Genome-wide association study of extreme high bone mass: Contribution of common genetic variation to extreme BMD phenotypes and potential novel BMD-associated genes

摘要

BackgroundGeneralised high bone mass (HBM), associated with features of a mild skeletal dysplasia, has a prevalence of 0.18% in a UK DXA-scanned adult population. We hypothesized that the genetic component of extreme HBM includes contributions from common variants of small effect and rarer variants of large effect, both enriched in an extreme phenotype cohort. MethodsWe performed a genome-wide association study (GWAS) of adults with either extreme high or low BMD. Adults included individuals with unexplained extreme HBM (n?=?240) from the UK with BMD Z-scores ≥+3.2, high BMD females from the Anglo-Australasian Osteoporosis Genetics Consortium (AOGC) (n?=?1055) with Z-scores +1.5 to +4.0 and low BMD females also part of AOGC (n?=?900), with Z-scores ?1.5 to ?4.0. Following imputation, we tested association between 6,379,332 SNPs and total hip and lumbar spine BMD Z-scores. For potential target genes, we assessed expression in human osteoblasts and murine osteocytes. ResultsWe observed significant enrichment for associations with established BMD-associated loci, particularly those known to regulate endochondral ossification and Wnt signalling, suggesting that part of the genetic contribution to unexplained HBM is polygenic. Further, we identified associations exceeding genome-wide significance between BMD and four loci: two established BMD-associated loci (5q14.3 containingMEF2Cand 1p36.12 containingWNT4) and two novel loci: 5p13.3 containingNPR3(rs9292469; minor allele frequency [MAF]?=?0.33%) associated with lumbar spine BMD and 11p15.2 containingSPON1(rs2697825; MAF?=?0.17%) associated with total hip BMD. Mouse models with mutations in eitherNpr3orSpon1have been reported, both have altered skeletal phenotypes, providing in vivo validation that these genes are physiologically important in bone.NRP3regulates endochondral ossification and skeletal growth, whilstSPON1modulates TGF-β regulated BMP-driven osteoblast differentiation. Rs9292469 (downstream ofNPR3) also showed some evidence for association with forearm BMD in the independent GEFOS sample (n?=?32,965). We foundSpon1was highly expressed in murine osteocytes from the tibiae, femora, humeri and calvaria, whereasNpr3expression was more variable. ConclusionWe report the most extreme-truncate GWAS of BMD performed to date. Our findings, suggest potentially new anabolic bone regulatory pathways that warrant further study.