Osteoporosis pp 203-235 | Cite as
Quantitative Trait Loci Mapping
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Abstract
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.
Keywords
QTL linkage association linkage disequilibrium microarrays eQTL whole genome association.Notes
Acknowledgments
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.
References
- 1.1. Falconer, D. S., Mackay, T. F. C. (1996) Introduction to Quantitative Genetics. Longman, Essex, UK.Google Scholar
- 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. Elston, R. C., Buxbaum, S., Jacobs, K. B., et al. (2000) Haseman and Elston revisited. Genet Epidemiol 19, 1–17.CrossRefPubMedGoogle Scholar
- 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. Hill, W. J., Robertson, A. (1968) Linkage disequilibrium in finite populations. Theor Appl Genet 38, 226–231.CrossRefGoogle Scholar
- 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. 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. 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. 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. 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. 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. 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. Jansen, R. C., Nap, J. P. (2001) Genetical genomics: the added value from segregation. Trends Genet 17, 388–391.CrossRefPubMedGoogle Scholar
- 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Syvanen, A. C. (2005) Toward genome-wide SNP genotyping. Nat Genet 37, S5–10.CrossRefPubMedGoogle Scholar
- 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. Lynch, M., Walsh, B. (1998) Genetics and Analysis of Quantitative Traits. Sinauer Associates,Sunderland, MA.Google Scholar
- 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Schaid, D. J. (1998) Transmission disequilibrium, family controls, and great expectations. Am J Hum Genet 63, 935–941.CrossRefPubMedGoogle Scholar
- 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. 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. 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. Blangero, J., Almasy, L. (1997) Multipoint oligogenic linkage analysis of quantitative traits.Genet Epidemiol 14, 959–964.CrossRefPubMedGoogle Scholar
- 44.44. Cockerham, C. C., Zeng, Z. B. (1996) Design III with marker loci. Genetics 143,1437–1456.PubMedGoogle Scholar
- 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. 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. 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. 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. 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. 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. 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. 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. 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. Lander, E. S., Schork, N. J. (1994) Genetic dissection of complex traits. Science 265,2037–2048.CrossRefPubMedGoogle Scholar
- 55.55. Allison, D. B. (1997) Transmission-disequilibrium tests for quantitative traits. Am J Hum Genet 60, 676–690.PubMedGoogle Scholar
- 56.56. Risch, N., Merikangas, K. (1996) The future of genetic studies of complex human diseases.Science 273, 1516–1517.CrossRefPubMedGoogle Scholar
- 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. 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. 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. 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. 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. 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. 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. 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. 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