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

摘要

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"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.376OT mutation is also associated with electrolyte imbalance, late onset of men-arche 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.%一项在来自数干名冰岛人的全基因组序列数据rn中搜寻变异体的工作(这些变异体对出现从病rn理上来说较低的骨矿物密度的风险可能会有直rn接影响)，识别出了一个罕见的无意义突变，rn除了那些与骨生理相关的表现型外，它还与一rn系列其他表现型相关。