- Association studies
- Linkage disequilibrium
- Multi-locus TDT
In the ‘indirect’ method of detecting genetic associations between a trait and a DNA variant, we type several markers in a gene or chromosome region of linkage disequilibrium. If there is association between markers and the trait, we presume the existence of one or more causal polymorphisms in the region. In order to obtain a sufficiently dense set of markers it will almost always be necessary to use single nucleotide polymorphisms (SNPs). Although there is an emerging literature on methods for choosing an optimal set of ‘haplotype tag SNPs’ (htSNPs) to detect association between a genetic region and a trait, less attention has been given to the problem of how such studies should be analysed when completed, and how the initial data which was used to select the htSNPs should be incorporated into the analysis. This paper discusses this problem for both population – and family-based association studies. The role of the R2 measure of association between a causal locus and various methods of scoring of marker haplotypes is highlighted. In most cases, the simplest method of scoring (locus coding), which does not require phase resolution, is shown generally to be more powerful than scoring methods that include haplotype information. A new ‘multi-locus TDT’ is also proposed.
Copyright © 2003 S. Karger AG, Basel
- Hugot JP, Chamaillard M, Zouall H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O’Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G: Association of NOD2 leucine-rich repeats with susceptibility to Crohn’s disease. Nature 2001;411:599–603.
- Ueda H, Howson JMM, Esposito L, Heward J, Snook H, Chamberlain G, Rainbow DB, Hunter KMD, Smith AN, Genova GD, Herr MH, Dahlman I, Payne F, Smyth D, Lowe C, Twells RCJ, Howlett S, Healy B, Nutland S, Rance HE, Everett V, Smink LJ, Lam AC, Cordell HJ, Walker NM, Bordin C, Hulme J, Motzo C, Cucca F, Hess JF, Metzker ML, Rogers J, Gregory S, Allahabadia A, Nithiyananthan R, Tuomilehto-Wolf E, Tuomilehto J, Bingley P, Gillespie KM, Undlien DE, Ronningen KS, Guja C, Ionescu-Tirgoviste C, Savage DA, Maxwell AP, Carson DJ, Patterson CC, Franklyn J, Clayton DG, Peterson LB, Wicker LS, Todd JA, Gough SC: Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003;423:506–511.
- Carlson CS, Eberle MA, Rieder MJ, Smith J D, Kruglyak L, Nickerson DA: Additional SNPs and linkage-disequilibrium analyses are necessary for whole-genome association studies in humans. Nat Genet 2003;33:518–21.
- Jeffreys AJ, Kauppi L, Neumann R: Intensely punctate meiotic recombination in the class ii region of the major histocompatibility complex. Nat Genet 2001;29:217–222.
- Cullen M, Perfetto SP, Klitz W, Nelson G, Carrington M: Abstract high-resolution patterns of meiotic recombination across the human major histocompatibility complex. Am J Hum Genet 2002;71:759–776.
- Johnson GCL, Esposito L, Barratt B J, Smith AN, Heward J, Genova GD, Ueda H, Cordell HJ, Eaves IA, Dudbridge F, Twells RCJ, Payne F, Hughes W, Nutland S, Stevens H, Carr P, Tuomilehto-Wolf E, Tuomilehto J, Gough SCL, Clayton DG, Todd JA: Haplotype tagging for the identification of common disease genes. Nat Genet 2001;29:233–237.
- Excoffier L: Analysis of population subdivision; in Balding DJ, Bishop M, Cannings C (eds): Handbook of Statistical Genetics. Chichester, Wiley, 2001.
- Stram DO, Haiman CA, Hirschharn J N, Altshuler D, Kolonel LN, Henderson BE, Pike M C: Choosing haplotype-tagging SNPs based on unphased genotype data using a preliminary sample of unrelated subjects with an example from the multiethnic cohort study. Hum Hered 2003;55:27–36.
- Todd JA: Tackling common disease. Nature 2001;411:537–539.
- Fan R, Knapp M: Genome association studies of complex diseases by case-control designs. Am J Hum Genet 2003;72:850–868.
- Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA: Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 2002;70:425–434.
- Zaykin DV, Westfall PH, Young SS, Karnoub MA, Wagner MJ, Ehm MG: Testing association of statistically inferred haplotypes with discreate and continuous traits in samples of unrelated individuals. Hum Hered 2002;53:79–91.
- Prentice RL, Pyke R: Logistic disease incidence models and case-control data. Biometrika 1978;65:153–158.
- Dempster A, Laird N, Rubin D: Maximum likelihood from incomplete data via the EM algorithm. J R Stat Soc Ser B 1977;39:1–22.
- Ke X, Cardon LR: Efficient selective screening of haplotype tag SNPs. Bioinformatics 2003;19:287–288.
- Zhang K, Deng M, Chen T, Waterman MS, Sun F: A dynamic programming algorithm for haplotype block partitioning. Proc Natl Acad Sci 2002;99:7335–7339.
- Excoffier L, Slatkin M: Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 1995;12:921–925.
- Barratt BJ, Payne F, Rance HE, Nutland S, Todd JA, Clayton DG: Identification of the sources of error in allele frequency estimations from pooled DNA indicates an optimal experimetal design. Ann Hum Genet 2002;66:393–405.
- 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;504:227–233.
- StataCorp: Stata statistical software: release 8.0. Stata Corporation, College Station, TX, 2003.
- Tukey JW: One degree of freedom for non–additivity. Biometrics 1949;5:232–242.
- Pregibon D: Goodness of link tests for generalized linear models. App Stat 1980;29:15–24.
David G. Clayton
JDRF/WT Diabetes and Inflammation Laboratory
Cambridge Institute for Medical Research, University of Cambridge
Cambridge, CB2 2XY (UK)
Tel. +44 1223 762669, Fax +44 1223 762640, E-Mail David.Clayton@cimr.cam.ac.uk
Received: May 23, 2003
Accepted after revision: August 4, 2003
Number of Print Pages : 14
Number of Figures : 4, Number of Tables : 1, Number of References : 22
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. 56, No. 1-3, Year 2003 (Cover Date: Released November 2003)
Journal Editor: J. Ott, New York, N.Y.
ISSN: 0001–5652 (print), 1423–0062 (Online)
For additional information: http://www.karger.ch/journals/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.