A genome-wide linkage scan for low spinal bone mineral density in a single extended family confirms linkage to 1p36.3

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Abstract

Osteoporotic fractures are an increasing cause of mortality and morbidity in ageing populations. A major risk determinant for these fractures is bone mineral density (BMD). Variation on BMD is thought, on the basis of twin and family studies, to be subject to a large amount of genetic variation and it has been hypothesised that this may be due to the influence of multiple genes. However, in families showing segregation of low or high BMD, single major genes have been shown to play a crucial role. We performed a genome-wide screen using 380 microsatellite markers in a single extended family (n=34) in which early-onset low spinal areal BMD segregates in an autosomal dominant-like fashion. A two-point linkage analysis was performed, revealing a maximum LOD score of 3.07 on 1p36.3 (D1S468), confirming results of previous linkage studies of BMD, while no other suggestive linkage peaks (LOD>2.2) were detected elsewhere in the genome. Microsatellite markers were subsequently genotyped for a ±6.9 Mb region surrounding D1S468. This revealed critical recombination events restricting the candidate region to 1.2 Mb and 19 genes. Sequencing analysis of the coding region of candidate genes WDR8 and EGFL3 revealed no mutations or disease-associated polymorphisms. Our results provide some evidence supporting the hypothesis that there are genetic determinants for spinal BMD on 1p36.3. Although no specific disease causing mutation has yet been found, the delineation of a relatively small candidate region in a single extended family opens perspectives to identify a major gene for spinal BMD.

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References

  1. 1

    Deng HW, Chen WM, Conway T 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: 160–177.

  2. 2

    Christian JC, Yu PL, Slemenda CW, Johnston Jr CC : Heritability of bone mass: a longitudinal study in aging male twins. Am J Hum Genet 1989; 44: 429–433.

  3. 3

    Flicker L, Hopper JL, Rodgers L, Kaymakci B, Green RM, Wark JD : Bone density determinants in elderly women: a twin study. J Bone Miner Res 1995; 10: 1607–1613.

  4. 4

    Gueguen R, Jouanny P, Guillemin F, Kuntz C, Pourel J, Siest G : Segregation analysis and variance components analysis of bone mineral density in healthy families. J Bone Miner Res 1995; 10: 2017–2022.

  5. 5

    Pocock NA, Eisman JA, Hopper JL, Yeates MG, Sambrook PN, Eberl S : Genetic determinants of bone mass in adults. A twin study. J Clin Invest 1987; 80: 706–710.

  6. 6

    Slemenda CW, Christian JC, Williams CJ, Norton JA, Johnston Jr CC : Genetic determinants of bone mass in adult women: a re-evaluation of the twin model and the potential importance of gene interaction on heritability estimates. J Bone Miner Res 1991; 6: 561–567.

  7. 7

    Liu YJ, Shen H, Xiao P et al: Molecular genetic studies of gene identification for osteoporosis: a 2004 update. J Bone Miner Res 2006; 21: 1511–1535.

  8. 8

    Shen H, Liu Y, Liu P, Recker RR, Deng HW : Nonreplication in genetic studies of complex diseases – lessons learned from studies of osteoporosis and tentative remedies. J Bone Miner Res 2005; 20: 365–376.

  9. 9

    Byers PH : Brittle bones – fragile molecules: disorders of collagen gene structure and expression. Trends Genet 1990; 6: 293–300.

  10. 10

    Gong Y, Slee RB, Fukai N et al: LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 2001; 107: 513–523.

  11. 11

    Cardon LR, Garner C, Bennett ST et al: Evidence for a major gene for bone mineral density in idiopathic osteoporotic families. J Bone Miner Res 2000; 15: 1132–1137.

  12. 12

    Deng HW, Livshits G, Yakovenko K et al: Evidence for a major gene for bone mineral density/content in human pedigrees identified via probands with extreme bone mineral density. Ann Hum Genet 2002; 66: 61–74.

  13. 13

    Livshits G, Deng HW, Nguyen TV, Yakovenko K, Recker RR, Eisman JA : Genetics of bone mineral density: evidence for a major pleiotropic effect from an intercontinental study. J Bone Miner Res 2004; 19: 914–923.

  14. 14

    Nguyen TV, Livshits G, Center JR, Yakovenko K, Eisman JA : Genetic determination of bone mineral density: evidence for a major gene. J Clin Endocrinol Metab 2003; 88: 3614–3620.

  15. 15

    Van Pottelbergh I, Goemaere S, Zmierczak H, De Bacquer D, Kaufman JM : Deficient acquisition of bone during maturation underlies idiopathic osteoporosis in men: evidence from a three-generation family study. J Bone Miner Res 2003; 18: 303–311.

  16. 16

    Crabbe P, Balemans W, Willaert A et al: Missense mutations in LRP5 are not a common cause of idiopathic osteoporosis in adult men. J Bone Miner Res 2005; 20: 1951–1959.

  17. 17

    Boivin G, Meunier PJ : Effects of bisphosphonates on matrix mineralization. J Musculoskelet Neuronal Interact 2002; 2: 538–543.

  18. 18

    Carter DR, Bouxsein ML, Marcus R : New approaches for interpreting projected bone densitometry data. J Bone Miner Res 1992; 7: 137–145.

  19. 19

    Tabensky AD, Williams J, DeLuca V, Briganti E, Seeman E : Bone mass, areal, and volumetric bone density are equally accurate, sensitive, and specific surrogates of the breaking strength of the vertebral body: an in vitro study. J Bone Miner Res 1996; 11: 1981–1988.

  20. 20

    Lindner TH, Hoffmann K : easyLINKAGE: a PERL script for easy and automated two-/multi-point linkage analyses. Bioinformatics 2005; 21: 405–407.

  21. 21

    Lander E, Kruglyak L : Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995; 11: 241–247.

  22. 22

    Koshizuka Y, Ikegawa S, Sano M, Nakamura K, Nakamura Y : Isolation, characterization, and mapping of the mouse and human WDR8 genes, members of a novel WD-repeat gene family. Genomics 2001; 72: 252–259.

  23. 23

    Nakayama M, Nakajima D, Nagase T, Nomura N, Seki N, Ohara O : Identification of high-molecular-weight proteins with multiple EGF-like motifs by motif-trap screening. Genomics 1998; 51: 27–34.

  24. 24

    Devoto M, Shimoya K, Caminis J et al: 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.

  25. 25

    Devoto M, Specchia C, Li HH et al: Variance component linkage analysis indicates a QTL for femoral neck bone mineral density on chromosome 1p36. Hum Mol Genet 2001; 10: 2447–2452.

  26. 26

    Karasik D, Myers RH, Hannan MT et al: Mapping of quantitative ultrasound of the calcaneus bone to chromosome 1 by genome-wide linkage analysis. Osteoporos Int 2002; 13: 796–802.

  27. 27

    Wynne F, Drummond FJ, Daly M et al: 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.

  28. 28

    Wilson SG, Reed PW, Bansal A et al: Comparison of genome screens for two independent cohorts provides replication of suggestive linkage of bone mineral density to 3p21 and 1p36. Am J Hum Genet 2003; 72: 144–155.

  29. 29

    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: 547–556.

  30. 30

    Xiao P, Shen H, Guo YF et al: Genomic regions identified for BMD in a large sample including epistatic interactions and gender-specific effects. J Bone Miner Res 2006; 21: 1536–1544.

  31. 31

    Streeten EA, McBride DJ, Pollin TI et al: Quantitative trait loci for BMD identified by autosome-wide linkage scan to chromosomes 7q and 21q in men from the Amish family Osteoporosis study. J Bone Miner Res 2006; 21: 1433–1442.

  32. 32

    Lee YH, Rho YH, Choi SJ, Ji JD, Song GG : Meta-analysis of genome-wide linkage studies for bone mineral density. J Hum Genet 2006; 51: 480–486.

  33. 33

    Ioannidis JP, Ng MY, Sham PC et al: Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass. J Bone Miner Res 2007; 22: 173–183.

  34. 34

    Bouxsein ML, Uchiyama T, Rosen CJ et al: Mapping quantitative trait loci for vertebral trabecular bone volume fraction and microarchitecture in mice. J Bone Miner Res 2004; 19: 587–599.

  35. 35

    Beamer WG, Shultz KL, Donahue LR et al: Quantitative trait loci for femoral and lumbar vertebral bone mineral density in C57BL/6J and C3H/HeJ inbred strains of mice. J Bone Miner Res 2001; 16: 1195–1206.

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Acknowledgements

We are grateful to the family for participating in this study. We thank Drs Moerman, Vanneste and Fryns for referral of the family and K Toye and B Lapauw for expert technical help in collecting the samples.

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Correspondence to Paul Coucke.

Additional information

Supplementary Information accompanies the paper on European Journal of Human Genetics website (http://www.nature.com/ejhg)

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Keywords

  • bone mineral density
  • genome-wide linkage analysis
  • 1p36.3

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