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. 2011 Apr;7(4):e1001372.
doi: 10.1371/journal.pgen.1001372. Epub 2011 Apr 21.

Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk

Emma L Duncan  1 , Patrick Danoy, John P Kemp, Paul J Leo, Eugene McCloskey, Geoffrey C Nicholson, Richard Eastell, Richard L Prince, John A Eisman, Graeme Jones, Philip N Sambrook, Ian R Reid, Elaine M Dennison, John Wark, J Brent Richards, Andre G Uitterlinden, Tim D Spector, Chris Esapa, Roger D Cox, Steve D M Brown, Rajesh V Thakker, Kathryn A Addison, Linda A Bradbury, Jacqueline R Center, Cyrus Cooper, Catherine Cremin, Karol Estrada, Dieter Felsenberg, Claus-C Glüer, Johanna Hadler, Margaret J Henry, Albert Hofman, Mark A Kotowicz, Joanna Makovey, Sing C Nguyen, Tuan V Nguyen, Julie A Pasco, Karena Pryce, David M Reid, Fernando Rivadeneira, Christian Roux, Kari Stefansson, Unnur Styrkarsdottir, Gudmar Thorleifsson, Rumbidzai Tichawangana, David M Evans, Matthew A Brown
Affiliations

Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk

Emma L Duncan et al. PLoS Genet. 2011 Apr.

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. SNP association plots for BMD-associated regions.
Discovery cohort association significance level is plotted against the left hand y-axis as -log10(P-values). Genetic coordinates are as per NCBI build 36.1. Filled circles represent genotyped SNPs, and outlined diamonds represent imputed SNPs. The recombination rate (cM/Mb as per HapMap data) is indicated by the purple dotted line and right hand y-axis. Genes and ESTs are indicated with their approximate sizes and direction of translation. (A) Chromosome 2q24 - GALNT3 region. SNP association plot of findings from TH case-control analysis of AOGC discovery set for a 500 kb region (166,100 kb to 166,600 kb) of chromosome 2. LD is indicated by colour scale in relationship to marker rs1863196. (B) Chromosome 6q22 - RSPO3 region. SNP association plot of findings from TH case-control analysis of AOGC discovery set for a 1,200 kb region (126,600 kb to 127,800 kb) of chromosome 6. LD is indicated by colour scale in relationship to marker rs13204965.
Figure 2
Figure 2. Areal BMD derived from DEXA analysis of 15- to 16-week-old GALNT3 mutant and wild-type mice.
P-values refer to Student t-test for two-way ANOVA across the three genotypes.
See this image and copyright information in PMC

References

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