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Nat Commun. 2017 Jul 25;8(1):121. doi: 10.1038/s41467-017-00108-3.

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

Author information

1
Department of Internal Medicine, Erasmus MC University, Rotterdam, 3015GE, The Netherlands.
2
The Generation R Study Group, Erasmus Medical Center, Rotterdam, 3015GE, The Netherlands.
3
Department of Epidemiology, Erasmus Medical Center, Rotterdam, 3015GE, The Netherlands.
4
University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, 4102, Australia.
5
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK.
6
Department of Computer Science and Biomedical Informatics of the University of Thessaly, Lamia, GR 35100, Greece.
7
Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, 45110, Greece.
8
COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, 2820, Denmark.
9
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
10
Division of GI, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
11
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
12
Steno Diabetes Center Copenhagen, Gentofte, 2820, Denmark.
13
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, W2 1PG, UK.
14
Departments of Anatomy and Cell Biology and Orthopaedic Surgery, School of Medicine, Indiana University, Indianapolis, IN, 46202, USA.
15
Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO, 64108, USA.
16
Department of Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad,, Iran.
17
Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02131, USA.
18
Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St Albans, Victoria, 3021, Australia.
19
Institute for Systems Genetics, New York University Langone Medical Center, New York, NY, 10016, USA.
20
Hebrew SeniorLife, Institute for Aging Research, Roslindale, MA, 02131, USA.
21
Department of Medicine Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA.
22
Broad Institute of MIT and Harvard, Boston, MA, 02115, USA.
23
Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, MA, 02115, USA.
24
Center for Musculoskeletal Research, University of Rochester, Rochester, NY, 14642, USA.
25
Department of Medical Biochemistry, Oslo University Hospital, Ullevaal, 0450, Oslo, Norway.
26
Unger-Vetlesen Institute, Oslo Diakonale Hospital, 0456, Oslo, Norway.
27
Department of Molecular Medicine, University of Oslo, 0372, Oslo, Norway.
28
Department of Physical Performance, Norwegian School of Sports Sciences, 0863, Oslo, Norway.
29
Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, 1311502, Israel.
30
School of Clinical Sciences, University of Bristol, Bristol, BS10 5NB, UK.
31
Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
32
Department of Internal Medicine, Erasmus MC University, Rotterdam, 3015GE, The Netherlands. f.rivadeneira@erasmusmc.nl.
33
The Generation R Study Group, Erasmus Medical Center, Rotterdam, 3015GE, The Netherlands. f.rivadeneira@erasmusmc.nl.
34
Department of Epidemiology, Erasmus Medical Center, Rotterdam, 3015GE, The Netherlands. f.rivadeneira@erasmusmc.nl.

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.Bone mineral density and lean skeletal mass are heritable traits. Here, Medina-Gomez and colleagues perform bivariate GWAS analyses of total body lean mass and bone mass density in children, and show genetic loci with pleiotropic effects on both traits.

PMID:
28743860
PMCID:
PMC5527106
DOI:
10.1038/s41467-017-00108-3
[Indexed for MEDLINE]
Free PMC Article

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