Genetic Analyses in a Sample of Individuals With High or Low BMD Shows Association With Multiple Wnt Pathway Genes

Abstract

Using a moderate-sized cohort selected with extreme BMD (n = 344; absolute value BMD, 1.5-4.0), significant association of several members of the Wnt signaling pathway with bone densitometry measures was shown. This confirms that extreme truncate selection is a powerful design for quantitative trait association studies of bone phenotypes.Introduction: Although the high heritability of BMD variation has long been established, few genes have been conclusively shown to affect the variation of BMD in the general population. Extreme truncate selection has been proposed as a more powerful alternative to unselected cohort designs in quantitative trait association studies. We sought to test these theoretical predictions in studies of the bone densitometry measures BMD, BMC, and femoral neck area, by investigating their association with members of the Wnt pathway, some of which have previously been shown to be associated with BMD in much larger cohorts, in a moderate-sized extreme truncate selected cohort (absolute value BMD Z-scores ‫ס‬ 1.5-4.0; n ‫ס‬ 344). Conclusions: This study shows that polymorphisms of multiple members of the Wnt pathway are associated with BMD variation. Furthermore, this study shows in a practical trial that study designs involving extreme truncate selection and moderate sample sizes can robustly identify genes of relevant effect sizes involved in BMD variation in the general population. This has implications for the design of future genome-wide studies of quantitative bone phenotypes relevant to osteoporosis.

WNT3A gene polymorphisms are associated with bone mineral density variation in postmenopausal mestizo women of an urban Mexican population: findings of a pathway-based high-density single nucleotide screening

“…Mutations in WNT3A (c.152A > G, p.K51R) and DKK1 (c.359G > T, p.R120L) have been shown to cause childhood-onset primary osteoporosis, manifested as reduced bone mineral density, peripheral fractures, and/or vertebral compression fractures (Korvala et al 2012). Moreover, common polymorphisms in genes belonging to this pathway have been nominally associated with BMD in Australian postmenopausal women using an extreme phenotype approach (Sims et al 2008). In the current study, we replicated the association of WNT3A and DKK2 polymorphisms with BMD in the Mexican population, providing further evidence of the role of this pathway in BMD variation.…”

“…Among these, LRP5 is recognized as one of the key bone regulatory genes that might influence BMD in the general population, and LRP5 polymorphisms have been consistently associated with BMD in different populations (Richards et al 2008;van Meurs et al 2008;Rivadeneira et al 2009). More recently WNT3A, known to affect osteoblast differentiation (Monroe et al 2012), was found to be associated with BMD in Australian postmenopausal women (Sims et al 2008); a meta-analysis combining five GWAS identified a large linkage disequilibrium (LD) block encompassing LRP4 associated with femoral neck and lumbar spine BMD (Styrkarsdottir et al 2008). It has also been suggested that LRP6 polymorphisms influence BMD (Sims et al 2008;van Meurs et al 2008); however, the results have been conflicting (Mencej-Bedrac et al 2009;Yerges et al 2010).…”

“…More recently WNT3A, known to affect osteoblast differentiation (Monroe et al 2012), was found to be associated with BMD in Australian postmenopausal women (Sims et al 2008); a meta-analysis combining five GWAS identified a large linkage disequilibrium (LD) block encompassing LRP4 associated with femoral neck and lumbar spine BMD (Styrkarsdottir et al 2008). It has also been suggested that LRP6 polymorphisms influence BMD (Sims et al 2008;van Meurs et al 2008); however, the results have been conflicting (Mencej-Bedrac et al 2009;Yerges et al 2010). Recently, Estrada et al (2012) performed a metaanalysis including data from 17 genome-wide association studies of European and East Asian ancestry, highlighting the critical role of several genes (WNT16, LRP5, DKK1, LRP4, WNT4.…”

Bivariate association analysis in selected samples: application to a GWAS of two bone mineral density phenotypes in males with high or low BMD

“…Our study used a design, with extreme truncate selection of unrelated males, aiming to improve power. The approach of studying samples drawn from the extremes of the population distribution of BMD has been used in several linkage studies of BMD variation, 25,27 but rarely in association studies, 28 and to our knowledge, never in samples drawn from the population of males. Owing to our relatively small GWA sample size, no SNP showed evidence of association to either one or both BMD phenotypes at genome-wide significance threshold of 1.7Â10 À7 (0.05/298 783 SNPs).…”

Building bone with a SOST-PTH partnership

“…Given that single-nucleotide polymorphisms of SOST that predispose to increased fracture risk and low BMD have been identified recently, (37)(38)(39)(40) the possibility that PTH may be less effective in these populations demands that additional treatment options are made available.…”