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. 2011 Jan 28:12:19.
doi: 10.1186/1471-2350-12-19.

A validation of the first genome-wide association study of calcaneus ultrasound parameters in the European Male Ageing Study

Delnaz Roshandel  1 , Wendy Thomson, Stephen R Pye, Steven Boonen, Herman Borghs, Dirk Vanderschueren, Ilpo T Huhtaniemi, Judith E Adams, Kate A Ward, Gyorgy Bartfai, Felipe Casanueva, Joseph D Finn, Gianni Forti, Aleksander Giwercman, Thang S Han, Krzysztof Kula, Michael E Lean, Neil Pendleton, Margus Punab, Alan J Silman, Frederick C Wu, Kate L Holliday, Terence W O'Neill; EMAS Study Group
Collaborators, Affiliations

A validation of the first genome-wide association study of calcaneus ultrasound parameters in the European Male Ageing Study

Delnaz Roshandel et al. BMC Med Genet. .

Abstract

Background: A number of single nucleotide polymorphisms (SNPs) have been associated with broadband ultrasound attenuation (BUA) and speed of sound (SOS) as measured by quantitative ultrasound (QUS) at the calcaneus in the Framingham 100K genome-wide association study (GWAS) but have not been validated in independent studies. The aim of this analysis was to determine if these SNPs are associated with QUS measurements assessed in a large independent population of European middle-aged and elderly men. The association between these SNPs and bone mineral density (BMD) measured using dual-energy X-ray absorptiometry (DXA) was also tested.

Methods: Men aged 40-79 years (N = 2960) were recruited from population registers in seven European centres for participation in an observational study of male ageing, the European Male Ageing Study (EMAS). QUS at the calcaneus was measured in all subjects and blood was taken for genetic analysis. Lumbar spine (LS), femoral neck (FN) and total hip (TH) BMD were measured by DXA in a subsample of 620 men in two centres. SNPs associated with BUA or SOS in the Framingham study with p < 10-4 were selected and genotyped using SEQUENOM technology. Linear regression was used to test for the association between SNPs and standardised (SD) bone outcomes under an additive genetic model adjusting for centre. The same direction of effect and p < 0.05 indicated replication.

Results: Thirty-four of 38 selected SNPs were successfully genotyped in 2377 men. Suggestive evidence of replication was observed for a single SNP, rs3754032, which was associated with a higher SOS (β(SD) = 0.07, p = 0.032) but not BUA (β(SD) = 0.02, p = 0.505) and is located in the 3'UTR of WDR77 (WD repeat domain 77) also known as androgen receptor cofactor p44. A single SNP, rs238358, was associated with BMD at the LS (β(SD) = -0.22, p = 0.014), FN (β(SD) = -0.31,p = 0.001) and TH (β(SD) = -0.36, p = 0.002) in a locus previously associated with LS BMD in large-scale GWAS, incorporating AKAP11 and RANKL.

Conclusions: We found suggestive evidence of association between a single SNP located in the 3'UTR of WDR77 with calcaneal ultrasound parameters. The majority of SNPs, associated with QUS parameters in the Framingham Study, were not replicated in an independent population sample of European men.

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Figures

Figure 1
Figure 1
Regional LD plot for rs3754032. The plot shows the linkage disequilibrium between rs3754032 and HapMap SNPs within 250 Kb, recombination rate and the genes in the region using Annotation and Proxy Search (SNAP) (http://www.broadinstitute.org/mpg/snap/index.php). The two dashed vertical lines show the location of HapMap SNPs which are in high LD (r2 ≥ 0.8) with rs3754032.
Figure 2
Figure 2
Regional LD plot for rs238358. The plot shows the linkage disequilibrium between rs238358 and the other HapMap SNPs in 500 kb, recombination rate and the genes in the region using Annotation and Proxy Search (SNAP) (http://www.broadinstitute.org/mpg/snap/index.php). The two dashed vertical lines show the location of HapMap SNPs which are in high LD (r2 ≥ 0.8) with rs238358.
See this image and copyright information in PMC

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