Osteoporosis pp 203-235 | Cite as

Quantitative Trait Loci Mapping

  • Dong-Hai Xiong
  • Jian-Feng Liu
  • Yan-Fang Guo
  • Yan Guo
  • Tie-Lin Yang
  • Hui Jiang
  • Yuan Chen
  • Fang Yang
  • Robert R Recker
  • Hong-Wen Deng
Part of the Methods In Molecular Biology™ book series (MIMB, volume 455)


This chapter presents current methods for mapping quantitative trait loci (QTLs) in natural populations especially in humans. We discussed the experimental designs for QTL mapping, traditional methods adopted such as linkage mapping approaches and methods for linkage disequilibrium (LD) mapping. Multiple traits and interaction analysis are also outlined. The application of modern genomic approaches, which mainly exploit the microarray technology, into QTL mapping was detailed. The latter are very recent protocols and are less developed than linkage and association methods at present. The main focus of this chapter is technical issues although statistical issues are also covered to certain extent. Finally, we summarize the limitations of the current QTL approaches and discuss the solutions to certain problems.


QTL linkage association linkage disequilibrium microarrays eQTL whole genome association. 



Investigators of this work were partially supported by grants from NIH (R01 AR050496, K01 AR02170-01, R01 AR45349-01, and R01 GM60402-01A1) and an LB595 grant from the state of Nebraska. The study also benefited from grants from National Science Foundation of China, Huo Ying Dong Education Foundation, HuNan Province, Xi'an Jiaotong University, and the Ministry of Education of China.


  1. 1.
    1. Falconer, D. S., Mackay, T. F. C. (1996) Introduction to Quantitative Genetics. Longman, Essex, UK.Google Scholar
  2. 2.
    2. Geldermann, H. (1975) Investigations on inheritance of quantitative characters in animals by gene markers. I. Methods. Theor Appl Genet 46, 319–330.CrossRefGoogle Scholar
  3. 3.
    3. Elston, R. C., Buxbaum, S., Jacobs, K. B., et al. (2000) Haseman and Elston revisited. Genet Epidemiol 19, 1–17.CrossRefPubMedGoogle Scholar
  4. 4.
    4. Hill, W. G. (1981) Estimation of effective population size from data on linkage disequilibrium. Genet Res 38, 209–216.CrossRefGoogle Scholar
  5. 5.
    5. Hill, W. J., Robertson, A. (1968) Linkage disequilibrium in finite populations. Theor Appl Genet 38, 226–231.CrossRefGoogle Scholar
  6. 6.
    6. Patil, N., Berno, A. J., Hinds, D. A., et al. (2001) Blocks of limited haplotype diversity revealed by high-resolution scanning of human chromosome 21. Science 294, 1719–1723.CrossRefPubMedGoogle Scholar
  7. 7.
    7. Gabriel, S. B., Schaffner, S. F., Nguyen, H., et al. (2002) The structure of haplotype blocks in the human genome. Science 296, 2225–2229.CrossRefPubMedGoogle Scholar
  8. 8.
    8. Williams, J. T., Van Eerdewegh, P., Almasy, L., et al. (1999) Joint multipoint linkage analysis of multivariate qualitative and quantitative traits. I. Likelihood formulation and simulation results. Am J Hum Genet 65, 1134–1147.CrossRefPubMedGoogle Scholar
  9. 9.
    9. Amos, C. I., Elston, R. C., Bonney, G. E., et al. (1990) A multivariate method for detecting genetic linkage, with application to a pedigree with an adverse lipoprotein phenotype. Am J Hum Genet 47, 247–254.PubMedGoogle Scholar
  10. 10.
    10. Schork, N. J. (1993) Extended multipoint identity-by-descent analysis of human quantitative traits: efficiency, power, and modeling considerations. Am J Hum Genet 53, 1306–1319.PubMedGoogle Scholar
  11. 11.
    11. Almasy, L., Dyer, T. D., Blangero, J. (1997) Bivariate quantitative trait linkage analysis: plei-otropy versus co-incident linkages. Genet Epidemiol 14, 953–958.CrossRefPubMedGoogle Scholar
  12. 12.
    12. Moore, J. H. (2003) The ubiquitous nature of epistasis in determining susceptibility to common human diseases. Hum Hered 56, 73–82.CrossRefPubMedGoogle Scholar
  13. 13.
    13. Jansen, R. C., Nap, J. P. (2001) Genetical genomics: the added value from segregation. Trends Genet 17, 388–391.CrossRefPubMedGoogle Scholar
  14. 14.
    14. DeCook, R., Lall, S., Nettleton, D., et al. (2006) Genetic regulation of gene expression during shoot development in Arabinosis. Genetics 172, 1155–1164.CrossRefGoogle Scholar
  15. 15.
    15. Schadt, E. E., Monks, S. A., Drake, T. A., et al. (2003) Genetics of gene expression surveyed in maize, mouse and man. Nature 422, 297–302.CrossRefPubMedGoogle Scholar
  16. 16.
    16. Yaguchi, H., Togawa, K., Moritani, M., et al. (2005) Identification of candidate genes in the type 2 diabetes modifier locus using expression QTL. Genomics 85, 591–599.CrossRefPubMedGoogle Scholar
  17. 17.
    17. Hirschhorn, J. N., Daly, M. J. (2005) Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 6, 95–108.CrossRefPubMedGoogle Scholar
  18. 18.
    18. Herbert, A., Gerry, N. P., McQueen, M. B., et al. (2006) A common genetic variant is associated with adult and childhood obesity. Science 312, 279–283.CrossRefPubMedGoogle Scholar
  19. 19.
    19. John, S., Shephard, N., Liu, G., et al. (2004) Whole-genome scan, in a complex disease, using 11,245 single-nucleotide polymorphisms: comparison with microsatellites. Am J Hum Genet 75, 54–64.CrossRefPubMedGoogle Scholar
  20. 20.
    20. Klein, R. J., Zeiss, C., Chew, E. Y. , et al. (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389.CrossRefPubMedGoogle Scholar
  21. 21.
    21. Maraganore, D. M., de Andrade, M., Lesnick, T. G., et al. (2005) High-resolution whole-genome association study of Parkinson disease. Am J Hum Genet 77, 685–693.CrossRefPubMedGoogle Scholar
  22. 22.
    22. Namkung, J., Kim, Y., Park, T. (2005) Whole-genome association studies of alcoholism with loci linked to schizophrenia susceptibility. BMC Genet 6, S9.CrossRefPubMedGoogle Scholar
  23. 23.
    23. Spinola, M., Meyer, P., Kammerer, S., et al. (2006) Association of the PDCD5 locus with lung cancer risk and prognosis in smokers. J Clin Oncol 24, 1672–1678.CrossRefPubMedGoogle Scholar
  24. 24.
    24. Weaver, T. A. (2000) High-throughout SNP discovery and typing for genome-wide genetic analysis. A Trends Guide 20, 136–142.Google Scholar
  25. 25.
    25. Syvanen, A. C. (2005) Toward genome-wide SNP genotyping. Nat Genet 37, S5–10.CrossRefPubMedGoogle Scholar
  26. 26.
    26. Stoll, M., Kwitek-Black, A. E., Cowley, A. W., et al. (2000) New target regions for human hypertension via comparative genomics. Genome Res 10, 473–482.CrossRefPubMedGoogle Scholar
  27. 27.
    27. Lynch, M., Walsh, B. (1998) Genetics and Analysis of Quantitative Traits. Sinauer Associates,Sunderland, MA.Google Scholar
  28. 28.
    28. Haseman, J. K., Elston, R. C. (1972) The investigation of linkage between a quantitative trait and a marker locus. Behav Genet 2, 3–19.CrossRefPubMedGoogle Scholar
  29. 29.
    29. Almasy, L., Blangero, J. (1998) Multipoint quantitative-trait linkage analysis in general pedi grees. Amer J Hum Genet 62, 1198–1211.CrossRefPubMedGoogle Scholar
  30. 30.
    30. George, A. W., Visscher, P. M., Haley, C. S. (2000) Mapping quantitative trait loci in complex pedigrees: a two-step variance component approach. Genetics 156, 2081–2092.PubMedGoogle Scholar
  31. 31.
    31. Slate, J., Pemberton, J. M., Visscher, P. M. (1999) Power to detect QTL in a free-living pulig-enous population. Heredity 83, 327–336.CrossRefPubMedGoogle Scholar
  32. 32.
    32. Amos, C. I., Elston, R. C. (1989) Robust methods for the detection of genetic linkage for quantitative data from pedigrees. Genet Epidemiol 6, 349–360.CrossRefPubMedGoogle Scholar
  33. 33.
    33. Fulker, D. W., Cardon, L. R. (1994) A sib-pair approach to interval mapping of quantitative trait loci. Am J Hum Genet 54, 1092–1103.PubMedGoogle Scholar
  34. 34.
    34. Tiwari, H. K., Elston, R. C. (1997) Linkage of multilocus components of variance to polymor phic markers. Ann Hum Genet 61, 253–261.PubMedGoogle Scholar
  35. 35.
    35. Amos, C. I. (1994) Robust variance-components approach for assessing genetic linkage in pedigrees. Am J Hum Genet 54, 535–543.PubMedGoogle Scholar
  36. 36.
    36. Devlin, B., Roeder, K., Wasserman, L. (2001) Genomic control, a new approach to genetic-based association studies. Theor Popul Biol 60, 155–166.CrossRefPubMedGoogle Scholar
  37. 37.
    37. Devlin, B., Roeder, K., Bacanu, S. A. (2001) Unbiased methods for population-based associa tion studies. Genet Epidemiol 21, 273–284.CrossRefPubMedGoogle Scholar
  38. 38.
    38. Pritchard, J. K., Rosenberg, N. A. (1999) Use of unlinked genetic markers to detect population stratification in association studies. Am J Hum Genet 65, 220–228.CrossRefPubMedGoogle Scholar
  39. 39.
    39. Schaid, D. J. (1998) Transmission disequilibrium, family controls, and great expectations. Am J Hum Genet 63, 935–941.CrossRefPubMedGoogle Scholar
  40. 40.
    40. Benjamini, Y. A. H. Y. (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Stat Soc Series B 57, 289–300.Google Scholar
  41. 41.
    41. McIntyre, L. M., Martin, E. R., Simonsen, K. L., et al. (2000) Circumventing multiple testing: a multilocus Monte Carlo approach to testing for association. Genet Epidemiol 19, 18–29.CrossRefPubMedGoogle Scholar
  42. 42.
    42. Boomsma, D. I., Dolan, C. V. (1998) A comparison of power to detect a QTL in sib-pair data using multivariate phenotypes, mean phenotypes, and factor scores. Behav Genet 28,329–340.CrossRefPubMedGoogle Scholar
  43. 43.
    43. Blangero, J., Almasy, L. (1997) Multipoint oligogenic linkage analysis of quantitative traits.Genet Epidemiol 14, 959–964.CrossRefPubMedGoogle Scholar
  44. 44.
    44. Cockerham, C. C., Zeng, Z. B. (1996) Design III with marker loci. Genetics 143,1437–1456.PubMedGoogle Scholar
  45. 45.
    45. Thomas, D., Xie, R., Gebregziabher, M. (2004) Two-Stage sampling designs for gene associa tion studies. Genet Epidemiol 27, 401–414.CrossRefPubMedGoogle Scholar
  46. 46.
    46. Kruglyak, L., Daly, M. J., Reeve-Daly, M. P., et al. (1996) Parametric and nonparametric link age analysis: a unified multipoint approach. Am J Hum Genet 58, 1347–1363.PubMedGoogle Scholar
  47. 47.
    47. Abecasis, G. R., Cherny, S. S., Cookson, W. O., et al. (2002) Merlin: rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30, 97–101.CrossRefPubMedGoogle Scholar
  48. 48.
    48. Gudbjartsson, D. F., Jonasson, K., Frigge, M. L., et al. (2000) Allegro, a new computer pro gram for multipoint linkage analysis. Nat Genet 25, 12–13.CrossRefPubMedGoogle Scholar
  49. 49.
    49. Shmulewitz, D., Heath, S. C., Blundell, M. L., et al. (2006) Linkage analysis of quantitative traits for obesity, diabetes, hypertension, and dyslipidemia on the island of Kosrae, Federated States of Micronesia. Proc Natl Acad Sci U S A 103, 3502–3509.CrossRefPubMedGoogle Scholar
  50. 50.
    50. Abecasis, G. R., Cardon, L. R., Cookson, W. O. (2000) A general test of association for quan titative traits in nuclear families. Am J Hum Genet 66, 279–292.CrossRefPubMedGoogle Scholar
  51. 51.
    51. Horvath, S., Xu, X., Laird, N. M. (2001) The family based association test method: strategies for studying general genotype: phenotype associations. Eur J Hum Genet 9, 301–306.CrossRefPubMedGoogle Scholar
  52. 52.
    52. Deng, H. W., Chen, W. M., Recker, R. R. (2000) QTL fine mapping by measuring and testing for Hardy-Weinberg and linkage disequilibrium at a series of linked marker loci in extreme samples of populations. Am J Hum Genet 66, 1027–1045.CrossRefPubMedGoogle Scholar
  53. 53.
    53. Deng, H. W., Shen, H., Xu, F. H., et al. (2002) Tests of linkage and/or association of genes for vitamin D receptor, osteocalcin, and parathyroid hormone with bone mineral density. J Bone Miner Res 17, 678–686.CrossRefPubMedGoogle Scholar
  54. 54.
    54. Lander, E. S., Schork, N. J. (1994) Genetic dissection of complex traits. Science 265,2037–2048.CrossRefPubMedGoogle Scholar
  55. 55.
    55. Allison, D. B. (1997) Transmission-disequilibrium tests for quantitative traits. Am J Hum Genet 60, 676–690.PubMedGoogle Scholar
  56. 56.
    56. Risch, N., Merikangas, K. (1996) The future of genetic studies of complex human diseases.Science 273, 1516–1517.CrossRefPubMedGoogle Scholar
  57. 57.
    57. Xiong, M. M., Krushkal, J., Boerwinkle, E. (1998) TDT statistics for mapping quantitative trait loci. Ann Hum Genet 62, 431–452.CrossRefPubMedGoogle Scholar
  58. 58.
    58. Abecasis, G. R., Noguchi, E., Heinzmann, A., et al. (2001) Extent and distribution of linkage disequilibrium in three genomic regions. Am J Hum Genet 68, 191–197.CrossRefPubMedGoogle Scholar
  59. 59.
    59. Mangin, B., Thoquet, P., Olivier, J., et al. (1999) Temporal and multiple quantitative trait loci analyses of resistance to bacterial wilt in tomato permit the resolution of linked loci. Genetics 151, 1165–1172.PubMedGoogle Scholar
  60. 60.
    60. Weller, J. I., Song, J. Z., Heyen, D. W., et al. (1998) A new approach to the problem of multiple comparisons in the genetic dissection of complex traits. Genetics 150, 1699–1706.PubMedGoogle Scholar
  61. 61.
    61. Eaves, L. J. (1994) Effect of genetic architecture on the power of human linkage studies to resolve the contribution of quantitative trait loci. Heredity 72, 175–192.CrossRefPubMedGoogle Scholar
  62. 62.
    62. Mitchell, B. D., Ghosh, S., Schneider, J. L., et al. (1997) Power of variance component linkage analysis to detect epistasis. Genet Epidemiol 14, 1017–1022.CrossRefPubMedGoogle Scholar
  63. 63.
    63. Moore, J. H., Williams, S. M. (2002) New strategies for identifying gene-gene interactions in hypertension. Ann Med 34, 88–95.CrossRefPubMedGoogle Scholar
  64. 64.
    64. Storey, J. D., Tibshirani, R. (2003) Statistical significance for genomewide studies. Proc Natl Acad Sci U S A 100, 9440–9445.CrossRefPubMedGoogle Scholar
  65. 65.
    65. Hao, K., Li, C., Rosenow, C., et al. (2004) Detect and adjust for population stratification in population-based association study using genomic control markers: an application of Affymetrix Genechip Human Mapping 10 K array. Eur J Hum Genet 12, 1001–1006.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Dong-Hai Xiong
    • 1
  • Jian-Feng Liu
    • 2
  • Yan-Fang Guo
    • 3
  • Yan Guo
    • 3
  • Tie-Lin Yang
    • 3
  • Hui Jiang
    • 4
  • Yuan Chen
    • 4
  • Fang Yang
    • 4
  • Robert R Recker
    • 1
  • Hong-Wen Deng
    • 2
  1. 1.Osteoporosis Research CenterCreighton UniversityOmahaNE
  2. 2.Departments of Orthopedic Surgery and Basic Medical SciencesUniversity of Missouri-Kansas CityKansas CityMO
  3. 3.The Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetic, School of Life Science and TechnologyXi'an Jiaotong UniversityXi'anP.R. China
  4. 4.Laboratory of Molecular and Statistical Genetics, College of Life SciencesHunan Normal UniversityChangshaP.R. China

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