Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits

Analysis of whole-genome sequence data of Icelandic individuals has revealed a rare nonsense mutation within the LGR4 gene that is strongly associated with, among other things, low bone mineral density, late onset of menarche, and increased risk of biliary tract cancer. A search through whole-genome sequence data from thousands of Icelandic individuals for variants that may have a direct effect on the risk of pathologically low bone mineral density has identified a rare nonsense mutation that associates with a wide range of phenotypes in addition to those related to bone physiology. The mutation, found within the leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4) gene, is strongly associated with osteoporotic fractures, and also with electrolyte imbalance, hormonal imbalance and an increased risk of squamous cell carcinoma of the skin and biliary tract cancer. The phenotype of carriers of this mutation overlaps with that of Lgr4 knockout mice. 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.