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Vol. 70, No. 1, 2010
Issue release date: June 2010
Free Access
Hum Hered 2010;70:23–33
(DOI:10.1159/000298326)

Testing Haplotype-Environment Interactions Using Case-Parent Triads

Shi M. · Umbach D.M. · Weinberg C.R.
Biostatistics Branch, NIEHS, NIH, DHHS, Research Triangle Park, N.C., USA
email Corresponding Author

Abstract

Objective: Joint analysis of multiple SNP markers can be informative, but studying joint effects of haplotypes and environmental exposures is challenging. Population structure can involve both genes and exposures and a case-control study is susceptible to bias from either source of stratification. We propose a procedure that uses case-parent triad data and, though not fully robust, resists bias from population structure. Methods: Our procedure assumes that haplotypes under study have no influence on propensity to exposure. Then, under a no-interaction null hypothesis (multiplicative scale), transmission of a causative haplotype from parents to affected offspring might show distortion from Mendelian proportions but should be independent of exposure. We used this insight to develop a permutation test of no haplotype-by-exposure interaction. Results: Simulations showed that our proposed test respects the nominal Type I error rate and provides good power under a variety of scenarios. We illustrate by examining whether SNP variants in GSTP1 modify the association between maternal smoking and oral clefting. Conclusion: Our procedure offers desirable features: no need for haplotype estimation, validity under unspecified genetic main effects, tolerance to Hardy-Weinberg disequilibrium, ability to handle missing genotypes and a relatively large number of SNPs. Simulations suggest resistance to bias due to exposure-related population stratification.


 goto top of outline Key Words

  • Haplotype-environment interaction
  • Gene-environment interaction
  • Case-parent triad
  • Permutation test
  • Non-parametreic test
  • Population stratification

 goto top of outline Abstract

Objective: Joint analysis of multiple SNP markers can be informative, but studying joint effects of haplotypes and environmental exposures is challenging. Population structure can involve both genes and exposures and a case-control study is susceptible to bias from either source of stratification. We propose a procedure that uses case-parent triad data and, though not fully robust, resists bias from population structure. Methods: Our procedure assumes that haplotypes under study have no influence on propensity to exposure. Then, under a no-interaction null hypothesis (multiplicative scale), transmission of a causative haplotype from parents to affected offspring might show distortion from Mendelian proportions but should be independent of exposure. We used this insight to develop a permutation test of no haplotype-by-exposure interaction. Results: Simulations showed that our proposed test respects the nominal Type I error rate and provides good power under a variety of scenarios. We illustrate by examining whether SNP variants in GSTP1 modify the association between maternal smoking and oral clefting. Conclusion: Our procedure offers desirable features: no need for haplotype estimation, validity under unspecified genetic main effects, tolerance to Hardy-Weinberg disequilibrium, ability to handle missing genotypes and a relatively large number of SNPs. Simulations suggest resistance to bias due to exposure-related population stratification.

Copyright © 2010 S. Karger AG, Basel


 goto top of outline References
  1. Umbach DM, Weinberg CR: The use of case-parent triads to study joint effects of genotype and exposure. Am J Hum Genet 2000;66:251–261.
  2. Gauderman WJ: Sample size requirements for matched case-control studies of gene- environment interaction. Stat Med 2002;21:35–50.
  3. Schaid DJ: Case-parents design for gene- environment interaction. Genet Epidemiol 1999;16:261–273.
  4. Kistner EO, Shi M, Weinberg CR: Using cases and parents to study multiplicative gene-by-environment interaction. Am J Epidemiol 2009;170:393–400.
  5. Cordell HJ: Properties of case/pseudocontrol analysis for genetic association studies: effects of recombination, ascertainment, and multiple affected offspring. Genet Epidemiol 2004;26:186–205.
  6. Self SG, Longton G, Kopecky KJ, Liang KY: On estimating hla/disease association with application to a study of aplastic anemia. Biometrics 1991;47:53–61.
  7. Allen AS, Satten GA: Inference on haplotype/disease association using parent-affected-child data: the projection conditional on parental haplotypes method. Genet Epidemiol 2007;31:211–223.
  8. Dudbridge F: Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Hum Hered 2008;66:87–98.
  9. Vansteelandt S, Demeo DL, Lasky-Su J, Smoller JW, Murphy AJ, McQueen M, Schneiter K, Celedon JC, Weiss ST, Silverman EK, Lange C: Testing and estimating gene-environment interactions in family-based association studies. Biometrics 2008;64:458–467.
  10. Laird NM, Horvath S, Xu X: Implementing a unified approach to family-based tests of association. Genet Epidemiol 2000;19(suppl 1):S36–S42.
  11. Shi M, Umbach DM, Weinberg CR: Identification of risk-related haplotypes with the use of multiple snps from nuclear families. Am J Hum Genet 2007;81:53–66.
  12. Schaid DJ: General score tests for associations of genetic markers with disease using cases and their parents. Genet Epidemiol 1996;13:423–449.
  13. Weinberg CR, Wilcox AJ, Lie RT: A log-linear approach to case-parent-triad data: Assessing effects of disease genes that act either directly or through maternal effects and that may be subject to parental imprinting. Am J Hum Genet 1998;62:969–978.
  14. Piegorsch WW, Weinberg CR, Taylor JA: Non-hierarchical logistic models and case-only designs for assessing susceptibility in population-based case-control studies. Stat Med 1994;13:153–162.
  15. Zhang K, Sun F, Zhao H: Haplore: a program for haplotype reconstruction in general pedigrees without recombination. Bioinformatics 2005;21:90–103.
  16. Cordell HJ, Barratt BJ, Clayton DG: Case/pseudocontrol analysis in genetic association studies: a unified framework for detection of genotype and haplotype associations, gene-gene and gene-environment interactions, and parent-of-origin effects. Genet Epidemiol 2004;26:167–185.
  17. Raijmakers MT, Steegers EA, Peters WH: Glutathione s-transferases and thiol concentrations in embryonic and early fetal tissues. Hum Reprod 2001;16:2445–2450.
  18. Henderson CJ, Smith AG, Ure J, Brown K, Bacon EJ, Wolf CR: Increased skin tumorigenesis in mice lacking pi class glutathione s-transferases. Proc Natl Acad Sci USA 1998;95:5275–5280.
  19. Shi M, Christensen K, Weinberg CR, Romitti P, Bathum L, Lozada A, Morris RW, Lovett M, Murray JC: Orofacial cleft risk is increased with maternal smoking and specific detoxification-gene variants. Am J Hum Genet 2007;80:76–90.

 goto top of outline Author Contacts

Dr. Clarice R. Weinberg
Biostatistics Branch, Mail Drop: A3-03 101/A315
National Institute of Environmental Health Sciences
Research Triangle Park, NC 27709 (USA)
Tel. +1 919 541 4927, Fax +1 919 541 4311, E-Mail weinber2@niehs.nih.gov


 goto top of outline Article Information

Received: August 3, 2009
Accepted after revision: January 31, 2010
Published online: April 23, 2010
Number of Print Pages : 11
Number of Figures : 2, Number of Tables : 2, Number of References : 19


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 70, No. 1, Year 2010 (Cover Date: June 2010)

Journal Editor: Devoto M. (Philadelphia, Pa.)
ISSN: 0001-5652 (Print), eISSN: 1423-0062 (Online)

For additional information: http://www.karger.com/HHE


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Objective: Joint analysis of multiple SNP markers can be informative, but studying joint effects of haplotypes and environmental exposures is challenging. Population structure can involve both genes and exposures and a case-control study is susceptible to bias from either source of stratification. We propose a procedure that uses case-parent triad data and, though not fully robust, resists bias from population structure. Methods: Our procedure assumes that haplotypes under study have no influence on propensity to exposure. Then, under a no-interaction null hypothesis (multiplicative scale), transmission of a causative haplotype from parents to affected offspring might show distortion from Mendelian proportions but should be independent of exposure. We used this insight to develop a permutation test of no haplotype-by-exposure interaction. Results: Simulations showed that our proposed test respects the nominal Type I error rate and provides good power under a variety of scenarios. We illustrate by examining whether SNP variants in GSTP1 modify the association between maternal smoking and oral clefting. Conclusion: Our procedure offers desirable features: no need for haplotype estimation, validity under unspecified genetic main effects, tolerance to Hardy-Weinberg disequilibrium, ability to handle missing genotypes and a relatively large number of SNPs. Simulations suggest resistance to bias due to exposure-related population stratification.



 goto top of outline Author Contacts

Dr. Clarice R. Weinberg
Biostatistics Branch, Mail Drop: A3-03 101/A315
National Institute of Environmental Health Sciences
Research Triangle Park, NC 27709 (USA)
Tel. +1 919 541 4927, Fax +1 919 541 4311, E-Mail weinber2@niehs.nih.gov


 goto top of outline Article Information

Received: August 3, 2009
Accepted after revision: January 31, 2010
Published online: April 23, 2010
Number of Print Pages : 11
Number of Figures : 2, Number of Tables : 2, Number of References : 19


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 70, No. 1, Year 2010 (Cover Date: June 2010)

Journal Editor: Devoto M. (Philadelphia, Pa.)
ISSN: 0001-5652 (Print), eISSN: 1423-0062 (Online)

For additional information: http://www.karger.com/HHE


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Umbach DM, Weinberg CR: The use of case-parent triads to study joint effects of genotype and exposure. Am J Hum Genet 2000;66:251–261.
  2. Gauderman WJ: Sample size requirements for matched case-control studies of gene- environment interaction. Stat Med 2002;21:35–50.
  3. Schaid DJ: Case-parents design for gene- environment interaction. Genet Epidemiol 1999;16:261–273.
  4. Kistner EO, Shi M, Weinberg CR: Using cases and parents to study multiplicative gene-by-environment interaction. Am J Epidemiol 2009;170:393–400.
  5. Cordell HJ: Properties of case/pseudocontrol analysis for genetic association studies: effects of recombination, ascertainment, and multiple affected offspring. Genet Epidemiol 2004;26:186–205.
  6. Self SG, Longton G, Kopecky KJ, Liang KY: On estimating hla/disease association with application to a study of aplastic anemia. Biometrics 1991;47:53–61.
  7. Allen AS, Satten GA: Inference on haplotype/disease association using parent-affected-child data: the projection conditional on parental haplotypes method. Genet Epidemiol 2007;31:211–223.
  8. Dudbridge F: Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Hum Hered 2008;66:87–98.
  9. Vansteelandt S, Demeo DL, Lasky-Su J, Smoller JW, Murphy AJ, McQueen M, Schneiter K, Celedon JC, Weiss ST, Silverman EK, Lange C: Testing and estimating gene-environment interactions in family-based association studies. Biometrics 2008;64:458–467.
  10. Laird NM, Horvath S, Xu X: Implementing a unified approach to family-based tests of association. Genet Epidemiol 2000;19(suppl 1):S36–S42.
  11. Shi M, Umbach DM, Weinberg CR: Identification of risk-related haplotypes with the use of multiple snps from nuclear families. Am J Hum Genet 2007;81:53–66.
  12. Schaid DJ: General score tests for associations of genetic markers with disease using cases and their parents. Genet Epidemiol 1996;13:423–449.
  13. Weinberg CR, Wilcox AJ, Lie RT: A log-linear approach to case-parent-triad data: Assessing effects of disease genes that act either directly or through maternal effects and that may be subject to parental imprinting. Am J Hum Genet 1998;62:969–978.
  14. Piegorsch WW, Weinberg CR, Taylor JA: Non-hierarchical logistic models and case-only designs for assessing susceptibility in population-based case-control studies. Stat Med 1994;13:153–162.
  15. Zhang K, Sun F, Zhao H: Haplore: a program for haplotype reconstruction in general pedigrees without recombination. Bioinformatics 2005;21:90–103.
  16. Cordell HJ, Barratt BJ, Clayton DG: Case/pseudocontrol analysis in genetic association studies: a unified framework for detection of genotype and haplotype associations, gene-gene and gene-environment interactions, and parent-of-origin effects. Genet Epidemiol 2004;26:167–185.
  17. Raijmakers MT, Steegers EA, Peters WH: Glutathione s-transferases and thiol concentrations in embryonic and early fetal tissues. Hum Reprod 2001;16:2445–2450.
  18. Henderson CJ, Smith AG, Ure J, Brown K, Bacon EJ, Wolf CR: Increased skin tumorigenesis in mice lacking pi class glutathione s-transferases. Proc Natl Acad Sci USA 1998;95:5275–5280.
  19. Shi M, Christensen K, Weinberg CR, Romitti P, Bathum L, Lozada A, Morris RW, Lovett M, Murray JC: Orofacial cleft risk is increased with maternal smoking and specific detoxification-gene variants. Am J Hum Genet 2007;80:76–90.