Hum Hered 2003;55:56–65

Estimation and Tests of Haplotype-Environment Interaction when Linkage Phase Is Ambiguous

Lake S.L.a,b · Lyon H.a · Tantisira K.a · Silverman E.K.a · Weiss S.T.a,c · Laird N.M.d · Schaid D.J.e
aChanning Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.; bEigenStat, Brookline, Mass.; cHarvard-Partners Center for Genetics and Genomics, Partners Health Care, Boston, Mass.; dDepartment of Biostatistics, Harvard School of Public Health, Boston, Mass., and eDepartments of Health Sciences Research and Medical Genetics, Mayo Clinic/Foundation, Rochester, Minn., USA
email Corresponding Author

 goto top of outline Key Words

  • Haplotype
  • Association
  • Gene-environment interaction
  • Generalized linear model

 goto top of outline Abstract

In the study of complex traits, the utility of linkage analysis and single marker association tests can be limited for researchers attempting to elucidate the complex interplay between a gene and environmental covariates. For these purposes, tests of gene-environment interactions are needed. In addition, recent studies have indicated that haplotypes, which are specific combinations of nucleotides on the same chromosome, may be more suitable as the unit of analysis for statistical tests than single genetic markers. The difficulty with this approach is that, in standard laboratory genotyping, haplotypes are often not directly observable. Instead, unphased marker phenotypes are collected. In this article, we present a method for estimating and testing haplotype-environment interactions when linkage phase is potentially ambiguous. The method builds on the work of Schaid et al. [2002] and is applicable to any trait that can be placed in the generalized linear model framework. Simulations were run to illustrate the salient features of the method. In addition, the method was used to test for haplotype-smoking exposure interaction with data from the Childhood Asthma Management Program.

Copyright © 2003 S. Karger AG, Basel

 goto top of outline References
  1. Zhou W, Thurston SW, Liu G, Xu LL, Miller DP, Wain JC, Lynch TJ, Su L, Christiani DC: The interaction between microsomal epoxide hydrolase polymorphisms and cumulative cigarette smoking in different histological subtypes of lung cancer. Cancer Epidemiol Biomarkers Prev 2001;10(5):461–466.
  2. Zhang S, Pakstis AJ, Kidd KK, Zhao H: Comparisons of two methods for haplotype reconstruction and haplotype frequency estimation from population data. Am J Hum Genet 2001;69:906–912.
  3. Zaykin DV, Westfall PH, Young SS, Karnoub MA, Wagner MJ, Ehm MG: Testing association of statistically inferred haplotypes with discrete and continuous traits in samples of unrelated individuals. Hum Hered 2002;53:79–91.
  4. Umetsu DT, DeKruyff RH: Interleukin 10: The missing link in asthma regulation? Am J Resp Cell Mol Biol 1999;21:562–563.
  5. Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV: An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 1997;24:1–8.
  6. Stephens M, Smith NJ, Donnelly P: A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001b;68:978–989.
  7. Stephens JC, Schneider JA, Tanguay DA, Choi J, Acharya T, Stanley SE, Jiang R: Haplotype variation and linkage disequilibrium in 313 human genes. Science 2001a;293:489–493.
  8. Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA: Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 2002;70:425–434.
  9. Nui T, Qin ZS, Xu X, Liu JS: Bayesian haplotype inference for multiple linked single-nucleotide polymorphisms. Am J Hum Genet 2002;68:978–989.

    External Resources

  10. Nelson HH, Kelsey KT, Mott LA, Karagas MR: The XRCCA Arg399Gln polymorphism, sunburn, and non-melanoma skin cancer: Evidence of gene-environment interaction. Cancer Res 2002;62(1):152–155.
  11. Meilijson I: A fast improvement to the EM algorithm on its own terms. JRSSB 1989;51(1):127–138.
  12. McLachlan GJ, Krishnan T: The EM algorithm and extensions. New York, Wiley, 1997.
  13. Lucassen AM, Julier C, Beressi JP, Boitard C, Froguel P, Lathrop M, Bell JI: Susceptibility to insulin dependent diabetes mellitus maps to a 4.1 kb segment of DNA spanning the insulin gene and associated VNTR. Nat Genet 1993;4:305–310.
  14. Louis TA: Finding the observed information matrix when using the EM algorithm. J R Statist Soc B 1982;44(2):226–233.
  15. Long JC, Williams RC, Urbanek M: An EM algorithm and testing strategy for multiple-locus haplotypes. Am J Hum Genet 1995;56:799–810.
  16. Little R, Rubin D: Statistical analysis with missing data. New York, Wiley, 1987.
  17. Lin S, Cutler DJ, Zwick ME, Chakravarti A: Haplotype inference in random population samples. Am J Hum Genet 2002;71:1129–1137.
  18. Lim S, Crawley E, Woo P, Barnes PJ: Haplotypes associated with low interleukin 10 production in patients with severe asthma. Lancet 1998;352:113.
  19. Kaluza W, et al: IL10.G microsatellites mark promoter haplotypes associated with protection against the development of reactive arthritis in Finnish patients. Arthritis Rheum 2001;44:1209–1214.
  20. Judson R, Stephens JC, Windemuth A: The predictive power of haplotypes in clinical response. Pharmacogenomics 2000;1(1):15–26.
  21. Johnson GCL, Esposito L, Barratt BJ, Smith AN, Heward J, DiGenova G, Ueda Hironori, Cordell HJ, Eaves IA, Dudbridge F, Twells RCJ, Payne F, Hughes W, Nutland S, Stevens H, Carr P, Tuomilehto-Wolf E, Tuomilehto J, Gough SCL, Clayton DG, Todd JA: Haplotype tagging for the identification of common disease genes. Nat Genet 2001;29:233–237.
  22. Ibrahim JG: Incomplete data in generalized linear models. JASA 1990;85:765–769.
  23. Hajeer AH, Lazarus M, Turner D, Mageed RA, Vencovsky J, Sinnott P, Hutchinson IV, Ollier WE: IL-10 gene promoter polymorphisms in rheumatoid arthritis. Scand J Rheumatol 1998;27:142–145.
  24. Gibson AW, et al: Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus. J Immunol 2001;166:3915–3922.
  25. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenthal B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D: The structure of haplotype blocks in the human genome. Science 2002;296:2225–2229.
  26. Fallin D, Cohen A, Esioux L, Chumakov I, Blumenfeld M, Cohen D, Schork N: Genetic analysis of case/control data using estimated haplotype frequencies: Application to APOE locus variation and Alzheimer’s disease. Genome Res 2001;11:143–151.
  27. Excoffier L, Slatkin M: Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 1995;12:921–927.
  28. Efron B, Tibshirani RJ: An introduction to the bootstrap. New York, Chapman and Hall, 1993.
  29. Drysdale CM, McGraw DW, Stack CB, Stephens JC, Judson RS, Nandabalan K, Arnold K,Ruano G, Liggett SB: Complex promoter and coding region β2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. PNAS 2000;97(19):10483–10488.
  30. Devlin B, Roeder K, Wasserman L: Genomic control for association studies: A semiparametric test to detect excess-haplotype sharing. Biostatistics 2001;1(4):369–388.
  31. Devlin B, Roeder K, Wasserman L: Genomic control, a new approach to genetic-based association studies. Theor Popul Biol 2001;60(3):155–166.
  32. Devlin B, Roder K: Genomic control for association studies. Biometrics 1999;55:997–1004.
  33. Dempster A, Laird NM, Rubin D: Maximum likelihood from incomplete data via the EM algorithm. JRSS B 1977;39:1–22.
  34. Daly MJ, Rioux JD, Schaffner SF, Hudson TJ, Lander ES: High-resolution haplotype structure in the human genome. Nat Genet 2001;29:229–232.
  35. Clayton D: A generalization of the transmission/disequilibrium test for uncertain haplotype transmission. Am J Hum Genet 1999;65:1170–1177.
  36. Clark AG: Inference for haplotypes from PCR-amplified samples of diploid populations. Mol Biol Evol 1990;7:111–122.
  37. Chiano MN, Clayton DG: Fine genetic mapping using haplotype analysis and the missing data problem. Ann Hum Genet 1998;62:55–60.

    External Resources

  38. Childhood Asthma Research Group: Long-term effects of budesonide or nedocromil in children with asthma. New Engl J Med 2000;343(15):1054–1063.
  39. Childhood Asthma Research Group: The Childhood Asthma Management Program (CAMP): Design, rationale, and methods. Con Clin Trials 1999;20:91–120.
  40. Borish L, et al: Interleukin-10 regulation in normal and asthmatic subjects. J Allergy Clin Immunol 1997;97:1288–1296.
  41. Akey J, Jin L, Xiong M: Haplotypes vs. single marker linkage disequilibrium tests: What do we gain? Eur J Hum Genet 2001;9:291–300.

 goto top of outline Author Contacts

Dr. Stephen Lake
Channing Laboratory
181 Longwood Avenue
Boston, MA 02115 (USA)
Tel. +1 617 596 6936, Fax +1 617 525 0958, E-Mail

 goto top of outline Article Information

Received: March 6, 2003
Accepted: May 7, 2003
Number of Print Pages : 10
Number of Figures : 0, Number of Tables : 4, Number of References : 41

 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)
Founded 1950 as Acta Genetica et Statistica Medica by Gunnar Dahlberg; Continued by M. Hauge (1965–1983)

Vol. 55, No. 1, Year 2003 (Cover Date: Released August 2003)

Journal Editor: J. Ott, New York, N.Y.
ISSN: 0001–5652 (print), 1423–0062 (Online)

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