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Table of Contents
Vol. 64, No. 4, 2007
Issue release date: July 2007
Hum Hered 2007;64:203–213
(DOI:10.1159/000103512)

Non-Replication and Inconsistency in the Genome-Wide Association Setting

Ioannidis J.P.A.
Clinical and Molecular Epidemiology Unit and Evidence-Based Medicine and Clinical Trials Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Biomedical Research Institute-Foundation for Research and Technology-Hellas, Ioannina, Greece; Department of Medicine, Tufts University School of Medicine, Boston, Mass.., USA
email Corresponding Author

Abstract

Non-replication and inconsistency had been common features in the search for common variants of candidate genes affecting the risk of complex diseases. They may continue to require attention in the current era, when massive hypothesis-free testing of genetic variants is feasible. An empirical evaluation of the early experience with genome-wide association (GWA) studies suggests several examples where proposed associations have failed to be replicated by subsequent investigations. Non-replication and inconsistency is defined here in the framework of cumulative meta-analysis. Ideally, associations exist, GWA finds them, and subsequent investigations should replicate them. However, a number of other possibilities need to be considered. No common genetic variants may associate with the phenotype of interest and GWA may find nothing; or associations may exist, but GWA may miss them. Associations that do not exist may be falsely selected by the GWA and subsequent studies may appropriately refute them or falsely replicate them. Finally, GWA may find true associations that are nevertheless falsely non-replicated in the subsequent studies; or associations may be genuinely inconsistent across study populations. A list of options is presented for consideration in each of these scenarios.


 goto top of outline Key Words

  • Replication
  • Heterogeneity
  • Inconsistency
  • Bias
  • Genome-wide association
  • Gene
  • Polymorphism

 goto top of outline Abstract

Non-replication and inconsistency had been common features in the search for common variants of candidate genes affecting the risk of complex diseases. They may continue to require attention in the current era, when massive hypothesis-free testing of genetic variants is feasible. An empirical evaluation of the early experience with genome-wide association (GWA) studies suggests several examples where proposed associations have failed to be replicated by subsequent investigations. Non-replication and inconsistency is defined here in the framework of cumulative meta-analysis. Ideally, associations exist, GWA finds them, and subsequent investigations should replicate them. However, a number of other possibilities need to be considered. No common genetic variants may associate with the phenotype of interest and GWA may find nothing; or associations may exist, but GWA may miss them. Associations that do not exist may be falsely selected by the GWA and subsequent studies may appropriately refute them or falsely replicate them. Finally, GWA may find true associations that are nevertheless falsely non-replicated in the subsequent studies; or associations may be genuinely inconsistent across study populations. A list of options is presented for consideration in each of these scenarios.

Copyright © 2007 S. Karger AG, Basel


 goto top of outline References
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 goto top of outline Author Contacts

Prof. John P.A. Ioannidis, Chairman
Department of Hygiene and Epidemiology
University of Ioannina School of Medicine
GR–45110 Ioannina (Greece)
Tel. +30 265 109 7807, Fax +30 265 109 7867, E-Mail jioannid@cc.uoi.gr


 goto top of outline Article Information

Received: February 5, 2007
Accepted after revision: April 4, 2007
Published online: June 6, 2007
Number of Print Pages : 11
Number of Figures : 2, Number of Tables : 3, Number of References : 87


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 64, No. 4, Year 2007 (Cover Date: July 2007)

Journal Editor: Devoto, M. (Philadelphia, Pa.)
ISSN: 0001–5652 (print), 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

Non-replication and inconsistency had been common features in the search for common variants of candidate genes affecting the risk of complex diseases. They may continue to require attention in the current era, when massive hypothesis-free testing of genetic variants is feasible. An empirical evaluation of the early experience with genome-wide association (GWA) studies suggests several examples where proposed associations have failed to be replicated by subsequent investigations. Non-replication and inconsistency is defined here in the framework of cumulative meta-analysis. Ideally, associations exist, GWA finds them, and subsequent investigations should replicate them. However, a number of other possibilities need to be considered. No common genetic variants may associate with the phenotype of interest and GWA may find nothing; or associations may exist, but GWA may miss them. Associations that do not exist may be falsely selected by the GWA and subsequent studies may appropriately refute them or falsely replicate them. Finally, GWA may find true associations that are nevertheless falsely non-replicated in the subsequent studies; or associations may be genuinely inconsistent across study populations. A list of options is presented for consideration in each of these scenarios.



 goto top of outline Author Contacts

Prof. John P.A. Ioannidis, Chairman
Department of Hygiene and Epidemiology
University of Ioannina School of Medicine
GR–45110 Ioannina (Greece)
Tel. +30 265 109 7807, Fax +30 265 109 7867, E-Mail jioannid@cc.uoi.gr


 goto top of outline Article Information

Received: February 5, 2007
Accepted after revision: April 4, 2007
Published online: June 6, 2007
Number of Print Pages : 11
Number of Figures : 2, Number of Tables : 3, Number of References : 87


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 64, No. 4, Year 2007 (Cover Date: July 2007)

Journal Editor: Devoto, M. (Philadelphia, Pa.)
ISSN: 0001–5652 (print), 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

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  2. Thomas DC, Haile RW, Duggan D: Recent developments in genomewide association scans: A workshop summary and review. Am J Hum Genet 2005;77:337–345.
  3. Wang WY, Barratt BJ, Clayton DG, Todd JA: Genome-wide association studies: Theoretical and practical concerns. Nat Rev Genet 2005;6:109–118.
  4. Hirschhorn JN, Daly MJ: Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 2005;6:95–108.
  5. Thomas DC: Are we ready for genome-wide association studies? Cancer Epidemiol Biomarkers Prev 2006;15:595–598.
  6. Marchini J, Donnelly P, Cardon LR: Genome-wide strategies for detecting multiple loci that influence complex diseases. Nat Genet 2005;37:413–417.
  7. Wang H, Thomas DC, Pe’er I, Stram DO: Optimal two-stage genotyping designs for genome-wide association scans. Genet Epidemiol 2006;30:356–368.
  8. Thomas D, Xie R, Gebregziabher M: Two-stage sampling designs for gene association studies. Genet Epidemiol 2004;27:401–414.
  9. Kuchiba A, Tanaka NY, Ohashi Y: Optimum two-stage designs in case-control association studies using false discovery rate. J Hum Genet 2006;51:1046–1054.
  10. Skol AD, Scott LJ, Abecasis GR, Boehnke M: Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat Genet 2006;38:209–213.
  11. Todd JA: Statistical false positive or true disease pathway? Nat Genet 2006;38:731–733.
  12. Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG: Replication validity of genetic association studies. Nat Genet 2001;29:306–309.
  13. Wacholder S, Chanock S, Garcia-Closas M, El Ghormli L, Rothman N: Assessing the probability that a positive report is false: An approach for molecular epidemiology studies. J Natl Cancer Inst 2004;96:434–442.
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