multivariate Analysis
Musculoskeletal Development/genetics
Polymorphism, Single Nucleotide
Quantitative Trait Loci/genetics
Sterol Regulatory Element Binding Protein 1/genetics

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Medina-Gomez, C., Kemp, J. P., Dimou, N. L., Kreiner, E., Chesi, A., Zemel, B. S., Bønnelykke, K., Boer, C. G., Ahluwalia, T. S., Bisgaard, H., Evangelou, E., Heppe, D. H. M., Bonewald, L. F., Gorski, J. P., Ghanbari, M., Demissie, S., Duque, G., Maurano, M. T., Kiel, D. P., ... Rivadeneira, F. (2017). Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus. Nature Communications, 8, [121]. https://doi.org/10.1038/s41467-017-00108-3

Medina-Gomez, C, Kemp, JP, Dimou, NL, Kreiner, E, Chesi, A, Zemel, BS, Bønnelykke, K, Boer, CG, Ahluwalia, TS, Bisgaard, H, Evangelou, E, Heppe, DHM, Bonewald, LF, Gorski, JP, Ghanbari, M, Demissie, S, Duque, G, Maurano, MT, Kiel, DP, Hsu, Y-H, C J van der Eerden, B, Ackert-Bicknell, C, Reppe, S, Gautvik, KM, Raastad, T, Karasik, D, van de Peppel, J, Jaddoe, VWV, Uitterlinden, AG, Tobias, JH, Grant, SFA, Bagos, PG, Evans, DM & Rivadeneira, F 2017, 'Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus', Nature Communications, vol. 8, 121. https://doi.org/10.1038/s41467-017-00108-3

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title = "Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus",

abstract = "Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% (95% CI: 34-52%) for TBLH-BMD, and 39% (95% CI: 30-48%) for TB-LM, with a shared genetic component of 43% (95% CI: 29-56%). We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5. Variants in the TOM1L2/SREBF1 locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that SREBF1 is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass.",

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author = "Carolina Medina-Gomez and Kemp, {John P} and Dimou, {Niki L} and Eskil Kreiner and Alessandra Chesi and Zemel, {Babette S} and Klaus B{\o}nnelykke and Boer, {Cindy G} and Ahluwalia, {Tarunveer S} and Hans Bisgaard and Evangelos Evangelou and Heppe, {Denise H M} and Bonewald, {Lynda F} and Gorski, {Jeffrey P} and Mohsen Ghanbari and Serkalem Demissie and Gustavo Duque and Maurano, {Matthew T} and Kiel, {Douglas P} and Yi-Hsiang Hsu and {C J van der Eerden}, Bram and Cheryl Ackert-Bicknell and Sjur Reppe and Gautvik, {Kaare M} and Truls Raastad and David Karasik and {van de Peppel}, Jeroen and Jaddoe, {Vincent W V} and Uitterlinden, {Andr{\'e} G} and Tobias, {Jonathan H} and Grant, {Struan F A} and Bagos, {Pantelis G} and Evans, {David M} and Fernando Rivadeneira",

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T1 - Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus

AU - Medina-Gomez, Carolina

AU - Kemp, John P

AU - Dimou, Niki L

AU - Kreiner, Eskil

AU - Chesi, Alessandra

AU - Zemel, Babette S

AU - Bønnelykke, Klaus

AU - Boer, Cindy G

AU - Ahluwalia, Tarunveer S

AU - Bisgaard, Hans

AU - Evangelou, Evangelos

AU - Heppe, Denise H M

AU - Bonewald, Lynda F

AU - Gorski, Jeffrey P

AU - Ghanbari, Mohsen

AU - Demissie, Serkalem

AU - Duque, Gustavo

AU - Maurano, Matthew T

AU - Kiel, Douglas P

AU - Hsu, Yi-Hsiang

AU - C J van der Eerden, Bram

AU - Ackert-Bicknell, Cheryl

AU - Reppe, Sjur

AU - Gautvik, Kaare M

AU - Raastad, Truls

AU - Karasik, David

AU - van de Peppel, Jeroen

AU - Jaddoe, Vincent W V

AU - Uitterlinden, André G

AU - Tobias, Jonathan H

AU - Grant, Struan F A

AU - Bagos, Pantelis G

AU - Evans, David M

AU - Rivadeneira, Fernando

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% (95% CI: 34-52%) for TBLH-BMD, and 39% (95% CI: 30-48%) for TB-LM, with a shared genetic component of 43% (95% CI: 29-56%). We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5. Variants in the TOM1L2/SREBF1 locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that SREBF1 is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass.

AB - Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% (95% CI: 34-52%) for TBLH-BMD, and 39% (95% CI: 30-48%) for TB-LM, with a shared genetic component of 43% (95% CI: 29-56%). We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5. Variants in the TOM1L2/SREBF1 locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that SREBF1 is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass.

KW - Body Weight

KW - Bone Density

KW - Carrier Proteins/genetics

KW - Child

KW - Female

KW - Gene Expression

KW - Genetic Pleiotropy

KW - Genome-Wide Association Study/methods

KW - Humans

KW - Male

KW - Meta-Analysis as Topic

KW - Multivariate Analysis

KW - Musculoskeletal Development/genetics

KW - Polymorphism, Single Nucleotide

KW - Quantitative Trait Loci/genetics

KW - Sterol Regulatory Element Binding Protein 1/genetics

U2 - 10.1038/s41467-017-00108-3

DO - 10.1038/s41467-017-00108-3

M3 - Journal article

C2 - 28743860

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 121

ER -

Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus

Abstract

Keywords

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