ICCBH2015 Oral Communications (1) (22 abstracts)
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-Gomez 1 , John P Kemp 2, , Denise H M Heppe 1 , Jon H Tobias 4 , Albert Hofman 1 , M Carola Zillikens 1 , Andre G Uitterlinden 1 , Vincent W V Jaddoe 1 , David M Evans 2, & Fernando Rivadeneira 1
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.
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