Design, Analysis, and Interpretation of Genome-Wide Association Scans

344 Pages·2013·3.124 MB·English

by  Daniel Stram

Statistics for Biology and Health
Daniel O. Stram
Design, Analysis,
and Interpretation
of Genome-Wide
Association Scans
Statistics for Biology and Health
Series Editors:
M. Gail
K. Krickeberg
J. Samet
A. Tsiatis
W. Wong
For furthervolumes:
http://www.springer.com/series/2848

Daniel O. Stram
Design, Analysis,
and Interpretation
of Genome-Wide
Association Scans
DanielO.Stram
DepartmentofPreventiveMedicine
UniversityofSouthernCalifornia
KeckSchoolofMedicine
LosAngeles,CA,USA
ISSN1431-8776
ISBN978-1-4614-9442-3 ISBN978-1-4614-9443-0(eBook)
DOI10.1007/978-1-4614-9443-0
SpringerNewYorkHeidelbergDordrechtLondon
LibraryofCongressControlNumber:2013954411
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Acknowledgments
AcknowledgmentsareduetoMalcolmPike,LarryKolonel,andBrianHenderson
for their vision in initiating the Multiethnic Cohort Study in Hawaii and Los
Angeles.Myworkongeneticassociationstudiesbeganwitha6-monthsabbatical
spentat theWhitehead Institute/MITCenterforGenomeResearchin2002which
wasitselfanoffshootoftheearlycollaborationsdevelopedbetweentheMECand
the Brave New World of twenty-first-century human genetics. Thanks to David
Altshuler,MarkDaly,DavidReich,NickPatterson,NoelBurtt,ItsikPe’er,andthe
many others from whom I learned enormously at that time. Additional sabbatical
support in 2010 initiated the development of the material presented here into its
currentform.SpecialthankstovaluedcolleaguesincludingChrisHaiman,LoicLe
Marchand,IonaCheng,LeighPearce,PeterKraftandDuncanThomas,aswellas
many students, with whom it has been a pleasure to work with during hugely
excitingtimes.
Jianqi Zhang helped assess the text and homework problems from a student’s
pointofview.DianeLemastersassistedmewithgraphicsandcharts.
vii

Contents
1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 HistoricalPerspective. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 DNABasics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.2.1 OrganizationofChromosomes. . . . . . . . . . . . . . . . . . . . 3
1.2.2 OrganizationofDNA. . .. . . .. . . . .. . . . .. . . .. . . . .. 4
1.2.3 DNAandProtein. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1.3 TypesofGeneticVariation. . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.3.1 Single-NucleotideVariantsandPolymorphisms. . . . . . . 6
1.3.2 Insertions/Deletions. . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
1.3.3 LargerStructuralVariants. . . . . . . . . . . . . . . . . . . . . . . 11
1.3.4 ExonicVariationandDisease. . . . . . . . . . . . . . . . . . . . . 12
1.3.5 Non-exonicSNPsandDisease. . . . . . . . . . . . . . . . . . . . 12
1.3.6 SNPHaplotypes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
1.3.7 Microsatellites. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
1.3.8 MitochondrialVariation. . . . . . . . . . . . . . . . . . . . . . . . . 14
1.4 OverviewofGenotypingMethods. . . . . . . . . . . . . . . . . . . . . . . 14
1.4.1 SNPCalling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
1.5 OverviewofGWASGenotypeArrays. . . . . . . . . . . . . . . . . . . . 18
1.6 SoftwareandDataResources. . . . . . . . . . . . . . . . . . . . . . . . . . 18
1.7 WebResources. .. . . . .. . . . .. . . . .. . . .. . . . .. . . . .. . . . .. 19
1.7.1 BasicGenomics. .. . . . . . . . .. . . . . . . . .. . . . . . . . .. . 19
1.7.2 GWASAssociations. . . . . . . . . . . . . . . . . . . . . . . . . . . 20
1.7.3 Annotation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
1.8 HardwareandOperatingSystems. . . . . . . . . . . . . . . . . . . . . . . 22
1.9 DataExample.. . . .. . . .. . . .. . . .. . . .. . . .. . . .. . . .. . . .. 23
1.9.1 SaveYourWork. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2 TopicsinQuantitativeGenetics. . . . . . . . . . . . . . . . . . . . . . . . . . . 31
2.1 DistributionofaSingleDiallelicVariant
inaRandomlyMixingPopulation. . . . . . . . . . . . . . . . . . . . . . . 32
ix