Linkage and association for bone mineral density and heel ultrasound measurements with a simple tandem repeat polymorphism near the osteocalcin gene in female dizygotic twins.
In this confirmatory candidate gene study, we investigated possible linkage and association for bone density, heel ultrasound and bone turnover with the osteocalcin gene using the nearby (50-180kb) microsatellite marker D1S3737. Non-identical twin sisters aged 18-75 years at first interview were recruited for the study from the St Thomas' UK Adult Twin Registry with 1366 women being genotyped for marker D1S3737. Linkage, allelic association and joint linkage and association tests were carried out using quantitative transmission disequilibrium tests (QTDT), along with post-hoc multivariate tests of linkage and association. Phenotypes tested were bone mineral density (BMD) at the spine, left forearm and left total hip; quantitative ultrasound measurements of the heel including velocity of ultrasound (VOS) and broadband ultrasound attenuation (BUA); and bone turnover markers, urine deoxypyridinoline (DPD), serum osteocalcin, bone specific and total alkaline phosphatase (ALP). BMD and ultrasound variables showed evidence of pleiotropic linkage ( p = 0.05) and association ( p = 0.02) with the marker in postmenopausal women. Bone markers showed little or no evidence of linkage and association for any age group. Evidence for pleiotropic linkage appeared to be strongest for BUA and spine BMD in postmenopausal women. The univariate test statistic for BUA was chi(2)(1)=12.8 ( p = 0.0003), equivalent to a LOD score of 2.8. DPD showed borderline evidence of linkage to the marker for women of all ages. Multivariate model-fitting showed allele 10 to be negatively associated with BMD, VOS and BUA via a common pathway, suggesting the putative functional polymorphism affects both bone content and structure through shared underlying metabolic pathways. It is likely that the alleles are in linkage disequilibrium with functional polymorphism(s) in or nearby the osteocalcin gene, which may contribute to the onset of osteoporosis.
Twin Research and Genetic Epidemiology Unit, St Thomas' Hospital, London SE1 7EH, UK. toby.andrew@kcl.ac.uk
T
T
Andrew
Y T
YT
Mak
P
P
Reed
A J
AJ
MacGregor
T D
TD
Spector
D000328:Adult; D015519:Bone Density / Q000235:genetics*; D016723:Bone Remodeling / Q000235:genetics; D002111:Calcaneus / Q000000981:diagnostic imaging*; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D008875:Middle Aged; D015999:Multivariate Analysis; D015675:Osteocalcin / Q000235:genetics*; D011110:Polymorphism, Genetic; D020080:Tandem Repeat Sequences / Q000235:genetics*; D014429:Twins, Dizygotic; D014463:Ultrasonography
D015675:Osteocalcin