Genome-Wide Association Study Using Extreme Truncate Selection Identifies Novel Genes Affecting Bone Mineral Density and Fracture Risk

Abstract

Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55–85 years), with either extreme high or low hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0, n = 1055, or −4.0 to −1.5, n = 900), with replication in cohorts of women drawn from the general population (n = 20,898). The study replicates 21 of 26 known BMD–associated genes. Additionally, we report suggestive association of a further six new genetic associations in or around the genes CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 is also reported, which has high bone mass, supporting the involvement of this gene in BMD determination. In addition to identifying further genes associated with BMD, this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies.

Genetics of osteoporosis: searching for candidate genes for bone fragility

“…A remaining locus identified by Styrkarsdottir and cols., rs7524102, was strongly associated with both spine and hip BMD but obvious candidate genes lacked in its vicinity. Subsequent GWAS have confirmed this locus on larger cohorts (20,(50)(51)(52), with p-value reaching 7.4x10 -57 for association with hip BMD (20). Since these signals map to an intergenic region, the association has been attributed to the closest gene, ZBTB40.…”

MECHANISMS IN ENDOCRINOLOGY: Genetics of human bone formation

“…In the last decade, several genome-wide association studies (GWASs) and meta-analyses of GWASs have been performed in populations with ever-increasing sample sizes (14,97,98,99,100,101). Such large studies made it possible to identify associated variants in a hypothesisfree manner, which results in the identification of novel genes and previously unknown functional pathways.…”

Genetic Studies of Endophenotypes From Spine CT Scans Provide Novel Insights Into the Contribution of Mechanosensory Pathways to Vertebral Fractures and Spinal Curvature

“…Only one locus was found to associate with morphometric vertebral fracture (SLC1A3) and one with clinical vertebral fracture (ZBTB40). Whilst the latter is well established to associate with spine and hip BMD and fracture risk (24)(25)(26) , SLC1A3 represents a novel BMD and fracture association. Minimal evidence was detected to suggest the other novel loci associated with vBMD (FMN2/GREM2), were also associated with vertebral fracture; this is despite the fact that the FMN2/GREM2 locus has previously been associated with both trabecular vBMD (measured by pQCT) and fracture risk in a much smaller population (3) .…”