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

doi: 10.1038/s41467-017-00108-3.

Carolina Medina-Gomez 1 2 3, Niki L Dimou 6 7, Eskil Kreiner 8, Alessandra Chesi 9, Babette S Zemel 10 11, Klaus Bønnelykke 8, Cindy G Boer 1, Tarunveer S Ahluwalia 8 12, Hans Bisgaard 8, Evangelos Evangelou 7 13, Denise H M Heppe 2 3, Lynda F Bonewald 14, Jeffrey P Gorski 15, Mohsen Ghanbari 3 16, Serkalem Demissie 17, Gustavo Duque 18, Matthew T Maurano 19, Douglas P Kiel 20 21 22, Yi-Hsiang Hsu 20 22 23, Bram C J van der Eerden 1, Cheryl Ackert-Bicknell 24, Sjur Reppe 25 26, Kaare M Gautvik 26 27, Truls Raastad 28, David Karasik 20 29, Jeroen van de Peppel 1, Vincent W V Jaddoe 2, André G Uitterlinden 1 2 3, Jonathan H Tobias 30, Struan F A Grant 9 11 31, Pantelis G Bagos 6, David M Evans 4 5, Fernando Rivadeneira 32 33 34

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

Carolina Medina-Gomez et al. Nat Commun. 2017.

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.

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Conflict of interest statement

E.K. is now working as medical specialist at Novo Nordisk A/S. All other authors declare no competing financial interests.

Figures

Fig. 1

Fig. 1

Manhattan plot of the meta-analyses for musculoskeleta traits. a TBLH-BMD and TB-LM bivariate meta-analysis. b TBLH-BMD meta-analysis. c TB-LM meta-analysis. Dashed red and yellow lines mark the GWS threshold (P < 5×10−8) and suggestive threshold (P < 1×10−6), respectively

Fig. 2

Fig. 2

Regional association plot for the bivariate meta-analysis of TBLH-BMD and TB-LM displaying the 17p11.2 locus. Genetic coordinates are as per Hapmap phase II-CEU

Fig. 3

Fig. 3

17p11.2 locus displaying binding peaks and interaction tracks by CTCF ChIA-PET data together with histone marks based on chromatin state characterization. Predicted strong interactions shared in MCF-7 or K562 cell lines are shadowed in blue while a weaker interaction in both cell lines is shadowed in pink. These interactions overlap with predicted CTCF binding sites in osteoblast, myoblast and myotubes, hypothetically localizing SNPs in TOM1L2 close to transcribed regions in SREBF1 and A_TPAF2_. Histone markers in muscular cells display high representation of associated SNPs in active enhancer predicted regions. Chromatin states are defined as follows, Bright Red: Active Promote, Orange: Strong enhancer, Yellow: Weak/poised enhancer, Blue: Insulator, Dark Green: Transcriptional elongation, Light Green: Weak transcribed

Fig. 4

Fig. 4

Expression profile of SREBF1 during osteoblastogenesis. qPCR data of the SREBF1 expression relative to GAPDH in two different donors. Error bars are defined as SD from two technical replicates at each time point. SREBF1 expression peaks at onset of mineralization

Fig. 5

Fig. 5

Schematic representation of the plausible role of rs7501812 in the pleiotropic modulation of BMD and lean mass. The G-allele from rs7501812 upregulates the expression of SREBF1 both in skeletal muscle and bone. This overexpression would be expected to result in higher levels of the active form of SREBP-1. SREBP-1 exerts opposite effects on bone and muscle biogenesis. While it promotes osteoblast mineralization, it inhibits myoblast differentiation, . Ultimately, this modulation would result in higher BMD and lower lean mass, as we observed in our bivariate GWAS analysis

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