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

• Published in: Nature
• Main Authors: Styrkarsdottir, Unnur, Thorleifsson, Gudmar, Sulem, Patrick, Gudbjartsson, Daniel F, Sigurdsson, Asgeir, Jonasdottir, Aslaug, Jonasdottir, Adalbjorg, Oddsson, Asmundur, Helgason, Agnar, Magnusson, Olafur T, Walters, G Bragi, Frigge, Michael L, Helgadottir, Hafdis T, Johannsdottir, Hrefna, Bergsteinsdottir, Kristin, Ogmundsdottir, Margret H, Center, Jacqueline R, Nguyen, Tuan V, Eisman, John A, Christiansen, Claus, Steingrimsson, Erikur, Jonasson, Jon G, Tryggvadottir, Laufey, Eyjolfsson, Gudmundur I, Theodors, Asgeir, Jonsson, Thorvaldur, Ingvarsson, Thorvaldur, Olafsson, Isleifur, Rafnar, Thorunn, Kong, Augustine, Sigurdsson, Gunnar, Masson, Gisli, Thorsteinsdottir, Unnur, Stefansson, Kari
• Other Authors: deCODE Genet Amgen, IS-101 Reykjavik, Iceland Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden Univ Iceland, Biomed Ctr, Fac Med, Dept Biochem & Mol Biol, IS-101 Reykjavik, Iceland Garvan Inst Med Res, Sydney, NSW 2010, Australia St Vincents Hosp, Sydney, NSW 2010, Australia Univ New S Wales, Sydney, NSW 2010, Australia UNDA, Sydney, NSW 2010, Australia CCBR, DK-2750 Ballerup, Denmark Natl Univ Hosp Iceland, Landspitali, Dept Pathol, IS-101 Reykjavik, Iceland Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland Iceland Canc Registry, IS-105 Reykjavik, Iceland Iceland Med Ctr Laeknasetrid, Lab Mjodd RAM, IS-109 Reykjavik, Iceland Natl Univ Hosp Iceland, Landspitali, Dept Gastroenterol, IS-101 Reykjavik, Iceland Natl Univ Hosp Iceland, Landspitali, Dept Surg, IS-101 Reykjavik, Iceland Akureyri Hosp, Dept Orthoped Surg, IS-600 Akureyri, Iceland Univ Akureyri, Inst Hlth Sci, IS-600 Akureyri, Iceland Natl Univ Hosp Iceland, Landspitali, Dept Clin Biochem, IS-101 Reykjavik, Iceland Natl Univ Hosp Iceland, Landspitali, Dept Endocrinol & Metab, IS-101 Reykjavik, Iceland
• Format: Article in Journal/Newspaper
• Language: English
• Published: Nature Publishing Group 2014
• Subjects: Animals; Australia; Biliary Tract Neoplasms; Bone Density; Carcinoma; Squamous Cell; Codon; Nonsense; Denmark; Down-Regulation; Female; Heterozygote; Humans; Iceland; Male; Menarche; Mice; Knockout; Osteoporotic Fractures; Phenotype; Receptors; G-Protein-Coupled; Skin Neoplasms; Testosterone; Water-Electrolyte Imbalance
• Online Access: http://hdl.handle.net/2336/317206; https://doi.org/10.1038/nature12124

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field. 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 BMD. 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. European Commission HEALTH-F2-2008-201865-GEFOS Lung GO Sequencing Project HL-102923 WHI Sequencing Project HL-102924 Broad GO Sequencing Project HL-102925 Seattle GO Sequencing Project HL-102926 Heart GO Sequencing Project HL-103010