title: Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits.
abstract: 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.
authors: deCODE Genetics/Amgen, 101 Reykjavik, Iceland. unnurth@decode.is
authors: Unnur
authors: U
authors: Styrkarsdottir
authors: Gudmar
authors: G
authors: Thorleifsson
authors: Patrick
authors: P
authors: Sulem
authors: Daniel F
authors: DF
authors: Gudbjartsson
authors: Asgeir
authors: A
authors: Sigurdsson
authors: Aslaug
authors: A
authors: Jonasdottir
authors: Adalbjorg
authors: A
authors: Jonasdottir
authors: Asmundur
authors: A
authors: Oddsson
authors: Agnar
authors: A
authors: Helgason
authors: Olafur T
authors: OT
authors: Magnusson
authors: G Bragi
authors: GB
authors: Walters
authors: Michael L
authors: ML
authors: Frigge
authors: Hafdis T
authors: HT
authors: Helgadottir
authors: Hrefna
authors: H
authors: Johannsdottir
authors: Kristin
authors: K
authors: Bergsteinsdottir
authors: Margret H
authors: MH
authors: Ogmundsdottir
authors: Jacqueline R
authors: JR
authors: Center
authors: Tuan V
authors: TV
authors: Nguyen
authors: John A
authors: JA
authors: Eisman
authors: Claus
authors: C
authors: Christiansen
authors: Erikur
authors: E
authors: Steingrimsson
authors: Jon G
authors: JG
authors: Jonasson
authors: Laufey
authors: L
authors: Tryggvadottir
authors: Gudmundur I
authors: GI
authors: Eyjolfsson
authors: Asgeir
authors: A
authors: Theodors
authors: Thorvaldur
authors: T
authors: Jonsson
authors: Thorvaldur
authors: T
authors: Ingvarsson
authors: Isleifur
authors: I
authors: Olafsson
authors: Thorunn
authors: T
authors: Rafnar
authors: Augustine
authors: A
authors: Kong
authors: Gunnar
authors: G
authors: Sigurdsson
authors: Gisli
authors: G
authors: Masson
authors: Unnur
authors: U
authors: Thorsteinsdottir
authors: Kari
authors: K
authors: Stefansson
mesh_terms: D000818:Animals; D001315:Australia; D001661:Biliary Tract Neoplasms / Q000235:genetics*; D015519:Bone Density / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D018389:Codon, Nonsense / Q000235:genetics*; D003718:Denmark; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D007055:Iceland; D008297:Male; D008572:Menarche / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D058866:Osteoporotic Fractures / Q000235:genetics*; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics*; D013739:Testosterone / Q000032:analysis; D014883:Water-Electrolyte Imbalance / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; C411562:LGR4 protein, human; C496200:LGR4 protein, mouse; D043562:Receptors, G-Protein-Coupled; D013739:Testosterone
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