Further genetic evidence suggesting a role for the RhoGTPase-RhoGEF pathway in osteoporosis

Benjamin Mullin, Richard Prince, C. Mamotte, T.D. Spector, D.J. Hart, F. Dudbridge, Scott Wilson

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Abstract

Osteoporosis is a highly heritable trait that appears to be influenced by multiple genes. Genome-wide linkage studies have highlighted the chromosomal region 3p14-p21 as a quantitative trait locus for BMD. We have previously published evidence suggesting that the ARHGEF3 gene from this region is associated with BMD in women. The product of this gene activates the RHOA GTPase, the gene for which is also located within this region. The aim of this study was to evaluate the influence of genetic polymorphism in RHOA on bone density in women. Sequence variation within the RHOA gene region was determined using 9 single nucleotide polymorphisms (SNPs) in a discovery cohort of 769 female sibs. Of the 9 SNPs, one was found to be monomorphic with the others representing 3 distinct linkage disequilibrium (LD) blocks. Using FBAT software, significant associations were found between two of these LD blocks and BMD Z-score of the spine and hip (P = 0.001–0.036). The LD block tagged by the SNP rs17595772 showed maximal association, with the more common G allele at rs17595772 associated with decreased BMD Z-score. Genotyping for rs17595772 in a replication cohort of 780 postmenopausal women confirmed an association with BMD Z-score (P = 0.002–0.036). Again, the G allele was found to be associated with a reduced hip and spine BMD Z-score. These results support the implication of the RhoGTPase-RhoGEF pathway in osteoporosis, and suggest that one or more genes in this pathway may be responsible for the linkage observed between 3p14-p21 and BMD.
Original languageEnglish
Pages (from-to)387-391
JournalBone
Volume45
Issue number2
DOIs
Publication statusPublished - 2009

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Rho Guanine Nucleotide Exchange Factors
Osteoporosis
Linkage Disequilibrium
Genes
Single Nucleotide Polymorphism
Hip
Spine
Alleles
Quantitative Trait Loci
GTP Phosphohydrolases
Genetic Polymorphisms
Bone Density
Software
Genome

Cite this

Mullin, Benjamin ; Prince, Richard ; Mamotte, C. ; Spector, T.D. ; Hart, D.J. ; Dudbridge, F. ; Wilson, Scott. / Further genetic evidence suggesting a role for the RhoGTPase-RhoGEF pathway in osteoporosis. In: Bone. 2009 ; Vol. 45, No. 2. pp. 387-391.
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Further genetic evidence suggesting a role for the RhoGTPase-RhoGEF pathway in osteoporosis. / Mullin, Benjamin; Prince, Richard; Mamotte, C.; Spector, T.D.; Hart, D.J.; Dudbridge, F.; Wilson, Scott.

In: Bone, Vol. 45, No. 2, 2009, p. 387-391.

Research output: Contribution to journalArticle

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AU - Mullin, Benjamin

AU - Prince, Richard

AU - Mamotte, C.

AU - Spector, T.D.

AU - Hart, D.J.

AU - Dudbridge, F.

AU - Wilson, Scott

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AB - Osteoporosis is a highly heritable trait that appears to be influenced by multiple genes. Genome-wide linkage studies have highlighted the chromosomal region 3p14-p21 as a quantitative trait locus for BMD. We have previously published evidence suggesting that the ARHGEF3 gene from this region is associated with BMD in women. The product of this gene activates the RHOA GTPase, the gene for which is also located within this region. The aim of this study was to evaluate the influence of genetic polymorphism in RHOA on bone density in women. Sequence variation within the RHOA gene region was determined using 9 single nucleotide polymorphisms (SNPs) in a discovery cohort of 769 female sibs. Of the 9 SNPs, one was found to be monomorphic with the others representing 3 distinct linkage disequilibrium (LD) blocks. Using FBAT software, significant associations were found between two of these LD blocks and BMD Z-score of the spine and hip (P = 0.001–0.036). The LD block tagged by the SNP rs17595772 showed maximal association, with the more common G allele at rs17595772 associated with decreased BMD Z-score. Genotyping for rs17595772 in a replication cohort of 780 postmenopausal women confirmed an association with BMD Z-score (P = 0.002–0.036). Again, the G allele was found to be associated with a reduced hip and spine BMD Z-score. These results support the implication of the RhoGTPase-RhoGEF pathway in osteoporosis, and suggest that one or more genes in this pathway may be responsible for the linkage observed between 3p14-p21 and BMD.

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