Top

Osteoporosis International

Published in:

01-12-2007 | Original Article

Family-based association study of ROR2 polymorphisms with an array of radiographic hand bone strength phenotypes

Authors: S. Ermakov, I. Malkin, M. Keter, E. Kobyliansky, G. Livshits

Published in: Osteoporosis International | Issue 12/2007

Abstract

Summary

For the first time the study provides evidence of association of radiographic hand bone length (BL) and bone mineral density (BMD) with polymorphisms in ROR2 gene that plays important role in skeletal development. This contributes to better understanding of bone physiology and may have application in clinical practice.

Introduction and hypothesis

Bone size and bone mineral density (BMD) are major determinants of bone strength. Identification of genes affecting these traits’ variability is important for better understanding of normal and pathological bone physiology and identification of the individuals at risk for bone fracture. This study tested the hypothesis of association of radiographic hand bone length (BL) and BMD with polymorphisms in ROR2 gene that is important in skeletal development.

Methods

Nineteen ROR2 SNPs were genotyped in 705 individuals, belonging to 212 nuclear families. The four tagging SNPs (tSNPs) and the pairwise haplotypes between adjacent tSNPs were tested for association with series of hand BL and BMD measurements, adjusted for covariates, using family-based association tests.

Results

We observed significant associations with BL and BMD mean values for all 18 studied hand bones (p = 0.0080, 0.0030), mean BL and BMD for proximal phalanges (p = 0.0218, 0.0060) and metacarpal bones (p = 0.0014, 0.0004). In the latter, the association remained significant after correction for multiple testing.

Conclusions

The region of the first through the second ROR2 introns is most likely to contain the functional polymorphism/s responsible for the observed associations. Further studies are required to identify the ROR2 functional polymorphism/s affecting bone size and BMD variation.

Lane NE (2006) Epidemiology, etiology, and diagnosis of osteoporosis. Am J Obstet Gynecol 194:3–11CrossRef

Eisman JA (1999) Genetics of osteoporosis. Endocr Rev 20:788–804PubMedCrossRef

Peacock M, Turner CH, Econs MJ et al (2002) Genetics of osteoporosis. Endocr Rev 23:303–326PubMedCrossRef

Livshits G (2005) Genetic epidemiology of skeletal system aging in apparently healthy human population. Mech Ageing Dev 126:269–279PubMedCrossRef

Uitterlinden AG, van Meurs JB, Rivadeneira F et al (2006) Identifying genetic risk factors for osteoporosis. J Musculoskelet Neuronal Interact 6:16–26PubMed

DeChiara TM, Kimble RB, Poueymirou WT et al (2000) Ror2, encoding a receptor-like tyrosine kinase, is required for cartilage and growth plate development. Nat Genet 24:271–274PubMedCrossRef

Billiard J, Way DS, Seestaller-Wehr LM et al (2005) The orphan receptor tyrosine kinase Ror2 modulates canonical Wnt signaling in osteoblastic cells. Mol Endocrinol 19:90–101PubMedCrossRef

Afzal AR, Jeffery S (2003) One gene, two phenotypes: ROR2 mutations in autosomal recessive Robinow syndrome and autosomal dominant brachydactyly type B. Hum Mutat 22:1–11PubMedCrossRef

Patton MA, Afzal AR (2002) Robinow syndrome. J Med Genet 39:305–310PubMedCrossRef

10.

Takeuchi S, Takeda K, Oishi I et al (2000) Mouse Ror2 receptor tyrosine kinase is required for the heart development and limb formation. Genes Cells 5:71–78PubMedCrossRef

11.

Schwabe GC, Tinschert S, Buschow C et al (2000) Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B. Am J Hum Genet 67:822–831PubMedCrossRef

12.

Liu YZ, Xu FH, Shen H et al (2004) Genetic dissection of human stature in a large sample of multiplex pedigrees. Ann Hum Genet 68:472–488PubMedCrossRef

13.

Liu YZ, Xiao P, Guo YF et al (2006) Genetic linkage of human height is confirmed to 9q22 and Xq24. Hum Genet 119:295–304PubMedCrossRef

14.

Livshits G, Karasik D, Kobyliansky E (2002) Complex segregation analysis of the radiographic phalanges bone mineral density and their age related changes. J Bone Miner Res 17:1–10CrossRef

15.

Malkin I, Bigman G, Matias R et al (2006) Age-related changes of bone strength phenotypes: observational follow-up study of hand bone mineral density. Osteoporos Int 12; Epub ahead of print

16.

Bouxsein ML, Michaeli DA, Plass DB et al (1997) Precision and accuracy of computed digital absorptiometry for assessment of bone density of the hand. Osteoporos Int 7:444–449PubMedCrossRef

17.

Malkin I, Ginsburg E (2003) Program package for Mendelian analysis of pedigree data (MAN, Version 6). Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University; Technical Report

18.

Lewontin R (1974) The genetic basis of evolutionary change. Columbia University Press, New York

19.

Melton LJ 3rd, Khosla S, Achenbach SJ et al (2000) Effects of body size and skeletal site on the estimated prevalence of osteoporosis in women and men. Osteoporos Int 11:977–983PubMedCrossRef

20.

Schoenau E, Saggese G, Peter F et al (2004) From bone biology to bone analysis. Horm Res 61:257–269PubMedCrossRef

21.

Malkin I, Karasik D, Livshits G et al (2002) Modeling of age related bone loss using cross-sectional data. Ann Hum Biol 29:256–270PubMedCrossRef

22.

Rice T, Després JP, Daw EW et al (1997) Familial resemblance for abdominal visceral fat: the HERITAGE family study. Int J Obes Relat Metab Disord 21:1024–1031PubMedCrossRef

23.

Horvath S, Xu X, Laird NM (2001) The family based association test method: strategies for studying general genotype-phenotype associations. Eur J Hum Genet 9:301–306PubMedCrossRef

24.

Malkin I, Ginsburg E, Elston RC (2002) Increase in power of transmission disequilibrium tests for quantitative traits. Genet Epidemiol 23:234–244PubMedCrossRef

25.

Abecasis GR, Cardon LR, Cookson WS (2000) A general test of association for quantitative traits in nuclear families. Am J Hum Genet 66:279–292PubMedCrossRef

26.

Malkin I, Dahm S, Suk A et al (2005) Association of ANKH gene polymorphisms with radiographic hand bone size and geometry in a Chuvasha population. Bone 36:365–373PubMedCrossRef

27.

Malkin I, Ermakov S, Kobyliansky E et al (2006) Strong association between polymorphisms in ANKH locus and skeletal size traits. Hum Genet 120:42–51PubMedCrossRef

28.

Benjamini Y, Yekutieli D (2001) The control of the false discovery rate in multiple testing under dependency. Ann Stat 29:1165–1188CrossRef

Title: Family-based association study of ROR2 polymorphisms with an array of radiographic hand bone strength phenotypes
Authors: S. Ermakov
I. Malkin
M. Keter
E. Kobyliansky
G. Livshits
Publication date: 01-12-2007
Publisher: Springer-Verlag
Published in: Osteoporosis International / Issue 12/2007
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-007-0401-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Family-based association study of ROR2 polymorphisms with an array of radiographic hand bone strength phenotypes

Abstract

Summary

Introduction and hypothesis

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Summary

Introduction and hypothesis

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 12/2007

An association between socioeconomic, health and health behavioural indicators and fractures in young adult males

Hip fractures in users of first- vs. second-generation bisphosphonates

Interaction of bone morphogenetic proteins with cells of the osteoclast lineage: review of the existing evidence

Serum insulin-like growth factor-I level is associated with the presence of vertebral fractures in postmenopausal women with type 2 diabetes mellitus

Combining clinical factors and quantitative ultrasound improves the detection of women both at low and high risk for hip fracture

Fractures during growth: potential role of a milk-free diet