A Statistical Approach to Genetic Epidemiology: Concepts and Applications, with an e-Learning Platform

513 Pages·5.88 MB·english

by  Ziegler A.

Andreas Ziegler and Inke R. König
A Statistical Approach to
Genetic Epidemiology
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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
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produced. Nevertheless, authors, editors, and
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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
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Printing and Binding betz-druck GmbH,
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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