Vol. 73, No. 1, 2012
Issue release date: March 2012
Free Access
Hum Hered 2012;73:1–13
Original Paper
Add to my selection

A Generalized Sequential Bonferroni Procedure Using Smoothed Weights for Genome-Wide Association Studies Incorporating Information on Hardy-Weinberg Disequilibrium among Cases

Gao G.a · Kang G.b · Wang J.a · Chen W.a · Qin H.c · Jiang B.d · Li Q.e · Sun C.a · Liu N.d · Archer K.J.a · Allison D.B.d
aDepartment of Biostatistics, Virginia Commonwealth University, Richmond, Va., bDepartment of Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pa., cDepartment of Biostatistics and Epidemiology, Case Western Reserve University, Cleveland, Ohio, and dDepartment of Biostatistics, University of Alabama at Birmingham, Birmingham, Ala., USA; eAcademy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, PR China
email Corresponding Author

 goto top of outline Key Words

  • Generalized sequential Bonferroni procedure
  • Genome-wide association studies
  • Hardy-Weinberg disequilibrium
  • Multiple testing
  • Smoothed weights

 goto top of outline Abstract

Background/Objectives: For genome-wide association studies (GWAS) with case-control designs, one of the most widely used association tests is the Cochran-Armitage (CA) trend test assuming an additive mode of inheritance. The CA trend test often has higher power than other association tests under additive and multiplicative disease models. However, it can have very low power under a recessive disease model in GWAS. Although tests (such as MAX3) robust to different genetic models have been developed, they often have relatively lower power than the CA trend test under additive and multiplicative models. The goal of this study is to propose an efficient method that not only has higher power than the CA trend test under dominant and recessive models but also maintains the power of the CA trend test under additive and multiplicative models. Methods: We employed the generalized sequential Bonferroni (GSB) procedure of Holm to incorporate information from a Hardy-Weinberg disequilibrium (HWD) test into the CA trend test based on estimating weights from the p values of the HWD test. We proposed to smooth the weights to reduce possible noise. Results and Conclusions: Results from extensive simulation studies showed that the proposed GSB procedure can achieve the goal described above.

Copyright © 2011 S. Karger AG, Basel

 goto top of outline References
  1. Cochran WG: Some methods for strengthening the common χ2 tests. Biometrics 1954;10:417–451.

    External Resources

  2. Armitage P: Tests for linear trends in proportions and frequencies. Biometrics 1955;11:375–386.

    External Resources

  3. Sasieni PD: From genotypes to genes: doubling the sample size. Biometrics 1997;53:1253–1261.
  4. Zheng G, Ng HKT: Genetic model selection in two-phase analysis for case-control association studies. Biostatistics 2008;9:391–399.
  5. Nielsen DM, Ehm MG, Weir BS: Detecting marker-disease association by testing for Hardy-Weinberg disequilibrium at a marker locus. Am J Hum Genet 1999;63:1531–1540.
  6. Song K, Elston RC: A powerful method of combining measures of association and Hardy-Weinberg disequilibrium for fine-mapping in case-control studies. Stat Med 2006;25:105–126.
  7. Fisher RA: Statistical Methods for Research Workers. Oliver and Boyd, London, 1932.
  8. Hoh J, Wille A, Ott J: Trimming, weighting, and grouping SNPs in human case-control association studies. Genome Res 2001;11:2115–2119.
  9. Freidlin B, Zheng G, Li Z, Gastwirth JL: Trend tests for case-control studies of genetic markers: power, sample size and robustness. Hum Hered 2002;53:146–152 (erratum in Hum Hered 2009;68:220).
  10. Li Q, Zheng G, Li Z, Yu K: Efficient approximation of P-value of the maximum of correlated tests, with applications to genome-wide association studies. Ann Hum Genet 2008;72:397–406.
  11. Zang Y, Fung WK, Zheng G: Simple algorithms to calculate asymptotic null distributions for robust tests in case-control genetic association studies in R. J Stat Softw 2010;33:issue 8.
  12. Joo J, Kwak M, Zheng G: Improving power for testing genetic association in case-control studies by reducing alternative space. Biometrics 2009;66:266–276.
  13. Joo J, Kwak M, Ahn K, Zheng G: A robust genome-wide scan statistic of the Wellcome Trust Case-Control Consortium. Biometrics 2009;65:1115–1122.
  14. Holm S: A simple sequentially rejective multiple test procedure. Scand J Statist 1979;6:65–70.

    External Resources

  15. The Wellcome Trust Case Control Consortium (WTCCC): Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007;447:661–683.
  16. Weir BS: Genetic Data Analysis II: Methods for Discrete Population Genetic Data. Sinauer Associates, Inc., Sunderland, Mass., 1996.
  17. Zang Y, Fung WK, Zheng G: Tail strength to combine two p values: their correlation cannot be ignored. Am J Hum Genet 2009;84:291–295.
  18. Wigginton JE, Cutler DJ, Abecasis GR: A note on exact tests of Hardy-Weinberg equilibrium. Am J Hum Genet 2005;76:887–893.
  19. Yates F: Contingency tables involving small numbers and the χ2 test. J R Stat Soc (suppl) 1934;1:217–235.
  20. Kang G, Ye K, Liu N, Allison DB, Gao G: Weighted multiple hypothesis testing procedures. Stat Appl Genet Mol Biol 2009;8:Article 23.
  21. Roeder K, Wasserman L: Genome-wide significance levels and weighted hypothesis testing. Stat Sci 2009;24:398–413.
  22. Roeder K, Devlin B, Wasserman L: Improving power in genome-wide association studies: weights tip the scale. Genet Epidemiol 2007;31:741–747.
  23. Rohlfs RV, Weir BS: Distributions of Hardy-Weinberg equilibrium test statistics. Genetics 2008;180:1609–1616.
  24. Schaid DJ, Sommer SS: Genotype relative risks: methods for design and analysis of candidate-gene association studies. Am J Hum Genet 1993;53:1114–1126.
  25. Terwilliger JD, Ott J: Handbook of Human Genetic Linkage. Johns Hopkins University Press, Baltimore, 1994.
  26. Wu MC, Kraft P, Epstein MP, Taylor DM, Chanock SJ, Hunter DJ, Lin X: Powerful SNP-set analysis for case-control genome-wide association studies. Am J Hum Genet 2010;86:929–942.
  27. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D: Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006;38:904–909.
  28. Serfling RJ: Approximation Theorems of Mathematical Statistics. John Wiley & Sons, New York, 1980.

 goto top of outline Author Contacts

Guimin Gao
Department of Biostatistics, Virginia Commonwealth University
PO Box 980032
Richmond, VA 23298-0032 (USA)
Tel. +1 804 827 2775, E-Mail ggao3@vcu.edu

 goto top of outline Article Information

Guimin Gao and Guolian Kang contributed equally to this work.

Received: June 15, 2011
Accepted after revision: September 7, 2011
Published online: December 30, 2011
Number of Print Pages : 13
Number of Figures : 0, Number of Tables : 5, Number of References : 28
Additional supplementary material is available online - Number of Parts : 1

 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 73, No. 1, Year 2012 (Cover Date: March 2012)

Journal Editor: Devoto M. (Philadelphia, Pa./Rome)
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.