TY - JOUR
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 - Van Der Eerden, Bram C.J.
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
N1 - Publisher Copyright:
© 2017 The Author(s).
PY - 2017/7/25
Y1 - 2017/7/25
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.
UR - http://www.scopus.com/inward/record.url?scp=85026221320&partnerID=8YFLogxK
U2 - 10.1038/s41467-017-00108-3
DO - 10.1038/s41467-017-00108-3
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 28743860
AN - SCOPUS:85026221320
SN - 2041-1723
VL - 8
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 121
ER -