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Genetic epidemiology of osteoporosis: Past, present, and future

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Abstract

Research during the past several decades has unequivocally established a role of heredity in the etiology of osteoporosis. Major efforts are currently underway to identify the genes and allelic variants that confer genetic susceptibility to this common and disabling condition. Genome-wide linkage mapping in families, candidate gene association studies in unrelated individuals, and quantitative trait locus mapping in animal models are the primary strategies being used to search for the genetic contributors to osteoporosis. Genome-wide mapping efforts have identified the low-density lipoprotein receptor-related protein 5, bone morphogenetic protein 2, and 15-lipoxygenase as potential susceptibility genes for osteoporosis in the past few years, providing a rich new base for understanding bone biology. Candidate gene association analyses have also provided evidence for a modest role of allelic variants in several additional genes including collagen type ∣α∣, vitamin D receptor, and estrogen receptor-α. With the development of a high-density genome-wide polymorphism and haplotype map and continued improvements in high-throughput and cost-effective genotyping technologies, many more genetic contributors to osteoporosis will probably be identified in the near future. The results of this research should facilitate the development of new methods for diagnosing, preventing, and treating the growing clinical and public health problem of osteoporosis

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References and Recommended Reading

  1. Looker AC, Orwoll ES, Johnston CC, et al.: Prevalence of low femoral bone density in older US adults from NHANES III. J Bone Miner Res 1997, 12:1761–1768.

    Article  PubMed  CAS  Google Scholar 

  2. Melton LJ, Chrischilles EA, Cooper C, et al.: Perspective. How many women have osteoporosis? J Bone Miner Res 1992, 7:1005–1010.

    Article  PubMed  Google Scholar 

  3. Cummings SR, Melton LJ: Epidemiology and outcomes of osteoporotic fractures. Lancet 2002, 359:1761–1767.

    Article  PubMed  Google Scholar 

  4. Ray NF, Chan JK, Thamer M, Melton LJ, 3rd: Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res 1997, 12:24–35.

    Article  PubMed  CAS  Google Scholar 

  5. Cooper C, Campion G, Melton LJ: Hip fractures in the elderly: a world-wide projection. Osteoporos Int 1992, 2:285–289.

    Article  PubMed  CAS  Google Scholar 

  6. Jouanny P, Guillemin F, Kuntz C, et al.: Environmental and genetic factors affecting bone mass. Similarity of bone density among members of healthy families. Arthritis Rheum 1995, 38:61–67.

    Article  PubMed  CAS  Google Scholar 

  7. Peacock M, Turner CH, Econs MJ, Foroud T: Genetics of osteoporosis. Endocrine Reviews 2002, 23:303–326.

    Article  PubMed  CAS  Google Scholar 

  8. Andrew T, Antioniades L, Scurrah KJ, et al.: Risk of wrist fracture in women is heritable and is influenced by genes that are largely independent of those influencing BMD. J Bone Miner Res 2005, 20:67–74.

    Article  PubMed  Google Scholar 

  9. Cummings SR, Nevitt MC, Browner WS, et al.: Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 1995, 332:767–773.

    Article  PubMed  CAS  Google Scholar 

  10. Liu YZ, Liu YJ, Recker RR, Deng HW: Molecular studies of identification of genes for osteoporosis: the 2002 update. J Endocrinol 2003, 177:147–196.

    Article  PubMed  CAS  Google Scholar 

  11. Johnson ML, Gong G, Kimberling W, et al.: Linkage of a gene causing high bone mass to human chromosome 11 (11q12- 13). Am J Hum Genet 1997, 60:1326–1332.

    PubMed  CAS  Google Scholar 

  12. Little RD, Carulli JP, Del Mastro RG, et al.: A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet 2002, 70:11–19.

    Article  PubMed  CAS  Google Scholar 

  13. Boyden LM, Mao J, Belsky J, et al.: High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 2002, 346:1513–1521. Genetic and biochemical analyses were performed in a kindred with an autosomal dominant syndrome characterized by high BMD. Genetic analyses revealed linkage of the syndrome to chromosome 11q12-13, an interval that contained the LDL-receptor-related protein 5 (LRP5) gene. Affected kindred members had a mutation in LRP5 that segregated with the trait and was absent in control subjects. In vitro studies showed that the normal inhibition of Wnt signaling by another protein, Dickkopf-1, was defective in the presence of the LRP5 mutation and that this resulted in increased signaling due to unopposed Wnt activity.

    Article  PubMed  CAS  Google Scholar 

  14. 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.

    Article  PubMed  CAS  Google Scholar 

  15. Ferrari SL, Deutsch S, Choudhury U, et al.: 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.

    Article  PubMed  CAS  Google Scholar 

  16. Bollerslev J, Wilson SG, Dick IM, et al.: LRP5 gene polymorphisms predict bone mass and incident fractures in elderly australian women. Bone 2005, 36:599–606.

    Article  PubMed  CAS  Google Scholar 

  17. Styrkarsdottir U, Cazier JB, Kong A, et al.: Linkage of osteoporosis to chromosome 20p12 and association to BMP2. PLoS Biol 2003, 1:E69. This is the first identification of an osteoporosis susceptibility gene using conventional genome-wide linkage mapping in family members of probands with low BMD. The identified locus, bone morphogenic protein 2, is a regulator of osteoblast differentiation.

    Article  PubMed  Google Scholar 

  18. Wijsman EM, Amos CI: Genetic analysis of simulated oligogenic traits in nuclear and extended pedigrees: summary of GAW10 contributions. Genet Epidemiol 1997, 14:719–735.

    Article  PubMed  CAS  Google Scholar 

  19. Williams JT, Blangero J: Comparison of variance components and sibpair-based approaches to quantitative trait linkage analysis in unselected samples. Genet Epidemiol 1999, 16:113–134.

    Article  PubMed  CAS  Google Scholar 

  20. Shen H, Liu Y, Liu P, et al.: Nonreplication in genetic studies of complex diseases--lessons learned from studies of osteoporosis and tentative remedies. J Bone Miner Res 2005, 20:365–376.

    Article  PubMed  CAS  Google Scholar 

  21. Gabriel SB, Schaffner SF, Nguyen H, et al.: The structure of haplotype blocks in the human genome. Science 2002, 296:2225–2229.

    Article  PubMed  CAS  Google Scholar 

  22. Jeffreys AJ, Kauppi L, Neumann R: Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nat Genet 2001, 29:217–222.

    Article  PubMed  CAS  Google Scholar 

  23. Carlson CS, Eberle MA, Rieder MJ, et al.: Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet 2004, 74:106–120.

    Article  PubMed  CAS  Google Scholar 

  24. Cardon LR, Palmer LJ: Population stratification and spurious allelic association. Lancet 2003, 361:598–604.

    Article  PubMed  Google Scholar 

  25. Freedman ML, Reich D, Penney KL, et al.: Assessing the impact of population stratification on genetic association studies. Nat Genet 2004, 36:388–393.

    Article  PubMed  CAS  Google Scholar 

  26. Devlin B, Roeder K: Genomic control for association studies. Biometrics 1999, 55:997–1004.

    Article  PubMed  CAS  Google Scholar 

  27. Pritchard JK, Rosenberg NA: Use of unlinked genetic markers to detect population stratification in association studies. Am J Hum Genet 1999, 65:220–228.

    Article  PubMed  CAS  Google Scholar 

  28. Klein RF, Allard J, Avnur Z, et al.: Regulation of bone mass in mice by the lipoxygenase gene Alox15. Science 2004, 303:229–232. This report identifies the 15-lipoxygenase (Alox15) gene as a regulator of BMD in mice. Alox15 null-mice had increased BMD compared with wild-type control mice. Inhibitors of Alox15 prevented bone loss during ovariectomy in mice providing further support for Alox15 in the regulation of BMD.

    Article  PubMed  CAS  Google Scholar 

  29. Urano T, Shiraki M, Fujita M, et al.: Association of a single nucleotide polymorphism in the lipoxygenase ALOX15 5′- flanking region (-5229G/A) with bone mineral density. J Bone Miner Metab 2005, 23:226–230.

    Article  PubMed  CAS  Google Scholar 

  30. Turner CH, Hsieh YF, Muller R, et al.: Variation in bone biomechanical properties, microstructure, and density in BXH recombinant inbred mice. J Bone Miner Res 2001, 16:206–213.

    Article  PubMed  CAS  Google Scholar 

  31. 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.

    Article  PubMed  CAS  Google Scholar 

  32. Sheng MH, Baylink DJ, Beamer WG, et al.: Regulation of bone volume is different in the metaphyses of the femur and vertebra of C3H/HeJ and C57BL/6J mice. Bone 2002, 30:486–491.

    Article  PubMed  Google Scholar 

  33. Li X, Masinde G, Gu W, et al.: Genetic dissection of femur breaking strength in a large population (MRL/MpJ x SJL/J) of F2 Mice: single QTL effects, epistasis, and pleiotropy. Genomics 2002, 79:734–740.

    Article  PubMed  CAS  Google Scholar 

  34. Masinde GL, Wergedal J, Davidson H, et al.: Quantitative trait loci for periosteal circumference (PC): identification of single loci and epistatic effects in F2 MRL/SJL mice. Bone 2003, 32:554–560.

    Article  PubMed  CAS  Google Scholar 

  35. Seeman E: Growth in bone mass and size--are racial and gender differences in bone mineral density more apparent than real? J Clin Endocrinol Metab 1998, 83:1414–1419.

    Article  PubMed  CAS  Google Scholar 

  36. Hirschhorn JN, Daly MJ: Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 2005, 6:95–108.

    Article  PubMed  CAS  Google Scholar 

  37. Wang WY, Barratt BJ, Clayton DG, Todd JA: Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet 2005, 6:109–118.

    Article  PubMed  CAS  Google Scholar 

  38. Reneland R, Mah S, Kammerer S, et al.: Association between a variation in the phosphodiesterase 4D gene and bone mineral density. BMC Medical Genetics 2005, 6:9. This is the first report of the whole genome association mapping strategy for osteoporosis related traits. Analysis of 25,000 polymorphisms within 16,000 genes in DNA pools from subjects with low and high BMD identified an association between an allelic variant in the phosphodiesterase 4D gene and low BMD. Subsequent replication studies in an independent study sample confirmed the association with low BMD.

    Article  PubMed  CAS  Google Scholar 

  39. Havill LM, Mahaney MC, Cox LA, et al.: A QTL for normal variation in forearm BMD in pedigreed baboons maps to the ortholog of human chromosome 11q. J Clin Endocrinol Metab 2005, Mar 8

  40. Klein RF, Mitchell SR, Phillips TJ, et al.: Quantitative trait loci affecting peak bone mineral density in mice. J Bone Miner Res 1998, 13:1648–1656.

    Article  PubMed  CAS  Google Scholar 

  41. Shimizu M, Higuchi K, Bennett B, et al.: Identification of peak bone mass QTL in a spontaneously osteoporotic mouse strain. Mamm Genome 1999, 10:81–87.

    Article  PubMed  CAS  Google Scholar 

  42. Benes H, Weinstein RS, Zheng W, et al.: Chromosomal mapping of osteopenia-associated quantitative trait loci using closely related mouse strains. J Bone Miner Res 2000, 15:626–633.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, 15261, Pittsburgh, PA, USA

    Joseph M. Zmuda PhD

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  1. Joseph M. Zmuda PhD
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  2. Yah-Tyng Sheu MPH
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  3. Susan P. Moffett PhD
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Zmuda, J.M., Sheu, YT. & Moffett, S.P. Genetic epidemiology of osteoporosis: Past, present, and future. Curr Osteoporos Rep 3, 111–115 (2005). https://doi.org/10.1007/s11914-005-0019-5

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  • DOI: https://doi.org/10.1007/s11914-005-0019-5

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