- Family-based association
- Linkage disequilibrium
- Haplotype analysis
- Rare alleles and rare haplotypes
- Hardy-Weinberg disequilibrium
Objective: The Association in the Presence of Linkage test (APL) is a powerful statistical method that allows for missing parental genotypes in nuclear families. However, in its original form, the statistic does not easily extend to mixed nuclear family structures nor to multiple-marker haplotypes. Furthermore, the robustness of APL in practice has not been examined. Here we present a generalization of the APL model and examination of its robustness under a variety of non-standard scenarios. Methods: The generalization is made possible by incorporating a bootstrap variance estimator instead of the original robust variance estimator. This allows for use of more than two affected siblings. Haplotype analysis was accomplished by combining estimation of haplotype phase into the EM algorithm. Computer simulation was used to examine robustness of the APL to departures from test assumptions. Results: The extended APL tests both single-marker and multiple-marker haplotypes and shows more power than other association methods. Simulation results showed that the single-marker APL test is robust to the departure from HWE. For the haplotype test, violation of the HWE assumption can inflate type I error. We also evaluated general guidelines for the validity of APL with rare alleles and rare haplotypes. Software for the APL test is available from http://www.chg.duke.edu/research/apl.html.
Copyright © 2006 S. Karger AG, Basel
- 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.
- Martin ER, Kaplan NL, Weir BS: Tests for linkage and association in nuclear families. Am J Hum Genet 1997;61:439–448.
- Martin ER, Monks SA, Warren LL, Kaplan NL: A test for linkage and association in general pedigrees: the pedigree disequilibrium test. Am J Hum Genet 2000;67:146–154.
- Abecasis GR, Cookson WOC, Cardon LR: Pedigree tests of transmission disequilibrium. Eur J Hum Genet 2000;8:545–551.
- Rabinowitz D, Laird N: A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Hum Hered 2000;50:211–223.
- Horvath SM and Laird NM: A discordant-sibship test for disequilibrium and linkage: no need for parental data. Am J Hum Genet 1998;63:1886–1897.
- Monks SA, Kaplan NL, Weir BS: A comparative study of sibship tests of linkage and/or association. Am J Hum Genet 1998;63:1507–1516.
- Clayton D: A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. Am J Hum Genet 1999;65:1170–1177.
- Knapp M: The transmission/disequilibrium test and parental genotype reconstruction: the reconstruction-combined transmission/disequilibrium test. Am J Hum Genet 1999;64:861–870.
- Weinberg C: Allowing for missing parents in genetic studies of case-parent triads. Am J Hum Genet 1999;64:1186–1193.
- Martin, ER, Bass MP, Hauser ER, Kaplan NL: Accounting for linkage in family-based tests of association with missing parental genotypes. Am J Hum Genet 2003;73:1016–1026.
- Martin ER, Lai EH, Gilbert JR, Rogala AR, Afshari AJ, Riley J, Finch KL, Stevens JF, Livak KJ, Slotterbeck BD, Slifer SH, Warren LL, Conneally PM, Schmechel DE, Purvis I, Pericak-Vance MA, Roses AD, Vance JM: SNPing away at complex diseases: analysis of single-nucleotide polymorphisms around APOE in Alzheimer disease. Am J Hum Genet 2000;67:383–394.
- Lake SL, Blacker D, Laird NM: Family-based tests of association in the presence of linkage. Am J Hum Genet 2000;67:1515–1525.
- Dudbridge F: Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 2003;25:115–121.
- Horvath S, Xu X, Lake SL, Silverman EK, Weiss ST, Laird NM: Family-based tests for associating haplotypes with general phenotype data: application to asthma genetics. Genet Epidemiol 2004;26:61–69.
- Efron B, Tibshirani RJ: An introduction to the Bootstrap. Chapman & Hall/CRC, 1993.
- Whittemore AS, Tu IP: Simple, robust linkage tests for affected sibs. Am J Hum Genet 1998;62:1228–1242.
- Rao CR: Generalized inverse of matrices and its applications. Wiley, New York, 1971.
- Bass M, Martin ER, Hauser E: Pedigree generation for analysis of genetic linkage and association. Pac Symp Biocomput 2004;93–103.
Eden R. Martin, PhD
Duke University Medical Center, Box 3468
Durham, NC 27710 (USA)
Tel. +1 919 684 0601, Fax +1 919 684 0915
Received: February 3, 2006
Accepted after revision: May 10, 2006
Published online: July 27, 2006
Number of Print Pages : 11
Number of Figures : 2, Number of Tables : 6, Number of References : 19
Human Heredity (International Journal of Human and Medical Genetics)
Vol. 61, No. 4, Year 2006 (Cover Date: September 2006)
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.