Bone Abstracts (2015) 4 OC5 | DOI: 10.1530/boneabs.4.OC5

Bivariate analyses of BMD and lean mass in children identifies variants with novel pleiotropic effects across six BMD loci and in the TOM1L2 locus

Carolina Medina-Gomez1, John P Kemp2,3, Denise H M Heppe1, Jon H Tobias4, Albert Hofman1, M Carola Zillikens1, Andre G Uitterlinden1, Vincent W V Jaddoe1, David M Evans2,3 & Fernando Rivadeneira1

1Erasmus MC University, Rotterdam, The Netherlands; 2University of Queensland Diamantina Institute, Queensland, Australia; 3MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; 4School of Clinical Sciences, University of Bristol, Bristol, UK.

Background: Lean and bone mass are heritable traits with high phenotypic correlation (rho=0.44), likely reflecting the underlying mechanical and biochemical interactions between tissues.

Aim: Estimate the shared heritability (genetic correlation) of both traits in children and identify genetic determinants displaying pleiotropic effects on lean mass and bone mass accrual.

Methods: Participants make part of two prospective population-based birth cohorts, the Generation R Study (GenR) and the Avon Longitudinal Study of Parents and Children (ALSPAC). GenR children (n=4.071) born in Rotterdam, Netherlands are of multiethnic background with mean age=6.2, SD=0.37 years. ALSPAC children (n=4.820) born in Avon, UK had mean age=9.9, SD=0.32 years. Lean mass and BMD were measured with DXA (GE-Lunar iDXA/ Prodigy) and genome-wide genotyping (GenR: Illumina 660K, ALSPAC: Illumina 550K) imputed to HapMap. Shared heritability estimates derived from array data of GenR were obtained using GCTA (with modified admixed-aware relatedness estimates using REAP). GWAS in GenR and ALSPAC were ran using bivariate PLINK. Meta-analysis was performed by Fisher’s method. All analyses were adjusted for age, sex, height, fat percent (and 20 genomic principal components in GenR). P<5×10−8 was considered genome-wide significant (GWS).

Results: Heritability estimates were 0.31 for BMD and 0.40 for lean mass, with a genetic correlation of 0.3. The bivariate GWAS meta-analysis identified GWS associations with concordant effects on lean mass and BMD; mapping to six established BMD loci including: WNT4, GALNT3, CPED1/WNT16, RANKL, RIN3 and PPP6R3/LRP5. Another GWS signal mapping to the TOM1L2 locus, showed opposite correlations between lean mass (−0.46) and BMD (0.59). ENCODE analyses identified enhancers for SREBF1 in the same haplotype block.

Conclusion: Several variants at BMD loci exert pleiotropic effects on lean mass. Bivariate analysis is a powerful method for identifying novel pleiotropic effects. SREBF1 is a regulator of muscle protein synthesis down-regulating MYOD1, MYOG and MEF2C factors. Functional studies are required to unravel underlying pleiotropic mechanisms.

Disclosure: The authors declared no competing interests.