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LGR4 mutation associated with low BMD in Icelandic individuals


This whole-genome sequencing study focused on bone mineral density (BMD) as a dichotomous trait to identify variants associated with abnormally low BMD in an Icelandic population. BMD sites were total hip, lumbar spine (L2–L4), and whole body.

A total of 4931 individuals with a BMD level lower than one standard deviation (s.d.) below normal were included in the low BMD group. The control group comprised 69 034 individuals who had BMD above −1 s.d. and, for increased power, individuals who had not had their BMD measured at all.

About 34.2 million sequence variants (30.6 million SNPs and 3.6 million indels) were identified, including the gene encoding leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4), which lies in the 11p14 region. This rare nonsense mutation, which terminates LGR4 at position 126, completely disrupts the function of the protein and shows a strong association with pathologically low BMD and osteoporosis-related fractures. It was also linked with low testosterone, late menarche and an increased risk of skin and biliary tract cancer. Other variants in the same region included lin-7 homologue C and brain-derived neurotrophic factor.

Editor’s comment: The mutation identified has not been found in other samples from Caucasians and does not appear in the databases; it could therefore be of Icelandic origin. The cell-surface receptor LGR4 shows direct binding to R-spondins, which are agonists in the Wnt pathway. This pleiotropy is therefore not surprising, since Wnt signaling is involved in multiple functions.

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