復雜疾病的遺傳學-課件

復雜疾病的遺傳學

GeneticsofComplexTraits

andDiseases1ppt課件TheSpectrumofHumanCharacters2ppt課件DifferingConceptsofHealthandDiseaseWesternviewSetsupoppositesofhealthanddiseasePhysician’sdutytosupporthealthand“battledisease”PerceptionsofhealthanddiseaseasdistinctanddichotomousYeteveryonehassomeaspectoftheirhealththatisnotperfectatanypointintime3ppt課件DifferingConceptsofHealthandDiseaseEasternviewLackofbalanceHealthanddiseaserepresentextremesonacontinuumofrelativebalanceandimbalanceConsequenceofEasternviewMustconsiderourpatientscomprehensivelyTakeintoaccountbothgenesandenvironment4ppt課件“Simple”vs.“Complex”GeneticDiseasesGeneticdiseasecannotbeseparatedintorare“singlegene”diseasesandcommon“complex”diseasesManydiseaseshavebothgeneticandenvironmentalcomponentsMany(all?)diseasesaredeterminedbymorethanonegene5ppt課件Examplesof“Single-Gene”DisordersThatMayReallyBeMultifactorialPKUbecomesasymptomaticbyalteringdietModifiergenesandpolymorphismsincysticfibrosisΔF508R117Hand5T6ppt課件Examplesof“Environmental”DisordersThatMayAlsoBeGeneticAIDS–CCR5Δ32polymorphismTrauma–MAOAmutationAdversedrugeffects–CYP450polymorphisms7ppt課件EvaluatingRelativeContributionsofGenesandEnvironmentFamilialaggregationofdiseaseRelativeriskratiocomparesriskinfamilymemberstoriskinthegeneralpopulationConcordanceandallelesharingamongrelativesGeneticdiseasemorelikelythemorecloselyrelatedindividualsareSibpairandtwinstudies8ppt課件GeneticanalysisofqualitativetraitsMethods:measuringfamiliaraggregation

lrCase-controlstudy:9ppt課件RelativeRiskRatio(r)MeasureoffamilialaggregationofdiseaseComparestheprevalenceinrelativesofanaffectedprobandwithprevalenceinthegeneralpopulationInpractice,specifictoaparticularclassofrelative,e.g.,sibs,parents,etc.10ppt課件Familialaggregation:Affectedindividualstendtoclusterinfamilies.

prevalenceofthediseaseinarelative“r”ofanaffectedpersonlr=---------------------------------------------------populationprevalenceofthedisease?Thehigherthefamilialaggregation,thelargerther.?Ifr=1,thentherelativeisatnogreaterriskthananyoneinthegeneralpopulation.11ppt課件Case-controlstudyPrevalenceofCasesPrevalenceof

Controls>>xxConclusion:Familialclustering!12ppt課件GeneticanalysisofquantitativetraitsCorrelation:Heritability:13ppt課件Correlationisastatisticalmeasureofthedegreeofassociationofvariablephenomena(ameasureofthedegreeofresemblanceorrelationshipbetween2parameters).14ppt課件Coefficientofcorrelation(r)Positivecorrelation:r>1Nocorrelation:r=0Negativecorrelation:r<115ppt課件Heritability(h2):Theproportionofthetotalvariationofacharacterattributabletogeneticasopposedtoenvironmentfactors.CMZ--CDZh2

=-----------------------100--CDZ?IfcMZ>>cDZ

thenh2ishigh(approaches1)?IfcMZ=cDZthenh2islow(approaches0)

[c=concordance]16ppt課件

ConcordanceRateTraitorDisease

MZtwins

DZtwins

HeritabilityAlcoholism 0.6 0.3 0.6Autism 0.92 0.0 >1Cleftlip/palate 0.38 0.08 0.6Diabetes,type1 0.35-0.5 0.05-0.1 0.6-0.8Diabetes,type2 0.7-0.9 0.25-0.4 0.9-1.0Measles 0.95 0.87 0.16Schizophrenia 0.47 0.12 0.7Heritability(h2)forVariousDiseases17ppt課件CommonDisease

MendelianSubtype

InvolvedGene

Atherosclerosis

Familialhypercholesterolemia

LDLreceptor(LDLR)Breastcancer

Familialbreast/ovariancancer

BRCA1,BRCA2Amyotrophiclateral

FamilialALS

Superoxidedismutase(SOD1)SclerosisParkinsondisease FamilialParkinsondisease

-synucleinAlzheimerdisease FamilialAD

PS1,PS2,APPHypertension

Liddlesyndrome

Renalsodiumchannel(SCNN1B)

MendelianFormsofCommonComplexDiseases18ppt課件19ppt課件INCIDENCERATESFORHEREDITARYCANCERSINTHEU.S.

Hereditary HereditaryCancerType

Proportion

CasesperyearBreast 10% 18,000Ovary 5% 6,000Colon 10% 15,000Prostate 10% 25,000Melanoma 10% 3,000Medullarythyroid 25% 125Retinoblastoma 40% 70

20ppt課件DifferencesandSimilaritiesBetweenRare“SingleGene”DisordersandCommonComplexDiseases21ppt課件PhenotypesofAllGeneticDiseasesAreComplexTraitsTraditionallytherehasbeenadichotomySimpleMendeliandiseaseswereconsideredtoberare,singlegenedisordersComplexgeneticdiseaseswereconsideredtobecommon,polygenicdisorders22ppt課件PhenotypesofAllGeneticDiseasesAreComplexTraitsAcorollarywasthataspecificmutationinasinglegenedisorderwouldcorrelatewiththepresentationandprognosisamongdifferentindividualswiththatdiseaseInotherwords:Genotypewouldpredictphenotype23ppt課件PhenotypesofAllGeneticDiseasesAreComplexTraitsWenowrecognizethatthesamemutationmighthaveverydifferenteffectsindifferentindividuals,evenwithinthesamefamilyConclusion:Geneticandenvironmentalmodifiersinfluencethephenotypicexpressionevenfor“simple”Mendeliandisorders24ppt課件PhenotypesofAllGeneticDiseasesAreComplexTraitsTherefore:Singlegeneandmulti-genicdiseasesrepresentpointsonacontinuum,notdistinctentities25ppt課件CommonGeneticDiseasesandComplexGeneticEtiologiesIsacommon,complexdiseaseduetothesamesetofgeneticandenvironmentalinfluencesineachpatientwiththatdisorder?Answer:Probablynot!26ppt課件CommonGeneticDiseasesandComplexGeneticEtiologies

Type2DiabetesMellitus:NIDDM●Somepatientswiththisdiseasemayhaveaprimarygeneticmutation,whereasothersmayhaveapolygenicetiologyForthelatter,letusspeculate:Forthepopulation,25genesinvolvedForanyindividual,anaverageof5genesamongthese25geneshavethegreatestinfluenceTherefore,evenforthese“common”diseases,thecompositegenotypesforindividualpatientswillberelativelyrare27ppt課件StrategytofinddiseasesusceptibilitygenesforNIDDM28ppt課件SpectrumofComplexityforCommonDiseases:From“Simple”toComplex

Alzheimerdisease(AD)ComplexgeneticcontributionstoADmaycomefrom:Oneormoreincompletelypenetrantgenesthatactindependently;Multipleinteractinggenes;orCombinationofgeneticandenvironmentalfactors29ppt課件SpectrumofComplexityforCommonDiseases:From“Simple”toComplex

Alzheimerdisease(AD)FamilialADApproximately10%ofpatientshaveamonogenicformofADwithhighlypenetrant,age-related,autosomaldominantinheritancePresentsearlierthantypicalAD:asearlyas3rddecade(20s)comparedwith7th-9thdecadesfortypicalADThreegenes:PS1,PS2,APP30ppt課件Even“Sporadic”ADMayHaveaGeneticComponentApolipoproteinE(APOE)ProteincomponentofLDLparticleConstituentofamyloidplaquesinADThreealleles:2,3,44/4:>90%showADbyage802/3:<10%showADbyage804/-:25-50%showADbyage80EnvironmentalfactorsalsoinvolvedAssociationbetweenpresenceof4alleleandADfollowingheadtraumaisseeninprofessionalboxers31ppt課件GeneticTestingfor

APOEGenotypesTestingasymptomaticindividualsfor4remainscontroversialPoorpredictivevalueNoeffectivetherapeuticinterventionavailabletopreventonsetAvailablethroughdirect-to-consumermarketing32ppt課件Iftherearenotruesingle-genedisorders,

whydosingle-geneDNAtests?33ppt課件34ppt課件SequenceVariantsofUncertainClinicalSignificance:

LessonsfromBRCA1/BRCA2Completesequencingofbothgenesinover150,000people>10,000deleteriousmutationsandvariantsidentifiedEachweek,10-20newonesdetectedB.Ward(MyriadGenetics),personalcommunicationwithProf.GrodyWW,UCLA35ppt課件WholeGenomeAssociationStudies36ppt課件37ppt課件GWASResultsforStatin-InducedMyopathyN.Engl.J.Med.,Aug.21,200838ppt課件39ppt課件GeneticmappingofcomplextraitsLinkageanalysisAssociationstudies40ppt課件LinkageAnalysisStandardlodscoreanalysisNonparametriclinkageanalysis

41ppt課件LinkageAnalysisModel-based(parametric)LinkageAnalysis:Standardlodscoreanalysisiscalledparametricrequiresaprecisegeneticmodeldetailingthemodeofinheritancegenefrequenciespenetranceofeachgenotype42ppt課件Geneticmappingofcomplextraits

Linkageanalysis:

genomescanwhichanalyzesthediseasepedigreesusinghundredsofpolymorphicmarkers(STR)throughouttheentiregenome.L(θ)Lods(logoddsscore):Z(θ)=log[------------]L(1/2)43ppt課件Lodscore(z)Ameasureofthelikelihoodofgeneticlinkagebetweenloci.Thelog(base10)oftheoddsthatthelociarelinked(withrecombinationθ)ratherthanunlinked.Formendeliancharactersalodscoregreaterthan+3isevidenceoflinkage;onethatislessthan–2isevidenceagainstlinkage.44ppt課件Model-free(Nonparametric)LinkageAnalysisModel-freeIgnoreunaffectedpeople,andlookforallelesorchromosomalsegmentsthataresharedbyaffectedindividualsSharedsegmentmethodscanbeusedwithinnuclearfamilies(AffectedSibPairanalysis),withinknownextendedfamilies,orinwholepopulations

45ppt課件IdentitybyState(IBS)andIdentitybyDescent(IBD)

BothsibpairssharealleleA1.ThefirstsibpairhavetwoindependentcopiesofA1(IBSbutnotIBD);thesecondsibpairsharecopiesofthesamepaternalA1allele(IBD).Thedifferenceisonlyapparentiftheparentalgenotypesareknown.

46ppt課件SibPairAnalysis

Byrandomsegregationsibpairsshare0,1or2parentalhaplotypes1/4,1/2and1/4ofthetime,respectively.(B)Pairsofsibswhoarebothaffectedbyadominantconditionshareoneortwoparentalhaplotypesfortherelevantchromosomalsegment.(C)Pairsofsibswhoarebothaffectedbyarecessiveconditionsharebothparentalhaplotypesfortherelevantchromosomalsegment.47ppt課件Affectedsibling-pairanalysis48ppt課件SuggestedCriteriaforReportingLinkageCategoryoflinkageExpectedNo.ofoccurrencesbychancesinawholegenomescanRangeofapproximatepvalueRangeofapproximatelodscoresSuggestive17x10-4–3x10-52.2-3.5Significant0.052x10-5–4x10-73.6-5.3Highlysignificant0.001<3x10-7>5.4Confirmed0.01inasearchofacandidateregionthatgavesignificantlinkageinapreviousindependentstudyLodscore:3.6forIBDtestingofaffectedsibpairs,4.0forIBS49ppt課件50ppt課件Giventhatthelociaretrulylinked,withrecombinationfractionq,thelikelihoodofameiosisbeingnonrecombinantis1-θandthelikelihoodofitbeingrecombinantisθ.Ifthelociareinfactunlinked,thelikelihoodofameiosisbeingeitherrecombinantornonrecombinantis1/2.FamilyA

Therearefiverecombinantsandonenonrecombinant.Theoveralllikelihood,givenlinkage,is(1-θ)5.θThelikelihoodgivennolinkageis(1/2)6Thelikelihoodratiois(1-θ)5.θ/(1/2)6Thelodscore,Z,isthelogarithmofthelikelihoodratio.FamilyB

II1isphase-unknown.IfsheinheritedA1withthedisease,therearefivenonrecombinants