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

Sims, Anne-Marie, Shephard, Neil, Carter, Kim, Doan, Tracy, Dowling, Alison, Duncan, Emma L., Eisman, John, Jones, Graeme, Nicholson, Geoffrey, Prince, Richard, Seeman, Ego, Thomas, Gethin, Wass, John A. and Brown, Matthew A. (2008) 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: 499-505. doi:10.1359/JBMR.071113

Author Sims, Anne-Marie
Shephard, Neil
Carter, Kim
Doan, Tracy
Dowling, Alison
Duncan, Emma L.
Eisman, John
Jones, Graeme
Nicholson, Geoffrey
Prince, Richard
Seeman, Ego
Thomas, Gethin
Wass, John A.
Brown, Matthew A.
Title Genetic analyses in a sample of individuals with high or low BMD shows association with multiple wnt pathway genes
Journal name Journal of Bone and Mineral Research   Check publisher's open access policy
ISSN 0884-0431
Publication date 2008
Year available 2007
Sub-type Article (original research)
DOI 10.1359/JBMR.071113
Volume 23
Issue 4
Start page 499
End page 505
Total pages 7
Editor J. A. Eisman
Place of publication Malden, MA, United States
Publisher Wiley-Blackwell Publishing
Collection year 2008
Language eng
Subject C1
270207 Quantitative Genetics
780105 Biological sciences
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 = 1.5-4.0; n = 344). Materials and Methods: 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 BNID 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. Results: 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. 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.
Keyword Single nucleotide polymorphism
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status Non-UQ

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Created: Thu, 15 May 2008, 12:22:53 EST by Kylie Hengst on behalf of UQ Diamantina Institute