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

Styrkarsdottir, U; Thorleifsson, G; Sulem, P; Gudbjartsson, DF; Sigurdsson, A; Jonasdottir, A; Oddsson, A; Helgason, A; Magnusson, OT; Walters, GB; Frigge, ML; Helgadottir, HT; Johannsdottir, H; Bergsteinsdottir, K; Ogmundsdottir, MH; Center, JR; Nguyen, TV; Eisman, JA; Christiansen, C; Steingrimsson, E; Jonasson, JG; Tryggvadottir, L; Eyjolfsson, GI; Theodors, A; Jonsson, T; Ingvarsson, T; Olafsson, I; Rafnar, T; Kong, A; Sigurdsson, G; Masson, G; Thorsteinsdottir, U; Stefansson, K

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

Styrkarsdottir, U Thorleifsson, G Sulem, P Gudbjartsson, DF Sigurdsson, A Jonasdottir, A Oddsson, A Helgason, A Magnusson, OT Walters, GB Frigge, ML Helgadottir, HT Johannsdottir, H Bergsteinsdottir, K Ogmundsdottir, MH Center, JR Nguyen, TV

Eisman, JA Christiansen, C Steingrimsson, E Jonasson, JG Tryggvadottir, L Eyjolfsson, GI Theodors, A Jonsson, T Ingvarsson, T Olafsson, I Rafnar, T Kong, A Sigurdsson, G Masson, G Thorsteinsdottir, U Stefansson, K

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Publication Type:: Journal Article
Citation:: Nature, 2013, 497 (7450), pp. 517 - 520
Issue Date:: 2013-05-06

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Field	Value	Language
dc.contributor.author	Styrkarsdottir, U	en_US
dc.contributor.author	Thorleifsson, G	en_US
dc.contributor.author	Sulem, P	en_US
dc.contributor.author	Gudbjartsson, DF	en_US
dc.contributor.author	Sigurdsson, A	en_US
dc.contributor.author	Jonasdottir, A	en_US
dc.contributor.author	Oddsson, A	en_US
dc.contributor.author	Helgason, A	en_US
dc.contributor.author	Magnusson, OT	en_US
dc.contributor.author	Walters, GB	en_US
dc.contributor.author	Frigge, ML	en_US
dc.contributor.author	Helgadottir, HT	en_US
dc.contributor.author	Johannsdottir, H	en_US
dc.contributor.author	Bergsteinsdottir, K	en_US
dc.contributor.author	Ogmundsdottir, MH	en_US
dc.contributor.author	Center, JR	en_US
dc.contributor.author	Nguyen, TV https://orcid.org/0000-0002-3246-6281	en_US
dc.contributor.author	Eisman, JA	en_US
dc.contributor.author	Christiansen, C	en_US
dc.contributor.author	Steingrimsson, E	en_US
dc.contributor.author	Jonasson, JG	en_US
dc.contributor.author	Tryggvadottir, L	en_US
dc.contributor.author	Eyjolfsson, GI	en_US
dc.contributor.author	Theodors, A	en_US
dc.contributor.author	Jonsson, T	en_US
dc.contributor.author	Ingvarsson, T	en_US
dc.contributor.author	Olafsson, I	en_US
dc.contributor.author	Rafnar, T	en_US
dc.contributor.author	Kong, A	en_US
dc.contributor.author	Sigurdsson, G	en_US
dc.contributor.author	Masson, G	en_US
dc.contributor.author	Thorsteinsdottir, U	en_US
dc.contributor.author	Stefansson, K	en_US
dc.date.available	2013-03-27	en_US
dc.date.issued	2013-05-06	en_US
dc.identifier.citation	Nature, 2013, 497 (7450), pp. 517 - 520	en_US
dc.identifier.issn	0028-0836	en_US
dc.identifier.uri	http://hdl.handle.net/10453/116630
dc.description.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. © 2013 Macmillan Publishers Limited. All rights reserved.	en_US
dc.relation.ispartof	Nature	en_US
dc.relation.isbasedon	10.1038/nature12124	en_US
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject.classification	General Science & Technology	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Knockout	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Carcinoma, Squamous Cell	en_US
dc.subject.mesh	Biliary Tract Neoplasms	en_US
dc.subject.mesh	Skin Neoplasms	en_US
dc.subject.mesh	Water-Electrolyte Imbalance	en_US
dc.subject.mesh	Testosterone	en_US
dc.subject.mesh	Receptors, G-Protein-Coupled	en_US
dc.subject.mesh	Codon, Nonsense	en_US
dc.subject.mesh	Down-Regulation	en_US
dc.subject.mesh	Menarche	en_US
dc.subject.mesh	Bone Density	en_US
dc.subject.mesh	Heterozygote	en_US
dc.subject.mesh	Phenotype	en_US
dc.subject.mesh	Australia	en_US
dc.subject.mesh	Iceland	en_US
dc.subject.mesh	Denmark	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	Osteoporotic Fractures	en_US
dc.title	Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits	en_US
dc.type	Journal Article
utslib.citation.volume	7450	en_US
utslib.citation.volume	497	en_US
utslib.for	MD Multidisciplinary	en_US
utslib.for	1103 Clinical Sciences	en_US
utslib.for	090301 Biomaterials	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	closed_access	*
pubs.issue	7450	en_US
pubs.publication-status	Published	en_US
pubs.volume	497	en_US

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. © 2013 Macmillan Publishers Limited. All rights reserved.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/116630