DESCRIPTION:

List of positional candidate genes after correcting for multiple testing and controlling the false discovery rate from genome wide association studies (GWAS) retrieved from the NHGRI-EBI Catalog of published genome-wide association studies (http://www.ebi.ac.uk/gwas/). The disease/trait examined in this study, as reported by the authors, was Bone mineral density. The EFO term bone density was annotated to this set after curation by NHGRI-EBI. Intergenic SNPS were mapped to both the upstream and downstream gene. P-value uploaded. This gene set was generated using gwas2gs v. 0.1.8 and the GWAS Catalog v. 1.0.1.

LABEL:

GWAS: bone density

SCORE TYPE:

P-Value

DATE ADDED:

2017-05-02

DATE UPDATED:

2024-04-25

SPECIES:

AUTHORS:

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

TITLE:

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

JOURNAL:

Nature May 2013, Vol 497, pp. 517-20

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. PUBMED: 23644456
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