Login to MyKarger

New to MyKarger? Click here to sign up.



Login with Facebook

Forgot your password?

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login
(Shibboleth or Open Athens)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Original Paper

Free Access

Assessing Genuine Parents-Offspring Trios for Genetic Association Studies

Teo Y.Y.a, · Fry A.E.a, · Sanjoaquin M.A.a · Pederson B.c · Small K.S.a · Rockett K.A.a · Kwiatkowski D.P.a, b · Clark T.G.a, b

Author affiliations

aWellcome Trust Centre for Human Genetics, University of Oxford, Oxford, and bWellcome Trust Sanger Institute, Hinxton, Cambridge, UK; cUniversity of Iowa, Iowa City, Iowa, USA

Corresponding Author

Yik Y. Teo, DPil

Wellcome Trust Centre for Human Genetics

Roosevelt Drive

Oxford OX3 7BN (UK)

Tel. +44 1865 287 712; Fax +44 1865 287 501, E-Mail teo@well.ox.ac.uk

Related Articles for ""

Hum Hered 2009;67:26–37

Do you have an account?

Login Information





Contact Information












By signing up for MyKarger you will automatically participate in our year-End raffle.
If you Then Do Not wish To participate, please uncheck the following box.

Yes, I wish To participate In the year-End raffle And Get the chance To win some Of our most interesting books, And other attractive prizes.


I have read the Karger Terms and Conditions and agree.



Abstract

Objectives: Family-based association tests such as the transmission disequilibrium test (TDT) are dependent on the successful ascertainment of true nuclear family trios. Relationship misspecification inevitably occurs in a proportion of trios collected for genotyping which undetected can lead to a loss of power and increased Type I error due to biases in over-transmission of common alleles. Here, we introduce a method for evaluating the authenticity of nuclear family trios. Methods: Operating in a Bayesian framework, our approach assesses the extent of pedigree inconsistent genotype configurations in the presence of genotyping errors. Unlike other approaches, our method: (i) utilizes information from three individuals collectively (the whole trio) rather than consider two independent pairwise relationships; (ii) down-weighs SNPs with poor performance; (iii) does not require the user to pre-define a rate of genotyping error, which is often unknown to the user and seldom fixed across the different SNPs considered which available methods unrealistically assumed. Results: Simulation studies and comparisons with a real set of data showed that our approach is more likely to correctly identify the presence of true and misspecified trios compared to available software, accurately infers the extent of relationship misspecification in a trio and accurately estimates the genotyping error rates. Conclusions: Assessing relationship misspecification depends on the fidelity of the genotype data used. Available algorithms are not optimised for genotyping technology with varying rates of errors across the markers. Through our comparison studies, our approach is shown to outperform available methods for assessing relationship misspecifications.

© 2008 S. Karger AG, Basel


References

  1. Wellcome Trust Case Control Consortium: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007;447:661–678.
  2. Cavalli-Sforza LL, Menozzi P, Piazza A: The history and geography of human genes. Princeton, Princeton University Press, 1994.
  3. Reich DE, Goldstein DB: Detecting association in a case-control study while correcting for population stratification. Genet Epidemiol 2001;20:4–16.
  4. Freedman ML, Reich D, Penney KL, McDonald GJ, Mignault AA, Patterson N, Gabriel SB, Topol EJ, Smoller JW, Pato CN, Pato MT, Petryshen TL, Kolonel LN, Lander ES, Sklar P, Henderson B, Hirschhorn JN, Altshuler D: Assessing the impact of population stratification on genetic association studies. Nat Genet 2004;36:388–393.
  5. Marchini J, Cardon LR, Phillips MS, Donnelly P: The effects of human population structure on large genetic association studies. Nat Genet 2004;36:512–517.
  6. Helgason A, Yngvadóttir B, Hrafnkelsson B, Gulcher J, Stefánsson K: An Icelandic example of the impact of population structure on association studies. Nat Genet 2005;37:90–95.
  7. Laird NM, Lange C: Family-based designs in the age of large-scale gene-association studies. Nat Rev Genet 2006;7:385–394.
  8. Falk CT, Rubinstein P: Haplotype relative risks: an easy reliable way to construct a proper control sample for risk calculations. Ann Hum Genet 1987;51:227–233.
  9. Thomson G: Mapping disease genes: family-based association studies. Am J Hum Genet 1995;57:487–498.
  10. Terwilliger JD, Ott J: A haplotype-based ‘haplotype relative risk’ approach to detecting allelic associations. Hum Hered 1992;42:337–346.
  11. Spielman RS, McGinnis RE, Ewens WJ: Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993;52:506–516.
  12. 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.
  13. Laird NM, Horvath S, Xu X: Implementing a unified approach to family-based tests of association. Genet Epidemiol 2000;19:S36–S42.
  14. Cordell HJ, Clayton DG: A unified stepwise regression procedure for evaluating the relative effects of polymorphisms within a gene using case/control or family data: application to HLA in type 1 diabetes. Am J Hum Genet 2002;70:124–141.
  15. Ewens WJ, Spielman RS: The transmission/disequilibrium test: history, subdivision, and admixture. Am J Hum Genet 1995;57:455–464.
  16. Bellis MA, Hughes K, Hughes S, Ashton JR: Measuring paternal discrepancy and its public health consequences. J Epidemiol Community Health 2005;59:749–754.
  17. Cerda-Flores RM, Barton SA, Marty-Gonzalex LF, Rivas F, Chakraborty R: Estimation of nonpaternity in the Mexican population of Nuevo Leon: a validation study with blood group markers. Am J Phys Anthropol 1999;109:281–293.
  18. Gordon D, Matise TC, Heath SC, Ott J: Power loss for multiallelic transmission/disequilibrium test when errors introduced: GAW11 simulated data. Genet Epidemiol 1999;17:S587–S592.
  19. Heath SC: A bias in TDT due to undetected genotyping errors. Am J Hum Genet Suppl 1998;63:A292.
  20. Mitchell AA, Cutler DJ, Chakravarti A: Undetected genotyping errors cause apparent overtransmission of common alleles in the transmission/disequilibrium test. Am J Hum Genet 2003;72:598–610.
  21. Gordon D, Heath SC, Liu X, Ott J: A transmission/disequilibrium test that allows for genotyping errors in the analysis of single-nucleotide polymorphism data. Am J Hum Genet 2001;69:371–380.
  22. Gordon D, Haynes C, Johnnidis C, Patel SB, Bowcock AM, Ott J: A transmission disequilibrium test for general pedigrees that is robust to the presence of random genotyping errors and any number of untyped parents. Eur J Hum Genet 2004;12:752–761.
  23. Gordon D, Heath SC, Ott J: True pedigree errors more frequent than apparent errors for single nucleotide polymorphisms. Hum Hered 1999;49:65–70.
  24. Blouin MS, Parsons M, Lacaille V, Lotz S: Use of microsatellite loci to classify individuals by relatedness. Mol Ecol 1996;5:393–401.
  25. Boehnke M, Cox NJ: Accurate inference of relationships in sib-pair linkage studies. Am J Hum Genet 1997;61:423–429.
  26. Broman KW, Weber JL: Estimation of pairwise relationships in the presence of genotyping errors. Am J Hum Genet 1998;63:1563–1564.
  27. Lynch M, Ritland K: Estimation of pairwise relatedness with molecular markers. Genetics 1999;152:1753–1766.
  28. Epstein MP, Duren WL, Boehnke M: Improved inference of relationship for pairs of individuals. Am J Hum Genet 2000;67:1219–1231.
  29. Sieberts SK, Wijsman EM, Thompson EA: Relationship inference from trios of individuals, in the presence of typing error. Am J Hum Genet 2002;70:170–180.
  30. Wang J: An estimator of pairwise relatedness using molecular markers. Genetics 2002;160:1203–1215.
  31. Blouin MS: DNA-based methods for pedigree reconstruction and kinship analysis in natural populations. Trends Ecol Evol 2003;18:503–511.
  32. Jones AG, Ardren WR: Methods of parentage analysis in natural populations. Mol Ecol 2003;12:2511–2523.
  33. Gilks WR, Richardson S, Spiegelhalter DJ (eds): Markov chain Monte Carlo in practice. London, Chapman & Hall, 1996.
  34. Leal SM, Yan K, Müller-Myhsok B: SimPed: A simulation program to generate haplotype and genotype data for pedigree structures. Hum Hered 2005;60:119–122.
  35. McPeek M, Sun L: Statistical tests for detection of misspecified relationships by use of genome-screen data. Am J Hum Genet 2000;66:1076–1094.
  36. Duren WL, Epstein M, Li M, Boehnke M: RELPAIR: A Program That Infers the Relationships of Pairs of Individuals Based on Marker Data. Version 2.0.1, http://csg.sph.umich.edu/boehnke/relpair.php, 2004.
  37. International HapMap Consortium: A haplotype map of the human genome. Nature 2005;437:1299–1320.

Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: October 18, 2007
Accepted: December 20, 2007
Published online: October 17, 2008
Issue release date: November 2008

Number of Print Pages: 12
Number of Figures: 4
Number of Tables: 4

ISSN: 0001-5652 (Print)
eISSN: 1423-0062 (Online)

For additional information: https://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.
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 government 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.