Bivariate genome-wide association analysis implicates pleiotropic effects at the SREBF1/TOM1L2 locus on bone mineral density and lean mass in children

Carolina Medina-Gomez; John Kemp; Niki L. Dimou; Eskil Kreiner-Moller; Alessandra Chesi; Babette S Zemel; Klaus Bønnelykke; Cindy G. Boer; Tarunveer S. Ahluwalia; Hans Bisgaard; Evangelos Evangelou; Denise H M Heppe; LF Bonewald; Jeffrey P. Gorski; Mohsen Ghanbari; Serkalem Demissie; Gustavo Duque; Matthew T Maurano; Douglas P Kiel; David Evans; Jonathan Tobias; Fernando Rivadeneira

doi:10.1038/s41467-017-00108-3

Bivariate genome-wide association analysis implicates pleiotropic effects at the SREBF1/TOM1L2 locus on bone mineral density and lean mass in children

Carolina Medina-Gomez, John Kemp, Niki L. Dimou, Eskil Kreiner-Moller, Alessandra Chesi, Babette S Zemel, Klaus Bønnelykke, Cindy G. Boer, Tarunveer S. Ahluwalia, Hans Bisgaard, Evangelos Evangelou, Denise H M Heppe, LF Bonewald, Jeffrey P. Gorski, Mohsen Ghanbari, Serkalem Demissie, Gustavo Duque, Matthew T Maurano, Douglas P Kiel, David EvansJonathan Tobias, Fernando Rivadeneira

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Abstract

Bone mineral density (BMD) 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 BMD (TBLH-BMD) 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 BMD loci: WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3 and PPP6R3/LRP5. Variants in the TOM1L2/SREBF1 locus exert opposing effects on 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
BMD and lean mass.

Original language	English
Article number	121
Number of pages	11
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/s41467-017-00108-3
Publication status	Published - 25 Jul 2017

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Professor Jonathan H Tobias
- Jon.Tobiasbristol.acuk
- Bristol Medical School (THS) - Professor of Rheumatology
- Bristol Population Health Science Institute
- Academic Rheumatology
- Musculoskeletal Research Unit
Person: Academic , Member

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Medina-Gomez, C., Kemp, J., Dimou, N. L., Kreiner-Moller, E., Chesi, A., Zemel, B. S., Bønnelykke, K., Boer, C. G., Ahluwalia, T. S., Bisgaard, H., Evangelou, E., Heppe, D. H. M., Bonewald, LF., Gorski, J. P., Ghanbari, M., Demissie, S., Duque, G., Maurano, M. T., Kiel, D. P., ... Rivadeneira, F. (2017). Bivariate genome-wide association analysis implicates pleiotropic effects at the SREBF1/TOM1L2 locus on bone mineral density and lean mass in children. Nature Communications, 8, [121]. https://doi.org/10.1038/s41467-017-00108-3

@article{36fadc4091e04979b952adf9701761c8,

title = "Bivariate genome-wide association analysis implicates pleiotropic effects at the SREBF1/TOM1L2 locus on bone mineral density and lean mass in children",

abstract = "Bone mineral density (BMD) is known to be a heritable, polygenic trait whereasgenetic 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 BMD (TBLH-BMD) 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 BMD loci: WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3 and PPP6R3/LRP5. Variants in the TOM1L2/SREBF1 locus exert opposing effects on 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 onBMD and lean mass.",

author = "Carolina Medina-Gomez and John Kemp and Dimou, {Niki L.} and Eskil Kreiner-Moller 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 LF Bonewald and Gorski, {Jeffrey P.} and Mohsen Ghanbari and Serkalem Demissie and Gustavo Duque and Maurano, {Matthew T} and Kiel, {Douglas P} and David Evans and Jonathan Tobias and Fernando Rivadeneira",

year = "2017",

month = jul,

day = "25",

doi = "10.1038/s41467-017-00108-3",

language = "English",

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journal = "Nature Communications",

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Medina-Gomez, C, Kemp, J, Dimou, NL, Kreiner-Moller, 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, Evans, D, Tobias, J & Rivadeneira, F 2017, 'Bivariate genome-wide association analysis implicates pleiotropic effects at the SREBF1/TOM1L2 locus on bone mineral density and lean mass in children', Nature Communications, vol. 8, 121. https://doi.org/10.1038/s41467-017-00108-3

TY - JOUR

T1 - Bivariate genome-wide association analysis implicates pleiotropic effects at the SREBF1/TOM1L2 locus on bone mineral density and lean mass in children

AU - Medina-Gomez, Carolina

AU - Kemp, John

AU - Dimou, Niki L.

AU - Kreiner-Moller, 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, LF

AU - Gorski, Jeffrey P.

AU - Ghanbari, Mohsen

AU - Demissie, Serkalem

AU - Duque, Gustavo

AU - Maurano, Matthew T

AU - Kiel, Douglas P

AU - Evans, David

AU - Tobias, Jonathan

AU - Rivadeneira, Fernando

PY - 2017/7/25

Y1 - 2017/7/25

N2 - Bone mineral density (BMD) is known to be a heritable, polygenic trait whereasgenetic 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 BMD (TBLH-BMD) 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 BMD loci: WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3 and PPP6R3/LRP5. Variants in the TOM1L2/SREBF1 locus exert opposing effects on 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 onBMD and lean mass.

AB - Bone mineral density (BMD) is known to be a heritable, polygenic trait whereasgenetic 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 BMD (TBLH-BMD) 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 BMD loci: WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3 and PPP6R3/LRP5. Variants in the TOM1L2/SREBF1 locus exert opposing effects on 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 onBMD and lean mass.

U2 - 10.1038/s41467-017-00108-3

DO - 10.1038/s41467-017-00108-3

M3 - Article (Academic Journal)

C2 - 28743860

VL - 8

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 121

ER -

Bivariate genome-wide association analysis implicates pleiotropic effects at the SREBF1/TOM1L2 locus on bone mineral density and lean mass in children

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