Andreas Ziegler and Inke R. König A Statistical Approach to Genetic Epidemiology Related Titles Elston, R. C., Johnson, W. Basic Biostatistics for Geneticists and Epidemiologists A Practical Approach 2009 ISBN: 978-0-470-02489-8 Balding, D. J., Bishop, M., Cannings, C. (eds.) Handbook of Statistical Genetics 2008 ISBN: 978-0-470-05830-5 Meyers, R. A. (ed.) Genomics and Genetics From Molecular Details to Analysis and Techniques 2007 ISBN: 978-3-527-31609-0 Klipp, E., Liebermeister, W., Wierling, C., Kowald, A., Lehrach, H., Herwig, R. Systems Biology A Textbook 2009 ISBN: 978-3-527-31874-2 Helms, V. Principles of Computational Cell Biology From Protein Complexes to Cellular Networks 2008 ISBN: 978-3-527-31555-0 Emmert-Streib, F., Dehmer, M. (eds.) Analysis of Microarray Data A Network-Based Approach 2008 ISBN: 978-3-527-31822-3 Andreas Ziegler and Inke R. König A Statistical Approach to Genetic Epidemiology With access to e-learning platform by Friedrich Pahlke Second Edition WILEY-VCH Verlag GmbH & Co. KGaA The Authors All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information Prof. Dr. Andreas Ziegler contained in these books, including this book, to Dr. Inke R. König be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may Institut für Medizinische Biometrie und inadvertently be inaccurate. Statistik Universität zu Lübeck Library of Congress Card No.: Maria-Goeppert-Str. 1 applied for 23562 Lübeck Germany British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at <http://dnb.d-nb.de>. (cid:164) 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Composition Uwe Krieg, Berlin Printing and Binding betz-druck GmbH, Darmstadt Cover Design Formgeber, Eppelheim Printed in the Federal Republic of Germany Printed on acid-free paper ISBN: 978-3-527-32389-0 To Anke To Marita and Nico Bo¨ddeker xvii Contents Forewordto theFirstEdition vii Forewordto theSecondEdition viii Preface xi Acknowledgments xv 1 Molecular Genetics 1 1.1 Genetic information 2 1.1.1 Locationofgenetic information 2 1.1.2 Interpretationofgenetic information 5 1.1.3 Translationofgenetic information 5 1.2 Transmissionofgenetic information 7 1.3 Variationsin genetic information 10 1.3.1 Individualdifferences in genetic information 10 1.3.2 Detection ofvariations 12 1.3.3 Probabilityfor detection ofvariations 16 1.4 Problems 18 2 FormalGenetics 21 2.1 Mendelandhislaws 22 2.2 Segregationpatterns 23 2.2.1 Autosomaldominantinheritance 24 2.2.2 Autosomalrecessive inheritance 25 2.2.3 X-chromosomaldominantinheritance 26 xviii 2.2.4 X-chromosomalrecessive inheritance 27 2.2.5 Y-chromosomalinheritance 28 2.3 ComplicationsofMendelian segregation 28 2.3.1 Variablepenetranceandexpression 29 2.3.2 Age-dependentpenetrance 31 2.3.3 Imprinting 33 2.3.4 Phenotypicandgenotypicheterogeneity 35 2.3.5 Complexdiseases 36 2.4 Hardy–Weinberglaw 38 2.5 Problems 43 3 Genetic Markers 47 3.1 Propertiesofgenetic markers 47 3.2 Types ofgenetic markers 52 3.2.1 Shorttandem repeats(STRs) 52 3.2.2 Singlenucleotide polymorphisms(SNPs) 54 3.3 Genotyping methodsfor SNPs 57 3.3.1 Restriction fragment length polymorphism analysis 58 3.3.2 Real-time polymerasechainreaction 58 3.3.3 Matrix assisted laser desorption/ionization time offlightgenotyping 61 3.3.4 Chip-basedgenotyping 61 3.3.5 Choiceofgenotypingmethod 63 3.4 Problems 65 4 DataQuality 67 4.1 Pedigreeerrors 68 4.2 Genotyping errorsinpedigrees 70 4.2.1 Frequencyofgenotypingerrors 70 4.2.2 Reasonsforgenotypingerrors 71 4.2.3 Mendelchecks 72 4.2.4 Checks fordoublerecombinants 74 4.3 Genotyping errors and Hardy–Weinberg equilibrium (HWE) 76 4.3.1 Causesofdeviations fromHWE 77 4.3.2 Testsfordeviation fromHWEfor SNPs 78 4.3.3 Testsfordeviation fromHWEfor STRs 81 4.3.4 Measuresfordeviation fromHWE 83 4.3.5 Testsforcompatibility with HWEfor SNPs 86 xix 4.4 Quality controlin high-throughputstudies 91 4.4.1 Samplequality control 94 4.4.2 SNPqualitycontrol 97 4.5 Cluster plotchecks andinternalvalidity 98 4.5.1 Clustercompactnessmeasures 101 4.5.2 Clusterconnectedness measures 101 4.5.3 Clusterseparationmeasures 101 4.5.4 Genotypestability measures 102 4.5.5 Combinationsofcriteria 102 4.6 Problems 109 5 Genetic MapDistances 113 5.1 Physicaldistance 113 5.2 Mapdistance 114 5.2.1 Distance 114 5.2.2 Specificmapfunctions 115 5.2.3 Correspondence between physical distance andmapdistance 116 5.2.4 Multilocus feasibility 117 5.3 Linkagedisequilibriumdistance 118 5.4 Problems 123 6 FamilyStudies 125 6.1 Familyhistorymethodandfamily studymethod 127 6.2 Familialcorrelationsandrecurrencerisks 129 6.2.1 Familialresemblance 129 6.2.2 Recurrenceriskratios 131 6.3 Heritability 134 6.3.1 Thesimple Falconermodel 135 6.3.2 ThegeneralFalconermodel 137 6.3.3 Kinship coefficient and Jacquard’s ∆ 7 coefficient 138 6.4 Twin andadoptionstudies 141 6.4.1 Twin studies 141 6.4.2 Adoptionstudies 142 6.5 Critiqueoninvestigating familialresemblance 143 6.6 Segregationanalysis 144 6.7 Problems 154 xx 7 Model-BasedLinkageAnalysis 155 7.1 Linkageanalysisbetween twogenetic markers 156 7.1.1 Linkageanalysisinphase-knownpedigrees 156 7.1.2 Linkageanalysisinphase-unknownpedigrees 160 7.1.3 Linkage analysis in pedigrees with missing genotypes 161 7.2 Linkage analysis between a genetic marker and a disease 167 7.2.1 Linkage analysis between a genetic marker anda diseasein phase-knownpedigrees 168 7.2.2 Linkage analysis between a genetic marker anda diseasein generalcases 172 7.2.3 Gain in information by genotyping additional individuals;powercalculations 177 7.3 Significancelevels in linkage analysis 180 7.4 Problems 184 8 Model-FreeLinkageAnalysis 189 8.1 Theprincipleofsimilarity 190 8.2 Mathematical foundationofaffected sib-pairanalysis 192 8.3 Commontests for affected sib-pairanalysis 193 8.3.1 Themaximum LODscoreandthetriangletest 194 8.3.2 Score-andWald–type1degreeoffreedomtests 201 8.3.3 Affected sib-pair tests using alleles shared identical bystate 206 8.4 Propertiesofaffected sib-pairtests 206 8.5 Sample size and power calculations for affected sib-pairstudies 207 8.5.1 Functional relation between identical by descentprobabilities andrecurrenceriskratios 207 8.5.2 Sample size and power calculations for the meantest usingrecurrenceriskratios 209 8.6 Extensionsto multiple markerloci 212 8.7 Extension to largesibships 213 8.8 Extension to largepedigrees 214 8.9 Extensionsoftheaffected sib-pairapproach 216 8.9.1 Covariatesin affected sib-pairanalyses 216 8.9.2 Multiple disease loci in affected sib-pair analyses 216 xxi 8.9.3 Estimating the position ofthe diseaselocus in affected sib-pairanalyses 217 8.9.4 Typingunaffected relatives in sib-pairanalyses 217 8.10 Problems 218 9 Quantitative Traits 221 9.1 Quantitative versusqualitative traits 222 9.2 TheHaseman–Elstonmethod 223 9.2.1 Theexpectedsquaredphenotypicdifferenceat thetraitlocus 225 9.2.2 Theexpectedsquaredphenotypicdifferenceat themarkerlocus 227 9.3 ExtensionsoftheHaseman–Elstonmethod 229 9.3.1 Doublesquaredtraitdifference 230 9.3.2 Extensionto largesibships 230 9.3.3 Haseman–Elston revisited and the new Haseman–Elstonmethod 231 9.3.4 Powerandsamplesizecalculations 234 9.4 Variancecomponentsmodels 237 9.4.1 Theunivariatevariancecomponentsmodel 237 9.4.2 Themultivariate variancecomponentsmodel 238 9.5 Random sib-pairs, extreme probands and extreme sib-pairs 240 9.6 Empiricaldetermination ofp-values 243 9.7 Problems 245 10 FundamentalConcepts ofAssociationAnalyses 247 10.1 Introductionto association 247 10.1.1 Principles ofassociation 247 10.1.2 Studydesignsforassociation 249 10.2 Linkagedisequilibrium 250 10.2.1 Allelic linkagedisequilibrium 250 10.2.2 Genotypic linkagedisequilibrium 255 10.2.3 Extent oflinkagedisequilibrium 259 10.3 Problems 262 11 AssociationAnalysisin UnrelatedIndividuals 265 11.1 Selection ofcases andcontrols 266