Bone Abstracts

Extreme high bone mass (HBM) may be monogenic (e.g. LRP5 mutations) or polygenic, due to variants in the same genes determining bone mineral density (BMD) as found in the general population. We aimed to determine how variation in established BMD loci, in different functional pathways, explains the HBM phenotype.

241 unexplained HBM cases (lumbar spine(LS)1+total hip(TH) Z-scores≥+4.4) were recruited from 15 UK centres, by screening 335 115 DXA scans. Established LRP5 mutations were excluded by Sanger sequencing (n=6). Infinium OmniExpress-12v1.0 genotypes were imputed to UK10K; 57 SNPs had certainty>0.8. Using Estrada’s Femoral Neck(FN) or LS Betas, we calculated weighted genetic risk scores (GRS^FN/GRS^LS) for total (n=57), Wnt (n=12), OPG-RANK-RANKL (n=3), endochrondral ossification (n=6) and mesenchymal stem cell (MSC) differentiation (n=4) annotated loci.

A one SD increase in total GRS^FN was associated with a 0.13 S.D. (−0.01, 0.27), P=0.06, increase in TH BMD^TH and 0.13 (0.01, 0.25), P=0.04, increase in total body BMD^TB, explaining 1.6 and 3.2% phenotypic variance respectively however, GRS^LS was independent of LS BMD^LS (0.12 (−0.05, 0.29), P=0.17, r²=0.8%).

Wnt GRS was associated with a 0.15 S.D. (0.01, 0.29), P=0.04, increase in BMD^TH (r²=2%), but was independent of BMD^TB (0.03 (−0.08, 0.15), P=0.57, r²=0.3%) and BMD^LS (−0.02 (−0.20, 0.15), P=0.79, r²=0%). Conversely, the endochrondral ossification GRS was independent of BMD^TH (0.01 (−0.13, 0.15), P=0.85, r²=0%) and BMD^LS (0.14 (−0.03, 0.31), P=0.11, r²=1.2%), but explained 2.3% of variance in BMD^TB (0.11 (−0.01, 0.23), P=0.08). Whereas, MSC GRS was associated with a 0.19 S.D. (0.02, 0.37), P=0.03, r²=2.2%) increase in BMD^LS, but was independent of both BMD^TB and BMD^TH (P>0.8, r²=0%). All BMD sites were independent of OPG-RANK-RANKL GRS.

In conclusion, BMD in HBM appears driven by osteoblast rather than osteoclast pathways. A greater proportion of phenotypic variance in i) hip BMD is explained by wnt pathway loci, ii) total body BMD by endochrondral ossification loci and iii) lumbar spine BMD by mesenchymal stem cell differentiation loci, suggesting differential genetic regulation of individual skeletal sites.