- Bone mineral density
Background: Chromosome 11q has not only been found to contain mutations responsible for the several Mendelian disorders of the skeleton, but it has also been linked to bone mineral density (BMD) variation in several genome-wide linkage studies. Furthermore, quantitative trait loci (QTL) affecting BMD in inbred mice and baboons have been mapped to a region syntenic to human chromosome 11q. The aim of the present study is to determine whether there is a QTL for BMD variation on chromosome 11q in the Chinese population. Methods: Nineteen microsatellite markers were genotyped for a 75 cM region on 11q13-25 in 306 Chinese families with 1,459 subjects. BMD (g/cm2) was measured by DXA. Linkage analyses were performed using the variance component linkage analysis method implemented in Merlin software. Results: For women, a maximum LOD score of 1.62 was achieved at 90.8 cM on 11q21 near the marker D11S4175 for femoral neck BMD; LOD scores greater than 1.0 were observed on 11q13 for trochanter BMD. For men, a maximum LOD score of 1.57 was achieved at 135.8 cM on 11q24 near the marker D11S4126 for total hip BMD. Conclusion: We have not only replicated the previous linkage finding on chromosome 11q but also identified two sex-specific QTL that contribute to BMD variation in Chinese women and men.
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- Huang QY, Kung AWC: Genetics of osteoporosis. Mol Genet Metab 2006;88:295–306.
- Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D, Zacharin M, Oexle K, Marcelino J, Suwairi W, Heeger S, Sabatakos G, Apte S, Adkins WN, Allgrove J, Arslan-Kirchner M, Batch JA, Beighton P, Black GC, Boles RG, Boon LM, Borrone C, Brunner HG, Carle GF, Dallapiccola B, De Paepe A, Floege B, Halfhide ML, Hall B, Hennekam RC, Hirose T, Jans A, Juppner H, Kim CA, Keppler-Noreuil K, Kohlschuetter A, LaCombe D, Lambert M, Lemyre E, Letteboer T, Peltonen L, Ramesar RS, Romanengo M, Somer H, Steichen-Gersdorf E, Steinmann B, Sullivan B, Superti-Furga A, Swoboda W, van den Boogaard MJ, Van Hul W, Vikkula M, Votruba M, Zabel B, Garcia T, Baron R, Olsen BR, Warman ML: LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 2001;107:513–523.
- Little RD, Carulli JP, Del Mastro RJ, Dupuis J, Osborne M, Folz C, Manning SP, Swain PM, Zhao SC, Eustace B, Lappe MM, Spitzer L, Zweier S, Braunschweiger K, Benchekroun Y, Hu X, Adair R, Chee L, FitzGerald MG, Tulig C, Caruso A, Tzellas N, Bawa A, Franklin B, McGuire S, Nogues X, Gong G, Allen KM, Anisowicz A, Morales AJ, Lomedico PT, Recker SM, Van Eerdewegh P, Recker RR, Johnson ML: A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet2002;70:11–19.
- Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP: High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 2002;346:1513–1521.
- Koay MA, Woon PY, Zhang Y, Miles LJ, Duncan EL, Ralston SH, Compston JE, Cooper C, Keen R, Langdahl BL, MacLelland A, O’Riordan J, Pols HA, Reid DM, Uitterlinden AG, Wass JA, Brown MA: Influence of LRP5 polymorphisms on normal variation in BMD. J Bone Miner Res 2004;19:1619–1627.
- Urano T, Shiraki M, Ezura Y, Fujita M, Sekine E, Hoshino S, Hosoi T, Orimo H, Emi M, Ouchi Y, Inoue S: Association of a single-nucleotide polymorphism in low-density lipoprotein receptor-related protein 5 gene with bone mineral density. J Bone Miner Metab 2004;22:341–345.
- Koh JM, Jung MH, Hong JS, Park HJ, Chang JS, Shin HD, Kim SY, Kim GS: Association between bone mineral density and LDL receptor-related protein 5 gene polymorphisms in young Korean men. J Korean Med Sci 2004;19:407–412.
- Mizuguchi T, Furuta I, Watanabe Y, Tsukamoto K, Tomita H, Tsujihata M, Ohta T, Kishino T, Matsumoto N, Minakami H, Niikawa N, Yoshiura K: LRP5, low-density-lipoprotein-receptor-related protein 5, is a determinant for bone mineral density. J Hum Genet 2005;49:80–86.
- Ferrari SL, Deutsch S, Choudhury U, Chevalley T, Bonjour JP, Dermitzakis ET, Rizzoli R, Antonarakis SE: Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with variation in vertebral bone mass, vertebral bone size, and stature in whites. Am J Hum Genet 2004;74:866–875.
- Koller DL, Ichikawa S, Johnson ML, Lai D, Xuei X, Edenberg HJ, Conneally PM, Hui SL, Johnston CC, Peacock M, Foroud T, Econs MJ: Contribution of the LRP5 gene to normal variation in peak BMD in women. J Bone Miner Res 2005;20:75–80.
- Zhang ZL, Qin YJ, He JW, Huang QR, Li M, Hu YQ, Liu YJ: Association of polymorphisms in low-density lipoprotein receptor-related protein 5 gene with bone mineral density in postmenopausal Chinese women. Acta Pharmacol Sin 2005;26:1111–1116.
- Bollerslev J, Wilson SG, Dick IM, Islam FM, Ueland T, Palmer L, Devine A, Prince RL: LRP5 gene polymorphisms predict bone mass and incident fractures in elderly Australian women. Bone 2005;36:599–606.
- Frattini A, Orchard PJ, Sobacchi C, Giliani S, Abinun M, Mattsson JP, Keeling DJ, Andersson AK, Wallbrandt P, Zecca L, Notarangelo LD, Vezzoni P, Villa A: Defects in TCIRGI subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat Genet 2000;25:343–346.
- Sobacchi C, Vezzoni P, Reid DM, McGuigan FE, Frattini A, Mirolo M, Albhaga OM, Musio A, Villa A, Ralston SH: Association between a polymorphism affecting an AP1 binding site in the promoter of the TCIRG1 gene and bone mass in women. Calcif Tissue Int 2004;74:35–41.
- Koller DL, Rodriguez LA, Christian JC, Slemenda CW, Econs MJ, Hui SL, Morin P, Conneally PM, Joslyn G, Curran ME, Peacock M, Johnston CC, Foroud T: Linkage of a QTL contributing to normal variation in bone mineral density to chromosome 11q12–13. J Bone Miner Res 1998;13:1903–1908.
- Koller DL, Econs MJ, Morin PA, Christian JC, Hui SL, Parry P, Curran ME, Rodriguez LA, Conneally PM, Joslyn G, Peacock M, Johnston CC, Foroud T: Genome scan for QTLs contributing to Normal Variation in Bone Mineral Density and Osteoporosis. J Clin Endocrinol Metab 2000;85:3116–3120.
- Peacock M, Koller DL, Hui SL, Johnston CC, Foroud T, Econs MJ: Peak bone mineral density at the hip is linked to chromosomes 14q and 15q. Osteoporos Int 2004;15:489–496.
- Devoto M, Shimoya K, Caminis J, Ott J, Tenenhouse A, Whyte MP, Sereda L, Hall S, Considine E, Williams CJ, Tromp G, Kuivaniemi H, Ala-Kokko L, Prockop DJ, Spotila LD: First-stage autosomal genome screen in extended pedigrees suggests genes predisposing to low bone mineral density on chromosomes 1p, 2p and 4q. Eur J Hum Genet 1998;6:151–157.
- Devoto M, Spotila LD, Stabley DL, Wharton GN, Rydbeck H, Korkko J, Kosich R, Prockop D, Tenenhouse A, Sol-Church K: Univariate and bivariate variance component linkage analysis of a whole-genome scan for loci contributing to bone mineral density. Eur J Hum Genet 2005;13:781–788.
- Shen H, Zhang YY, Long JR, Xu FH, Liu YZ, Xiao P, Zhao LJ, Xiong DH, Liu YJ, Dvornyk V, Rocha-Sanchez S, Liu PY, Li JL, Conway T, Davies KM, Recker RR, Deng HW: A genome-wide linkage scan for bone mineral density in an extended sample: evidence for linkage on 11q23 and xq27. J Med Genet 2004;41:743–751.
- Wynne F, Drummond FJ, Daly M, Brown M, Shanahan F, Molloy MG, Quane KA: Suggestive linkage of 2p22–25 and 11q12–13 with low bone mineral density at the lumbar spine in the Irish population. Calcif Tissue Int 2003;72:651–658.
- Livshits G, Trofimov S, Malkin I, Kobyliansky E: Transmission disequilibrium test for hand bone mineral density and 11q12–13 chromosomal segment. Osteoporos Int 2002;13:461–467.
- Klein RF, Mitchell SR, Phillips TJ, Belknap JK, Orwoll ES: Quantitative trait loci affecting peak bone mineral density in mice. J Bone Miner Res 1998;13:1648–1656.
- Havill LM, Mahaney MC, Cox LA, Morin PA, Joslyn G, Rogers J: A Quantitative trait locus for normal variation in forearm bone mineral density in pedigreed baboons maps to the ortholog of human chromosome 11q. J Clin Endocrinol Metab 2005;90:3638–3645.
- Kung AWC, Yeung SCC, Lau KS: Vitamin D receptor gene polymorphisms and peak bone mass in southern Chinese women. Bone 1998;22:389–393.
- Abecasis GR, Cherny SS, Cookson WO, Cardon LR: Merlin – rapid analysis of dense genetic map using sparse gene flow trees. Nat Genet 2002;30:97–101.
- Deng HW, Xu FH, Conway T, Deng XT, Li JL, Davies KM, Deng H, Johnson M, Recker RR: Is population bone mineral density variation linked to the marker D11S987 on chromosome 11q12–13? J Clin Endocrinol Metab 2001;86:3735–3741.
- Lander E, Kruglyak L: Genetic dissection of complex traits: Guidelines for interpretating the reporting results. Nat Genet 1995;11:241–247.
- Ng MYM, Sham PC, Paterson AD, Chan V, Kung AWC: Effects of environmental factors and gender on the heritability of bone mineral density and bone size. Ann Hum Genet 2006;70:428–438.
- Sham PC, Purcell S, Cherny SS, Abecasis GR: Powerful regression-based quantitative-trait linkage analysis of general pedigrees. Am J Hum Genet 2002;71:238–253.
- Weiss LA, Pan L, Abney M, Ober C: The sex-specific genetic architecture of quantitative traits in humans. Nat Genet 2006;38:218–222.
- Orwoll ES, Belknap JK, Klein RF: Gender specificity in the genetic determinants of peak bone mass. J Bone Miner Res 2001;16:1962–1971.
- Naganathan V, Macgregor A, Snieder H, Nguyen T, Spector T, Sambrook P: Gender differences in the genetic factors responsible for variation in bone density and ultrasound. J Bone Miner Res 2002;17:725–733.
- Karasik D, Cupples LA, Hannan MT, Kiel DP: Age, gender, and body mass effects on quantitative trait loci for bone mineral density: the Framingham Study. Bone 2003;33:308–316.
- Kammerer CM, Schneider JL, Cole SA, Hixson JE, Samollow PB, O’Connell JR, Perez R, Dyer TD, Almasy L, Blangero J, Bauer RL, Mitchell BD: Quantitative trait loci on chromosome 2p, 4p, and 13q influence bone mineral density of the forearm and hip in Mexican American. J Bone Miner Res 2003;18:2245–2252.
- Ralston SH, Galwey N, MacKay I, Albagha OME, Cardon L, Compston JE, Cooper C, Duncan E, Keen R, Langdahl B, McLellan A, O’Riordan J, Pols HA, Reid DM, Uitterlinden AG, Wass J, Bennett ST: Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS study. Hum Mol Genet 2005;14:943–951.
- Peacock M, Koller DL, Fishburn T, Krishnan S, Lai D, Hui SL, Johnston CC, Foroud T, Econs MJ: Sex-specific and non-sex-specific quantitative trait loci contribute to normal variation in bone mineral density in men. J Clin Endocrinol Metab 2005;90:3060–3066.
- International HapMap Consortium: A haplotype map of the human genome. Nature 2005;437:1299–1320.
Annie W.C. Kung, MD
Department of Medicine
The University of Hong Kong
Hong Kong, SAR (China)
Tel. +852 2855 4769, Fax +852 2816 2187, E-Mail firstname.lastname@example.org
The authors have no conflicts of interest.
Received: March 17, 2006
Accepted after revision: June 7, 2006
Published online: August 21, 2006
Number of Print Pages : 7
Number of Figures : 1, Number of Tables : 1, Number of References : 38
Human Heredity (International Journal of Human and Medical Genetics)
Vol. 61, No. 4, Year 2006 (Cover Date: September 2006)
Journal Editor: Devoto, M. (Philadelphia, Pa.)
ISSN: 0001–5652 (print), 1423–0062 (Online)
For additional information: http://www.karger.com/HHE
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