Low bone mineral density (BMD) is used as a parameter of osteoporosis. Genome-wide association studies of BMD have hitherto focused on BMD as a quantitative trait, yielding common variants of small effects that contribute to the population diversity in BMD1,2,3,4,5,6,7. Here we use BMD as a dichotomous trait, searching for variants that may have a direct effect on the risk of pathologically low BMD rather than on the regulation of BMD in the healthy population. Through whole-genome sequencing of Icelandic individuals, we found a rare nonsense mutation within the leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4) gene (c.376C>T) that is strongly associated with low BMD, and with osteoporotic fractures. This mutation leads to termination of LGR4 at position 126 and fully disrupts its function. The c.376C>T mutation is also associated with electrolyte imbalance, late onset of menarche and reduced testosterone levels, as well as an increased risk of squamous cell carcinoma of the skin and biliary tract cancer. Interestingly, the phenotype of carriers of the c.376C>T mutation overlaps that of Lgr4 mutant mice.
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We thank the subjects of the Icelandic deCODE study, the Danish PERF study and the Australian DOES study for their participation. We also thank the staff at deCODE Genetics core facilities and all our colleagues for their important contribution to this work. The authors would like to thank the NHLBI GO Exome Sequencing Project and its continuing studies, which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923); the WHI Sequencing Project (HL-102924); the Broad GO Sequencing Project (HL-102925); the Seattle GO Sequencing Project (HL-102926); and the Heart GO Sequencing Project (HL-103010). This work was supported in part by the European Commission (HEALTH-F2-2008-201865-GEFOS).
U.S., G.T., P.S., A.S., Aslaug J., Adalbjorg J., A.O., D.F.G., A.H., O.T.M., G.B.W., M.L.F., H.T.H., H.J., T.R., A.K., G.M., U.T. and K.S. are employees of deCODE Genetics/Amgen.
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Styrkarsdottir, U., Thorleifsson, G., Sulem, P. et al. Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits. Nature 497, 517–520 (2013) doi:10.1038/nature12124
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