Interspecies synteny mapping identifies a quantitative trait locus for bone mineral density on human chromosome Xp22

Parsons, Claire A.; Mroczkowski, Henry Joel; McGuigan, Fiona; Albagha, Omar; Manolagas, Stavros C.; Reid, David M.; Ralston, Stuart H.; Reis, Robert J. Shmookler

doi:10.1093/hmg/ddi346

Cited by 21 publications

(13 citation statements)

References 28 publications

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“…First, a QTL was found on the mouse X-chromosome for post-maturity change in spine BMD (Szumska et al, 2006). Then, the syntenic region on human chromosome Xp22 was tested in post-menopausal women by association mapping of the human QTL, which identified a gene that encodes a nuclear protein Pirin as possibly responsible for the observed signal (Parsons et al, 2005). This study provides a valuable example that interspecies synteny can be used to identify and refine QTLs for complex traits.…”

Section: X-chromosome: Possible Culprit?mentioning

confidence: 99%

Contribution of Gender‐Specific Genetic Factors to Osteoporosis Risk

Karasik

Ferrari

2008

Annals of Human Genetics

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SummaryCommon diseases result from the complex relationship between genetic and environmental factors. The aim of this review is to provide perspective for a conceptual framework aimed at studying the interplay of gender-specific genetic and environmental factors in the etiology of complex disease, using osteoporosis as an example.In recent years, gender differences in the heritability of the osteoporosis-related phenotypes have been reported and sex-specific quantitative-trait loci were discovered by linkage studies in humans and mice. Results of numerous allelic association studies also differed by gender. In most cases, it was not clear whether or not this phenomenon should be attributed to the effect of sex-chromosomes, sex hormones, or other intrinsic or extrinsic differences between the genders, such as the level of bioavailable estrogen and of physical activity. We conclude that there is need to consider gender-specific genetic and environmental factors in the planning of future association studies on the etiology of osteoporosis and other complex diseases prevalent in the general population.

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Section: X-chromosome: Possible Culprit?mentioning

confidence: 99%

Contribution of Gender‐Specific Genetic Factors to Osteoporosis Risk

Karasik

Ferrari

2008

Annals of Human Genetics

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“…In a related study, reported recently [14], we pursued the human X chromosome region corresponding to the interval expanded in Figure 6, by SNP association to BMD of the lumbar vertebrae. Using a population of 3224 postmenopausal women in the Aberdeen area, an association peak was observed within the X-chromosome interval implicated in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…As detailed below, we discovered two loci that exert significant effects on this trait in adult mice; of these, one on the X chromosome was reproduced in two independent crosses. Remarkably, the latter region corresponds closely to a polymorphic locus significantly associated with vertebral BMD in postmenopausal women [14]. Further studies will be required, to determine whether other bone-related QTLs, defined in the mouse, can readily be translated to humans in advance of gene identification.…”

Section: Introductionmentioning

confidence: 99%

A novel locus on the X chromosome regulates post-maturity bone density changes in mice

Szumska

Kang

Weinstein

et al. 2007

Bone

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Two mouse strains, AKR/J and SAMP6, were assessed longitudinally for bone mineral density of the spine. They displayed very different time courses of bone accrual, with the SAMP6 strain reaching a plateau for vertebral BMD at 3 months, whereas AKR/J mice continued to increase spine BMD for at least 8 months. Among 253 F 2 progeny of an AKR/J x SAMP6 cross, at 4 months of age the BMD variance was 5-6% of the mean, versus 15% for weight. Variance increased with age for every parameter measured, and was generally higher among males. The ratio of 6-month/4-month spine BMDs, termed ΔsBMD, had a normal distribution with 5.7% variance, and was largely independent of spine BMD (R=-0.23) or body weight (R=-0.12) at maturity. Heritability of the Δs BMD trait was calculated at 0.59. Genetic mapping identified two significant loci, both distinct from those observed for BMD at maturity -implying that different genes regulate skeletal growth vs. remodeling. A locus on the X chromosome, replicated in two mouse F 2 populations (P<10 -4 for combined discovery and confirmation), affects age-dependent BMD change for both spine and the full skeleton. Its position agrees with a very narrow region identified by association mapping for effects on lumbar bone density in postmenopausal women (Parsons et al., Hum Mol Genet 2005). A second locus, on chromosome 7, was observed in only one cross. Single-nucleotide polymorphisms (SNPs) are highly clustered near these loci, distinguishing the parental strains over only limited spans.

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“…One locus derived from animal studies which has been investigated in man is a region on chromosome X which was found to be linked to post maturity change of BMD in mice [21]. Mapping of the syntenic region of chromosome X in humans using a DNA pooling strategy showed evidence of an association between two polymorphisms in the Pirin gene and lumbar spine BMD [21]. This observation remains to be replicated in other studies however.…”

Section: Animal Studiesmentioning

confidence: 99%

“…Subsequent work showed that Darc knockout mice had reduced bone mass, and functional studies revealed that the likely mechanism by which Darc regulated BMD was through an effect on osteoclastic bone resorption, probably mediated by differences in the ability of Darc to bind chemokines in different mouse strains. One locus derived from animal studies which has been investigated in man is a region on chromosome X which was found to be linked to post maturity change of BMD in mice [21]. Mapping of the syntenic region of chromosome X in humans using a DNA pooling strategy showed evidence of an association between two polymorphisms in the Pirin gene and lumbar spine BMD [21].…”

Section: Animal Studiesmentioning

confidence: 99%

Osteoporosis as an Hereditary Disease

Ralston

2010

Clinic Rev Bone Miner Metab

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Osteoporosis is a common disease with a strong genetic component characterized by reduced bone mass and increased risk of fragility fractures. Twin and family studies have shown that bone mineral density (BMD) and other determinants of fracture risk such as ultrasound properties of bone, skeletal geometry, and bone turnover have a significant heritable component. Osteoporotic fractures also have a genetic component but heritability reduces dramatically with increasing age. Many different genetic variants contribute to the regulation of these phenotypes; most are common variants of small effect size, but there is evidence that rare variants of large effect size also contribute in some individuals. Genome wide association studies have recently been successfully employed to identifying genes that predispose to osteoporosis, although some of these had already been identified through the study of rare bone diseases. Although there has been extensive progress in understanding the genetic basis of osteoporosis over the past 10 years, most of the genetic variants that regulate bone mass remained to be discovered.

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Interspecies synteny mapping identifies a quantitative trait locus for bone mineral density on human chromosome Xp22

Cited by 21 publications

References 28 publications

Contribution of Gender‐Specific Genetic Factors to Osteoporosis Risk

Contribution of Gender‐Specific Genetic Factors to Osteoporosis Risk

A novel locus on the X chromosome regulates post-maturity bone density changes in mice

Osteoporosis as an Hereditary Disease

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