Abstract
Aim:
To identify pleiotropic quantitative trait loci (QTL) influencing bone size (BS) at different skeletal sites in Caucasians.
Methods:
In a sample containing 3899 Caucasians from 451 pedigrees, 410 microsatellite markers spaced ∼8.9 cM apart across the human genome were genotyped. Phenotypical and genetic correlations of BS at lumbar spine, hip (femoral neck, trochanter, and intertrochanter regions), and wrist (ultradistal, mid-distal, and one-third distal sites) were determined using bivariate quantitative genetic analysis. A principal component analysis (PCA) was performed to obtain principal component (PC) factors that were then subjected to variance components linkage analysis to identify regions linked to the PC.
Results:
Genetic correlations of BS at different skeletal sites ranged fr om 0.40 to 0.7 9 (P<0.001). The PCA yielded a PC named PCtotal, which explained up to 76% of the total (co)variation of all the BS at the 7 skeletal sites for the whole sample. We identified a QTL influencing the BS of multiple skeletal sites on chromosome 7 at 140 cM [logarithm of odds (LOD)=2.85] in the overall sample. Sex-specific evidence for linkage was observed on chromosome 11 at 53 cM (LOD =2.82) in the male-only data subset.
Conclusion:
Our study identified several genomic regions that may have pleiotropic effects on different skeletal sites. These regions may contain genes that play a critical role in overall bone development and osteoporosis at multiple skeletal sites, hence are biologically and clinically important.
Similar content being viewed by others
Article PDF
References
Peacock M, Turner CH, Liu G, Manatunga AK, Timmerman L, Johnston CC . Better discrimination of hip fracture using bone density, geometry and architecture. Osteoporos Int 1995; 5: 167–73.
Vega E, Ghiringhelli G, Mautalen C, Rey VG, Scaglia H, Zylberstein C . Bone mineral density and bone size in men with primary osteoporosis and vertebral fractures. Calcif Tissue Int 1998; 62: 465–9.
Seeman E, Duan Y, Fong C, Edmonds J . Fracture site-specific deficits in bone size and volumetric density in men with spine or hip fractures. J Bone Miner Res 2001; 16: 120–7.
Ammann P, Rizzoli R . Bone strength and its determinants. Osteoporos Int 2003; 14 Suppl 3: S13–18.
Stone KL, Seeley DG, Lui LY, Cauley JA, Ensrud K, Browner WS, et al. BMD at multiple sites and risk of fracture of multiple types: long-term results from the Study of Osteoporotic Fractures. J Bone Miner Res 2003; 18: 1947–54.
Liu YJ, Shen H, Xiao P, Xiong DH, Li LH, Recker RR, et al. Molecular genetic studies of gene identification for osteoporosis: a 2004 update. J Bone Miner Res 2006; 21: 1511–35.
Deng HW, Deng XT, Conway T, Xu FH, Heaney R, Recker RR . Determination of bone size of hip, spine, and wrist in human pedigrees by genetic and lifestyle factors. J Clin Densitom 2002; 5: 45–56.
Jian WX, Long JR, Deng HW . High heritability of bone size at the hip and spine in Chinese. J Hum Genet 2004; 49: 87–91.
Long JR, Liu PY, Lu Y, Xiong DH, Zhao LJ, Zhang YY, et al. Association between COL1A1 gene polymorphisms and bone size in Caucasians. Eur J Hum Genet 2004; 12: 383–8.
Lei SF, Deng FY, Xiao SM, Chen XD, Deng HW . Association and haplotype analyses of the COL1A2 and ER-alpha gene polymorphisms with bone size and height in Chinese. Bone 2005; 36: 533–41.
Ferrari SL, Deutsch S, Choudhury U, Chevalley T, Bonjour JP, Dermitzakis ET, et al. Polymorphisms in the low-density lipo-protein 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: 866–75.
Liu YJ, Liu XH, Lei SF, Li MX, Deng HW . Alpha2-HS glycoprotein gene is associated with bone size at the hip in Chinese. Yi Chuan Xue Bao 2005; 32: 1128–35.
Schuit SC, van Meurs JB, Bergink AP, van der KM, Fang Y, Leusink G, et al. Height in pre- and postmenopausal women is influenced by estrogen receptor alpha gene polymorphisms. J Clin Endocrinol Metab 2004; 89: 303–9.
Zmuda JM, Cauley JA, Kuller LH, Ferrell RE . A common promotor variant in the cytochrome P450c17alpha (CYP17) gene is associated with bioavailability testosterone levels and bone size in men. J Bone Miner Res 2001; 16: 911–7.
Huang QY, Xu FH, Shen H, Deng HY, Conway T, Liu YJ, et al. Genome scan for QTLs underlying bone size variation at 10 refined skeletal sites: genetic heterogeneity and the significance of phenotype refinement. Physiol Genomics 2004; 17: 326–31.
Deng HW, Shen H, Xu FH, Deng H, Conway T, Liu YJ, et al. Several genomic regions potentially containing QTLs for bone size variation were identified in a whole-genome linkage scan. Am J Med Genet A 2003; 119: 121–31.
Shen H, Long JR, Xiong DH, Guo YF, Xiao P, Liu YZ, et al. A genomewide scan for quantitative trait loci underlying areal bone size variation in 451 Caucasian families. J Med Genet 2006; 43: 873–80.
Tommasini SM, Nasser P, Jepsen KJ . Sexual dimorphism affects tibia size and shape but not tissue-level mechanical properties. Bone 2007; 40: 498–505.
Beck TJ, Ruff CB, Shaffer RA, Betsinger K, Trone DW, Brodine SK . Stress fracture in military recruits: gender differences in muscle and bone susceptibility factors. Bone 2000; 27: 437–44.
Cummings SR, Melton LJ . Epidemiology and outcomes of osteoporotic fractures. Lancet 2002; 359: 1761–7.
Kellie SE, Brody JA . Sex-specific and race-specific hip fracture rates. Am J Public Health 1990; 80: 326–8.
Deng HW, Deng H, Liu YJ, Liu YZ, Xu FH, Shen H, et al. A genomewide linkage scan for quantitative-trait loci for obesity phenotypes. Am J Hum Genet 2002; 70: 1138–51.
Deng HW, Chen WM, Conway T, Zhou Y, Davies KM, Stegman MR, et al. Determination of bone mineral density of the hip and spine in human pedigrees by genetic and life-style factors. Genet Epidemiol 2000; 19: 160–77.
Li JL, Deng H, Lai DB, Xu F, Chen J, Gao G, et al. Toward high-throughput genotyping: dynamic and automatic software for manipulating large-scale genotype data using fluorescently labeled dinucleotide markers. Genome Res 2001; 11: 1304–14.
O'Connell JR, Weeks DE . PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 1998; 63: 259–66.
Abecasis GR, Cherny SS, Cookson WO, Cardon LR . Merlin- rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002; 30: 97–101.
Almasy L, Blangero J . Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 1998; 62: 1198–211.
Yang YJ, Dvornyk V, Jian WX, Xiao SM, Deng HW . Genetic and environmental correlations between bone phenotypes and anthro-pometric indices in Chinese. Osteoporos Int 2005; 16: 1134–40.
Karasik D, Cupples LA, Hannan MT, Kiel DP . Genome screen for a combined bone phenotype using principal component analysis: the Framingham study. Bone 2004; 34: 547–56.
Blangero J, Williams JT, Almasy L . Robust LOD scores for variance component-based linkage analysis. Genet Epidemiol 2000; 19 Suppl 1: S8–14.
Lander E, Kruglyak L . Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995; 11: 241–7.
Koller DL, White KE, Liu G, Hui SL, Conneally PM, Johnston CC, et al. Linkage of structure at the proximal femur to chromosomes 3, 7, 8, and 19. J Bone Miner Res 2003; 18: 1057–65.
Kato R, Kishibayashi J, Shimokawa O, Harada N, Niikawa N, Matsumoto N . Congenital glaucoma and Silver-Russell pheno-type associated with partial trisomy 7q and monosomy 15q. Am J Med Genet 2001; 104: 319–22.
Holloway WR, Collier FM, Aitken CJ, Myers DE, Hodge JM, Malakellis M, et al. Leptin inhibits osteoclast generation. J Bone Miner Res 2002; 17: 200–9.
Livshits G, Pantsulaia I, Trofimov S, Kobyliansky E . Genetic variation of circulating leptin is involved in genetic variation of hand bone size and geometry. Osteoporos Int 2003; 14: 476–83.
Foldes J, Shih MS, Levy J . Bone structure and calcium metabolism in obese Zucker rats. Int J Obes Relat Metab Disord 1992; 16: 95–102.
Elefteriou F, Takeda S, Ebihara K, Magre J, Patano N, Kim CA, et al. Serum leptin level is a regulator of bone mass. Proc Natl Acad Sci USA 2004; 101: 3258–63.
Suresh R, Ambrose N, Roe C, Pluzhnikov A, Wittke-Thompson JK, Ng MC, et al. New complexities in the genetics of stuttering: significant sex-specific linkage signals. Am J Hum Genet 2006; 78: 554–63.
Weiss LA, Pan L, Abney M, Ober C . The sex-specific genetic architecture of quantitative traits in humans. Nat Genet 2006; 38: 218–22.
Masinde GL, Wergedal J, Davidson H, Mohan S, Li R, Li X, et al. Quantitative trait loci for periosteal circumference (PC): identification of single loci and epistatic effects in F2 MRL/SJL mice. Bone 2003; 32: 554–60.
Morimoto K, Shimizu T, Furukawa K, Morio H, Kurosawa H, Shirasawa T . Transgenic expression of the EXT2 gene in developing chondrocytes enhances the synthesis of heparan sulfate and bone formation in mice. Biochem Biophys Res Commun 2002; 292: 999–1009.
Stickens D, Zak BM, Rougier N, Esko JD, Werb Z . Mice deficient in Ext2 lack heparan sulfate and develop exostoses. Development 2005; 132: 5055–68.
Signori E, Massi E, Matera MG, Poscente M, Gravina C, Falcone G, et al. A combined analytical approach reveals novel EXT1/2 gene mutations in a large cohort of Italian multiple osteochondromas patients. Genes Chromosomes Cancer 2007; 46: 470–7.
Author information
Authors and Affiliations
Corresponding author
Additional information
The study was partially supported by grants from NIH (K01 AR02170-01, R01 AR45349-01, and R01 GM60402-01 A1), and also benefited from grants from the National Science Foundation of China (No 30230210, 30470534, and 30600364) and a Scientific Research Fund of Hunan Provincial Education Department (No 05B037).
Rights and permissions
About this article
Cite this article
Tan, Lj., Liu, Yz., Xiao, P. et al. Evidence for major pleiotropic effects on bone size variation from a principal component analysis of 451 Caucasian families. Acta Pharmacol Sin 29, 745–751 (2008). https://doi.org/10.1111/j.1745-7254.2008.00806.x
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1111/j.1745-7254.2008.00806.x
Keywords
This article is cited by
-
Pleiotropic loci underlying bone mineral density and bone size identified by a bivariate genome-wide association analysis
Osteoporosis International (2020)
-
Suggestion of GLYAT gene underlying variation of bone size and body lean mass as revealed by a bivariate genome-wide association study
Human Genetics (2013)
-
Genome-wide association study identifies HMGN3 locus for spine bone size variation in Chinese
Human Genetics (2012)
-
Porcine muscle sensory attributes associate with major changes in gene networks involving CAPZB, ANKRD1, and CTBP2
Functional & Integrative Genomics (2009)