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 languageEnglish
Article number121
Number of pages11
JournalNature Communications
Volume8
DOIs
Publication statusPublished - 25 Jul 2017

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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