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 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 and Fernando Rivadeneira ()
Additional contact information
Carolina Medina-Gomez: Erasmus MC University
John P. Kemp: University of Queensland Diamantina Institute, Translational Research Institute
Niki L. Dimou: Department of Computer Science and Biomedical Informatics of the University of Thessaly
Eskil Kreiner: University of Copenhagen
Alessandra Chesi: Children’s Hospital of Philadelphia
Babette S. Zemel: Children’s Hospital of Philadelphia
Klaus Bønnelykke: University of Copenhagen
Cindy G. Boer: Erasmus MC University
Tarunveer S. Ahluwalia: University of Copenhagen
Hans Bisgaard: University of Copenhagen
Evangelos Evangelou: University of Ioannina Medical School
Denise H. M. Heppe: The Generation R Study Group, Erasmus Medical Center
Lynda F. Bonewald: School of Medicine, Indiana University
Jeffrey P. Gorski: University of Missouri-Kansas City
Mohsen Ghanbari: Erasmus Medical Center
Serkalem Demissie: Boston University School of Public Health
Gustavo Duque: The University of Melbourne and Western Health
Matthew T. Maurano: New York University Langone Medical Center
Douglas P. Kiel: Hebrew SeniorLife, Institute for Aging Research
Yi-Hsiang Hsu: Hebrew SeniorLife, Institute for Aging Research
Bram van der Eerden: Erasmus MC University
Cheryl Ackert-Bicknell: University of Rochester
Sjur Reppe: Oslo University Hospital
Kaare M. Gautvik: Unger-Vetlesen Institute, Oslo Diakonale Hospital
Truls Raastad: Norwegian School of Sports Sciences
David Karasik: Hebrew SeniorLife, Institute for Aging Research
Jeroen van de Peppel: Erasmus MC University
Vincent W. V. Jaddoe: The Generation R Study Group, Erasmus Medical Center
André G. Uitterlinden: Erasmus MC University
Jonathan H. Tobias: University of Bristol
Struan F.A. Grant: Children’s Hospital of Philadelphia
Pantelis G. Bagos: Department of Computer Science and Biomedical Informatics of the University of Thessaly
David M. Evans: University of Queensland Diamantina Institute, Translational Research Institute
Fernando Rivadeneira: Erasmus MC University

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00108-3

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