A Genome-Screen of a Large Twin Cohort Reveals Linkage for Quantitative Ultrasound of the Calcaneus to 2q33–37 and 4q12–21

Wilson, Scott G.; Reed, P.; Andrew, Toby; Barber, Mathew; Lindersson, M.; Langdown, M; Thompson, David V.; Thompson, Elaine; Bailey, Mark E.S.; Chiano, Mathias; Kleyn, Patrick; Spector, TD

doi:10.1359/jbmr.0301224

Cited by 37 publications

(29 citation statements)

References 35 publications

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“…Subjects were assessed for an extensive range of phenotypes. Genome-wide linkage scans for bone 21,22 and eye disease 23 have been reported previously for this cohort. Here we report the data from genome-wide linkage scans for obesity-related traits (n ¼ 2188 individuals).…”

Section: Subjects and Clinical Assessmentmentioning

confidence: 78%

Linkage and potential association of obesity-related phenotypes with two genes on chromosome 12q24 in a female dizygous twin cohort

et al. 2006

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Obesity is a multifactorial disorder with a complex phenotype. It is a significant risk factor for diabetes and hypertension. We assessed obesity-related traits in a large cohort of twins and performed a genome-wide linkage scan and positional candidate analysis to identify genes that play a role in regulating fat mass and distribution in women. Dizygous female twin pairs from 1094 pedigrees were studied (mean age 47.0711.5 years (range 18 -79 years)). Nonparametric multipoint linkage analyses showed linkage for central fat mass to 12q24 (141 cM) with LOD 2.2 and body mass index to 8q11 (67 cM) with LOD 1.3, supporting previously established linkage data. Novel areas of suggestive linkage were for total fat percentage at 6q12 (LOD 2.4) and for total lean mass at 2q37 (LOD 2.4). Data from follow-up fine mapping in an expanded cohort of 1243 twin pairs reinforced the linkage for central fat mass to 12q24 (LOD 2.6; 143 cM) and narrowed the -1 LOD support interval to 22 cM. In all, 45 single-nucleotide polymorphisms (SNPs) from 26 positional candidate genes within the 12q24 interval were then tested for association in a cohort of 1102 twins. Single-point Monks -Kaplan analysis provided evidence of association between central fat mass and SNPs in two genes -PLA2G1B (P ¼ 0.0067) and P2RX4 (P ¼ 0.017). These data provide replication and refinement of the 12q24 obesity locus and suggest that genes involved in phospholipase and purinoreceptor pathways may regulate fat accumulation and distribution.

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Section: Subjects and Clinical Assessmentmentioning

confidence: 78%

Linkage and potential association of obesity-related phenotypes with two genes on chromosome 12q24 in a female dizygous twin cohort

et al. 2006

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“…Linkage studies have been spectacularly successful in identifying the genes that are responsible for rare, monogenic bone diseases characterized by abnormalities of bone mass such as osteopetrosis and sclerosing bone dysplasias (Janssens and Van Hul 2002;Balemans et al 2005). Linkage analysis has also been applied to the identification of chromosomal regions that harbor genes that regulate quantitative traits such as bone mass, bone geometry, and ultrasound properties of bone in the normal population (Koller et al 2003;Wilson et al 2003Wilson et al , 2004Ralston 2005). Linkage studies in osteoporosis classically involved genotyping a series of polymorphic microsatellite markers, typically spread at 10-cM intervals throughout the genome, and relating inheritance of alleles to the inheritance of bone mass within the family members.…”

Section: Linkage Analysis In Humansmentioning

confidence: 99%

Genetic regulation of bone mass and susceptibility to osteoporosis

Ralston¹,

Crombrugghe²

2006

Genes Dev.

291

229

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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 the heritability of bone mineral density (BMD) and other determinants of fracture risksuch as ultrasound properties of bone, skeletal geometry, and bone turnover-is high, although heritability of fracture is modest. Many different genetic variants of modest effect size are likely to contribute to the regulation of these phenotypes by interacting with environmental factors such as diet and exercise. Linkage studies in rare Mendelian bone diseases have identified several previously unknown genes that play key roles in regulating bone mass and bone turnover. In many instances, subtle polymorphisms in these genes have also been found to regulate BMD in the general population. Although there has been extensive progress in identifying the genetic variants that regulate susceptibility to osteoporosis, most of the genes and genetic variants that regulate bone mass and susceptibility to osteoporosis remain to be discovered.Osteoporosis is characterized by reduced bone mass, alterations in the microarchitecture of bone tissue, reduced bone strength, and an increased risk of fracture (Kanis et al. 1994). Osteoporosis is a common condition that affects up to 30% of women and 12% of men at some point in life. The prevalence of osteoporosis increases with age due to an imbalance in the rate at which bone is removed and replaced during the bone remodeling cycle, which is an important physiological process that is essential for maintenance of a healthy skeleton. Many factors influence the risk of osteoporosis-including diet, physical activity, medication use, and coexisting diseases-but one of the most important clinical risk factors is a positive family history, emphasizing the importance of genetics in the pathogenesis of osteoporosis. In this article, we first review the evidence for a genetic contribution to osteoporosis and related phenotypes, and discuss the mechanisms by which mutations and polymorphisms in genes that regulate susceptibility to osteoporosis affect major signaling pathways in bone. Genetic influences on osteoporosisGenetic factors have long been recognized as playing an important role in the pathogenesis of osteoporosis. Evidence from twin and family studies suggests that between 50% and 85% of the variance in peak bone mass is genetically determined, depending on skeletal site and the age of the subjects studied (Smith et al. 1973;Pocock et al. 1987;Krall and Dawson-Hughes 1993;Gueguen et al. 1995). Heritability studies have also shown evidence of significant genetic effects on other key determinants of osteoporotic fracture risk, including quantitative ultrasound properties of bone (Arden et al. 1996), femoral neck geometry (Arden et al. 1996), muscle strength (Arden and Spector 1997), bone turnover markers (Hunter et al. 2001), and body mass index (Kaprio et al. 1995). The role of genetic factors in the pathogenesis of bon...

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“…For example, genome-wide linkage scans have identified several QTL that strongly influence hip geometry (Koller et al 2001), while others have been performed that have identified QTL that regulate the quantitative ultrasound properties of bone (Wilson et al 2004).…”

Section: Human Linkage Studiesmentioning

confidence: 99%

Genetics of osteoporosis

Ralston

2007

Proc. Nutr. Soc.

107

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Osteoporosis is a common disease with a strong genetic component characterised by reduced bone mass and an increased risk of fragility fractures. Twin and family studies have shown that genetic factors contribute to osteoporosis by influencing bone mineral density (BMD), and other phenotypes that are associated with fracture risk, although the heritability of fracture itself is modest. Linkage studies have identified several quantitative trait loci that regulate BMD but most causal genes remain to be identified. In contrast, linkage studies in monogenic bone diseases have been successful in gene identification, and polymorphisms in many of these genes have been found to contribute to the regulation of bone mass in the normal population. Population-based studies have identified polymorphisms in several candidate genes that have been associated with bone mass or osteoporotic fracture, although individually these polymorphisms only account for a small amount of the genetic contribution to BMD regulation. Environmental factors such as diet and physical activity are also important determinants of BMD, and in some cases specific nutrients have been found to interact with genetic polymorphisms to regulate BMD. From a clinical standpoint, advances in knowledge about the genetic basis of osteoporosis are likely to be important in increasing the understanding of the pathophysiology of the disease; providing new genetic markers with which to assess fracture risk and in identifying genes and pathways that form molecular targets for the design of the next generation of drug treatments.

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A Genome-Screen of a Large Twin Cohort Reveals Linkage for Quantitative Ultrasound of the Calcaneus to 2q33–37 and 4q12–21

Cited by 37 publications

References 35 publications

Linkage and potential association of obesity-related phenotypes with two genes on chromosome 12q24 in a female dizygous twin cohort

Linkage and potential association of obesity-related phenotypes with two genes on chromosome 12q24 in a female dizygous twin cohort

Genetic regulation of bone mass and susceptibility to osteoporosis

Genetics of osteoporosis

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