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Vol. 59, No. 4, 2005
Issue release date: August 2005
Section title: Original Paper
Hum Hered 2005;59:220–227
(DOI:10.1159/000087122)

Linkage Disequilibrium Inflates Type I Error Rates in Multipoint Linkage Analysis when Parental Genotypes Are Missing

Boyles A.L. · Scott W.K. · Martin E.R. · Schmidt S. · Li Y.-J. · Ashley-Koch A. · Bass M.P. · Schmidt M. · Pericak-Vance M.A. · Speer M.C. · Hauser E.R.
Center for Human Genetics, Duke University Medical Center, Durham, N.C., USA
email Corresponding Author

Abstract

Objectives: Describe the inflation in nonparametric multipoint LOD scores due to inter-marker linkage disequilibrium (LD) across many markers with varied allele frequencies. Method: Using simulated two-generation families with and without parents, we conducted nonparametric multipoint linkage analysis with 2 to 10 markers with minor allele frequencies (MAF) of 0.5 and 0.1. Results: Misspecification of population haplotype frequencies by assuming linkage equilibrium caused inflated multipoint LOD scores due to inter-marker LD when parental genotypes were not included. Inflation increased as more markers in LD were included and decreased as markers in equilibrium were added. When marker allele frequencies were unequal, the r2 measure of LD was a better predictor of inflation than D′. Conclusion: This observation strongly supports the evaluation of LD in multipoint linkage analyses, and further suggests that unaccounted for LD may be suspected when two-point and multipoint linkage analyses show a marked disparity in regions with elevated r2 measures of LD. Given the increasing popularity of high-density genome-wide SNP screens, inter-marker LD should be a concern in future linkage studies.

© 2005 S. Karger AG, Basel


  

Key Words

  • Linkage disequilibrium
  • Measures of linkage disequilibrium
  • Linkage analysis
  • False positive rate
  • Parameter misspecification

References

  1. Matise TC, Sachidanandam R, Clark AG, Kruglyak L, Wijsman E, Kakol J, Buyske S, Chui B, Cohen P, de Toma C, Ehm M, Glanowski S, He C, Heil J, Markianos K, McMullen I, Pericak-Vance MA, Silbergleit A, Stein L, Wagner M, Wilson AF, Winick JD, Winn-Deen ES, Yamashiro CT, Cann HM, Lai E, Holden AL: A 3.9-centimorgan-resolution human single-nucleotide polymorphism linkage map and screening set. Am J Hum Genet 2003;73:271–284.
  2. Cardon LR, Abecasis GR: Using haplotype blocks to map human complex trait loci. Trends Genet 2003;19:135–140.
  3. Clerget-Darpoux F, Bonaiti-Pellie C, Hochez J: Effects of misspecifying genetic parameters in lod score analysis. Biometrics 1986;42:393–399.
  4. Ott J: Linkage analysis with misclassification at one locus. Clin Genet 1977;12:119–124.
  5. Risch N, Giuffra L: Model misspecification and multipoint linkage analysis. Hum Hered 1992;42:77–92.
  6. Huang Q, Shete S, Amos CI: Ignoring linkage disequilibrium among tightly linked markers induces false-positive evidence of linkage for affected sib pair analysis. Am J Hum Genet 2004;75:1106–1112.
  7. Bass MP, Martin ER, Hauser ER: Pedigree generation for analysis of genetic linkage and association. Pac Symp Biocomput 2004:93–103.

    External Resources

  8. Hauser ER, Boehnke M: Genetic linkage analysis of complex genetic traits by using affected sibling pairs. Biometrics 1998;54:1238–1246.
  9. Gibbs RA, The International HapMap Consortium: The International HapMap Project. Nature 2003;426:789–796.
  10. Terwilliger JD, Ott J: A haplotype-based ‘haplotype relative risk’ approach to detecting allelic associations. Hum Hered 1992;42:337–346.
  11. Abecasis GR, Wigginton JE: Linkage analysis with markers that are in linkage disequilibrium. Annual Meeting of the American Society of Human Genetics 2004, Abstract 94.

  

Author Contacts

Elizabeth R. Hauser, PhD
Duke University Medical Center
Box 3445
Durham, NC 27710 (USA)
Tel. +1 919 684 2063, Fax +1 919 684 2275, E-Mail Elizabeth.Hauser@duke.edu

  

Article Information

Received: November 19, 2004
Accepted after revision: May 6, 2005
Published online: July 26, 2005
Number of Print Pages : 8
Number of Figures : 4, Number of Tables : 2, Number of References : 11

  

Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 59, No. 4, Year 2005 (Cover Date: Released August 2005)

Journal Editor: Devoto, M. (Wilmington, Del.)
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

Objectives: Describe the inflation in nonparametric multipoint LOD scores due to inter-marker linkage disequilibrium (LD) across many markers with varied allele frequencies. Method: Using simulated two-generation families with and without parents, we conducted nonparametric multipoint linkage analysis with 2 to 10 markers with minor allele frequencies (MAF) of 0.5 and 0.1. Results: Misspecification of population haplotype frequencies by assuming linkage equilibrium caused inflated multipoint LOD scores due to inter-marker LD when parental genotypes were not included. Inflation increased as more markers in LD were included and decreased as markers in equilibrium were added. When marker allele frequencies were unequal, the r2 measure of LD was a better predictor of inflation than D′. Conclusion: This observation strongly supports the evaluation of LD in multipoint linkage analyses, and further suggests that unaccounted for LD may be suspected when two-point and multipoint linkage analyses show a marked disparity in regions with elevated r2 measures of LD. Given the increasing popularity of high-density genome-wide SNP screens, inter-marker LD should be a concern in future linkage studies.

© 2005 S. Karger AG, Basel


  

Author Contacts

Elizabeth R. Hauser, PhD
Duke University Medical Center
Box 3445
Durham, NC 27710 (USA)
Tel. +1 919 684 2063, Fax +1 919 684 2275, E-Mail Elizabeth.Hauser@duke.edu

  

Article Information

Received: November 19, 2004
Accepted after revision: May 6, 2005
Published online: July 26, 2005
Number of Print Pages : 8
Number of Figures : 4, Number of Tables : 2, Number of References : 11

  

Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 59, No. 4, Year 2005 (Cover Date: Released August 2005)

Journal Editor: Devoto, M. (Wilmington, Del.)
ISSN: 0001–5652 (print), 1423–0062 (Online)

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


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 11/19/2004
Accepted: 5/6/2005
Published online: 8/19/2005
Issue release date: August 2005

Number of Print Pages: 8
Number of Figures: 4
Number of Tables: 2

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. Matise TC, Sachidanandam R, Clark AG, Kruglyak L, Wijsman E, Kakol J, Buyske S, Chui B, Cohen P, de Toma C, Ehm M, Glanowski S, He C, Heil J, Markianos K, McMullen I, Pericak-Vance MA, Silbergleit A, Stein L, Wagner M, Wilson AF, Winick JD, Winn-Deen ES, Yamashiro CT, Cann HM, Lai E, Holden AL: A 3.9-centimorgan-resolution human single-nucleotide polymorphism linkage map and screening set. Am J Hum Genet 2003;73:271–284.
  2. Cardon LR, Abecasis GR: Using haplotype blocks to map human complex trait loci. Trends Genet 2003;19:135–140.
  3. Clerget-Darpoux F, Bonaiti-Pellie C, Hochez J: Effects of misspecifying genetic parameters in lod score analysis. Biometrics 1986;42:393–399.
  4. Ott J: Linkage analysis with misclassification at one locus. Clin Genet 1977;12:119–124.
  5. Risch N, Giuffra L: Model misspecification and multipoint linkage analysis. Hum Hered 1992;42:77–92.
  6. Huang Q, Shete S, Amos CI: Ignoring linkage disequilibrium among tightly linked markers induces false-positive evidence of linkage for affected sib pair analysis. Am J Hum Genet 2004;75:1106–1112.
  7. Bass MP, Martin ER, Hauser ER: Pedigree generation for analysis of genetic linkage and association. Pac Symp Biocomput 2004:93–103.

    External Resources

  8. Hauser ER, Boehnke M: Genetic linkage analysis of complex genetic traits by using affected sibling pairs. Biometrics 1998;54:1238–1246.
  9. Gibbs RA, The International HapMap Consortium: The International HapMap Project. Nature 2003;426:789–796.
  10. Terwilliger JD, Ott J: A haplotype-based ‘haplotype relative risk’ approach to detecting allelic associations. Hum Hered 1992;42:337–346.
  11. Abecasis GR, Wigginton JE: Linkage analysis with markers that are in linkage disequilibrium. Annual Meeting of the American Society of Human Genetics 2004, Abstract 94.