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.
Highlights
In this first large-scale bivariate GWAS metaanalysis of TBLH-BMD and TB-LM in pediatric cohorts, we identified eight Genome-wide significance (GWS) loci. For most of these loci the association with TBLH-BMD is the dominant association responsible for their significance, we report in the 17p11.2 locus, a stronger association with TB-LM compared to TBLH-BMD
TBLH-BMD and TB-LM measurements were adjusted by age, gender, height, fat percent (TB-FM/weight), and study specific covariates
We assessed the evidence of association of the GWS markers identified here (149 SNPs, Supplementary Data 3), in a bivariate analysis of previous powered GWAS meta-analyses of lean mass (total body (N ~ 38,000))[27] and BMD (lumbar spine and femoral neck (N ~ 32,000))[20] performed in adult and elderly population
Summary
The signal on 17p11.2 (lead SNP rs7501812, P = 1.4×10−10) was the only GWS signal where association was stronger with TBLM than with TBLH-BMD, mapping to a region not previously associated with neither trait The region underlying this signal (Fig. 2) extends along an LD-block harbouring several genes including MYO15A, LRRC48, MIR33B, C17orf39 [GID4], DRG2, RAI1, SREBF1, TOM1L2, ATPAF2, the latter seven all shown to be expressed in skeletal muscle[30]. We applied a bivariate analysis to the summary statistics of previously reported univariate GWAS meta-analyses of BMD and lean mass traits in adults[20, 27] (Supplementary Data 3). By interrogating the browser per gene, rather than per SNP, we generally found that alleles from the bivariate GWS SNPs associated with higher TBLH-BMD
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