Genetic analyses in a sample of individuals with high or low BMD shows association with multiple Wnt pathway genes

Sims, A.M., Shephard, N., Carter, K., Doan, T., Dowling, A., Duncan, Emma L., Eisman, J., Jones, G., Nicholson, G., Prince, R., Seeman, E., Thomas, G., Wass, J.A., & Brown, Matthew A. (2007) Genetic analyses in a sample of individuals with high or low BMD shows association with multiple Wnt pathway genes. Journal of Bone and Mineral Research, 23(4), pp. 499-506.

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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 = 1.5-4.0; n = 344).


Ninety-six tag-single nucleotide polymorphism (SNPs) lying in 13 Wnt signaling pathway genes were selected to tag common genetic variation (minor allele frequency [MAF] > 5% with an r(2) > 0.8) within 5 kb of all exons of 13 Wnt signaling pathway genes. The genes studied included LRP1, LRP5, LRP6, Wnt3a, Wnt7b, Wnt10b, SFRP1, SFRP2, DKK1, DKK2, FZD7, WISP3, and SOST. Three hundred forty-four cases with either high or low BMD were genotyped by Illumina Goldengate microarray SNP genotyping methods. Association was tested either by Cochrane-Armitage test for dichotomous variables or by linear regression for quantitative traits.


Strong association was shown with LRP5, polymorphisms of which have previously been shown to influence total hip BMD (minimum p = 0.0006). In addition, polymorphisms of the Wnt antagonist, SFRP1, were significantly associated with BMD and BMC (minimum p = 0.00042). Previously reported associations of LRP1, LRP6, and SOST with BMD were confirmed. Two other Wnt pathway genes, Wnt3a and DKK2, also showed nominal association with BMD.


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.

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ID Code: 89413
Item Type: Journal Article
Refereed: Yes
Keywords: Association, BMD, Single nucleotide polymorphism, Wnt, Dkk1 protein, DKK2 protein, fzd 7 protein, low density lipoprotein receptor related protein, low density lipoprotein receptor related protein 5, low density lipoprotein receptor related protein 6, protein derivative, sclerostin, secreted frizzled related protein 1, secreted frizzled related protein 2, unclassified drug, WISP3 protein, Wnt protein, Wnt10b protein, Wnt3a protein, wnt7b protein, aged, article, bone, bone densitometry, bone density, bone mineral, cohort analysis, controlled study, exon, femur neck, gene, gene frequency, genetic analysis, genetic trait, genetic variability, genome analysis, genotype, hip, human, linear regression analysis, microarray analysis, osteoporosis, phenotype, population, prediction, quantitative analysis, sample, sample size, theoretical study, Aged, 80 and over, Cohort Studies, Female, Humans, Male, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Wnt Proteins
DOI: 10.1359/jbmr.071113
ISSN: 0884-0431
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2007 Wiley-Blackwell Publishing
Deposited On: 23 Oct 2015 03:18
Last Modified: 19 Aug 2016 02:57

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