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

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 mi...

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Detalles Bibliográficos
Autores principales: Medina-Gomez, Carolina, Kemp, John P., Dimou, Niki L., Kreiner, Eskil, Chesi, Alessandra, Zemel, Babette S., Bønnelykke, Klaus, Boer, Cindy G., Ahluwalia, Tarunveer S., Bisgaard, Hans, Evangelou, Evangelos, Heppe, Denise H. M., Bonewald, Lynda F., Gorski, Jeffrey P., Ghanbari, Mohsen, Demissie, Serkalem, Duque, Gustavo, Maurano, Matthew T., Kiel, Douglas P., Hsu, Yi-Hsiang, C.J. van der Eerden, Bram, Ackert-Bicknell, Cheryl, Reppe, Sjur, Gautvik, Kaare M., Raastad, Truls, Karasik, David, van de Peppel, Jeroen, Jaddoe, Vincent W. V., Uitterlinden, André G., Tobias, Jonathan H., Grant, Struan F.A., Bagos, Pantelis G., Evans, David M., Rivadeneira, Fernando
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527106/
https://www.ncbi.nlm.nih.gov/pubmed/28743860
http://dx.doi.org/10.1038/s41467-017-00108-3
Descripción
Sumario: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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