Hum Hered 2001;51:64–78

A Robust Identity-by-Descent Procedure Using Affected Sib Pairs: Multipoint Mapping for Complex Diseases

Liang K.-Y.a · Chiu Y.-F.a · Beaty T.H.b
Departments of aBiostatistics and bEpidemiology, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Md., USA
email Corresponding Author

 goto top of outline Key Words

  • Affected sib pairs
  • Generalized estimating equations
  • Identity by descent
  • Multipoint
  • Robustness
  • Sample size and power

 goto top of outline Abstract

Multipoint linkage analysis is a powerful tool to localize susceptibility genes for complex diseases. However, the conventional lod score method relies critically on the correct specification of mode of inheritance for accurate estimation of gene position. On the other hand, allele-sharing methods, as currently practiced, are designed to test the null hypothesis of no linkage rather than estimate the location of the susceptibility gene(s). In this paper, we propose an identity-by-descent (IBD)-based procedure to estimate the location of an unobserved susceptibility gene within a chromosomal region framed by multiple markers. Here we deal with the practical situation where some of the markers might not be fully informative. Rather the IBD statistic at an arbitrary within the region is imputed using the multipoint marker information. The method is robust in that no assumption about the genetic mechanism is required other than that the region contains no more than one susceptibility gene. In particular, this approach builds upon a simple representation for the expected IBD at any arbitrary locus within the region using data from affected sib pairs. With this representation, one can carry out a parametric inference procedure to locate an unobserved susceptibility gene. In addition, here we derive a sample size formula for the number of affected sib pairs needed to detect linkage with multiple markers. Throughout, the proposed method is illustrated through simulated data. We have implemented this method including exploratory and formal model-fitting procedures to locate susceptibility genes, plus sample size and power calculations in a program, GENEFINDER, which will be made available shortly.

Copyright © 2000 S. Karger AG, Basel

 goto top of outline References
  1. Goldin LR: Detection of linkage under heterogeneity: comparison of two-locus vs. Admixture models. Genet Epidemiol 1992;9:61–66.
  2. Haldane JBS: The combination of linkage values and the calculation of distances between the loci of linked factors. J Genet 1919;8:299–309.
  3. Haseman JK, Elston RC: The investigation of linkage between a quantitative trait and a marker locus. Behav Genet 1972;2:3–19.
  4. Hauser ER, Boehnke M: Genetic linkage analysis of complex genetic traits by using affected sibling pairs. Biometrics 1998;54:1238–1246.
  5. Hodge SE, Elston R: Lods, wrods, and mods: The interpretation of lod scores calculated under different models. Genet Epidemiol 1994;11:329–342.
  6. Hodge SE, Vieland VJ: The essence of single ascertainment. Genetics 1996;144:1214–1223.
  7. Huber PJ: Robust estimation of a location parameter. Ann Math Statist 1964;35:73–101.
  8. Huber PJ: The behavior of maximum likelihood estimators under non-standard conditions. Proceedings of the Fifth Berkeley Symposium on Mathematical Statistics and Probability, 1967, vol 1, pp 221–233.
  9. Kong A, Cox NJ: Allele-sharing models: Lod scores and accurate linkage tests. Am J Hum Genet 1997;61:1179–1188.
  10. Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES: Parametric and nonparametric linkage analysis: A unified multipoint approach. Am J Hum Genet 1996;58:1347–1363.
  11. Lander ES, Kruglyak L: Genetic dissection of complex traits: Guidelines for interpreting and reporting linkage results. Nat Genet 1995;11:241–247.
  12. Liang KY, Rathouz PJ, Beaty TH: Determining linkage and mode of inheritance: Mod scores and other methods. Genet Epidemiol 1996;13:575–593.
  13. Liang KY, Zeger SL: Longitudinal data analysis using generalized linear models. Biometrika 1986;73:13–22.
  14. MacLean CJ, Bishop DT, Sherman SL, Diehl SR: Distribution of lod scores under uncertain mode of inheritance. Am J Hum Genet 1993;52:354–361.
  15. Risch N: Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet 1990a;46:222–228.
  16. Risch N: Linkage strategies for genetically complex traits: II. The power of affected relative pairs. Am J Hum Genet 1990b;46:229–241.
  17. Schork NJ, Boehnke M, Terwilliger JD, Ott J: Two-trait-locus linkage analysis: A powerful strategy for mapping complex genetic traits. Am J Hum Genet 1993;53:1127–1136.
  18. Smith CAB: Testing for heterogeneity of recombination fraction values in human genetics. Ann Hum Genet 1963;27:175–182.
  19. Suarez BK, Rice J, Reich T: The generalized sib pair IBD distribution: Its use in the detection of linkage. Am Hum Genet 1978;42:87–94.
  20. Teng J, Siegmund D: Multipoint linkage analysis using affected relative pairs and partially informative markers. Biometrics 1998;54:1247–1265.
  21. Vieland VJ, Hodge SE, Greenberg DA: Adequacy of single-locus approximations for linkage analysis of oligogenic traits. Genet Epidemiol 1992;9:45–59.

    External Resources

  22. Whittemore AS: Genome scanning for linkage: An overview. Am J Hum Genet 1996;59:704–716.
  23. Whittemore AS, Halpern J: A class of tests for linkage using affected pedigree members. Biometrics 1994;50:118–127.

 goto top of outline Author Contacts

Dr. Kung-Yee Liang
Department of Biostatistics, School of Hygiene and Public Health
Johns Hopkins University
Baltimore, MD 21205 (USA)
Fax +1 410 955 0958

 goto top of outline Article Information

Received: Received: May 21, 1999
Revision received: September 10, 1999
Accepted: October 6, 1999
Number of Print Pages : 15
Number of Figures : 9, Number of Tables : 1, Number of References : 23

 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. 51, No. 1-2, Year 2001 (Cover Date: Released October 2000)

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

For additional information:

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.