Introduction to Genetic EpidemiologyGenetic EpidemiologyGenes & EnvironmentNature-nurture questionSlide 5Slide 6Slide 7Slide 8Slide 9Biometrical ModelSlide 11Stature in adolescent twinsSlide 13Polygenic ModelSlide 15Slide 16Slide 17Slide 18Slide 19Causes of VariationStages of Genetic MappingPartitioning VariationSources of VarianceGenetic FactorsEnvironmental FactorsEstimating ComponentsDesigns to disentangle G+EInformative DesignsClassical Twin StudySlide 30MZ & DZ CorrelationsTwin CorrelationsExampleObserved StatisticsPath AnalysisSlide 36Model FittingMxSlide 40Slide 41Slide 42Slide 43Slide 44Slide 45Slide 46Slide 47Slide 48Slide 49Slide 50Slide 51Slide 52Introduction to Genetic EpidemiologyHGEN619, 2006Hermine H. MaesGenetic EpidemiologyEstablishing / Quantifying the role of genes and environment in variation in disease and complex traits ~ Answering questions about the importance of nature and nurture on individual differences Finding those genes and environmental factorsGenes & EnvironmentHow much of the variation in a trait is accounted for by genetic factors?Do shared environmental factors contribute significantly to the trait variation?The first of these questions addresses heritability, defined as the proportion of the total variance explained by genetic factorsNature-nurture questionSir Francis Galton: comparing the similarity of identical and fraternal twins yields information about the relative importance of heredity vs environment on individual differences Gregor Mendel: classical experiments demonstrated that the inheritance of model traits in carefully bred material agreed with a simple theory of particulate inheritance Ronald Fisher: first coherent account of how the ‘correlations between relatives’ explained ‘on the supposition of Mendelian inheritance’People and IdeasGalton (1865-ish)CorrelationFamily ResemblanceTwinsAncestral HeredityMendel (1865)Particulate InheritanceGenes: single in gamete double in zygoteSegregation ratiosDarwin (1858,1871)Natural SelectionSexual SelectionEvolutionFisher (1918)Correlation & MendelMaximum LikelihoodANOVA: partition of varianceSpearman (1904)Common Factor AnalysisWright (1921)Path AnalysisThurstone (1930's)Multiple Factor AnalysisMather (1949) &Jinks (1971)Biometrical GeneticsModel Fitting (plants)Joreskog (1960)CovarianceStructure AnalysisLISRELMorton (1974)Path Analysis &Family ResemblanceWatson &Crick (1953)Jinks & Fulker (1970)Model Fitting applied to humansMartin & Eaves (1977)Genetic Analysis ofCovariance StructureElston etc (19..)SegregationLinkageRao, Rice, Reich,Cloninger (1970's)AssortmentCultural InheritanceNeale (1990) MxMolecularGeneticsPopulationGenetics2000Biometrical Modelaa AAAa md-dhTo make the simple two-allele model concrete, let us imagine that we are talking about genesthat inf luence adult stature. Les us assume that the normal range of height f or males is f rom4 f eet 10 inches to 6 f eet 8 inches; that is, about 22 inches. And let us assume that eachsomatic chromosome has one gene of roughly equiv alent eff ect. Then, roughly speaking, weare thinking in terms of loci f or which the homozy gotes contribute +- 1/2 inch (f rom themidpoint), depending on whether they are AA , the increasing homozy gote, or aa , thedecreasing homozy gote. In reality, although some loci may contribute greater eff ects thanthis, others will almost certaily contribute less; thus we are talking about the kind of model inwhich any particular poly gene is hav ing an eff ect that would be diff icult to detect by themethods of classical genetics.in Biometrical Genetics chapter in Methodology f or Genetic Studies of Twins and Families1 Gene 3 Genotypes 3 Phenotypes01232 Genes 9 Genotypes 5 Phenotypes012345673 Genes 27 Genotypes 7 Phenotypes051015204 Genes 81 Genotypes 9 PhenotypesPolygenic TraitsStature in adolescent twinsStature190.0185.0180.0175.0170.0165.0160.0155.0150.0145.0Women7006005004003002001000Std. Dev = 6.40 Mean = 169.1N = 1785.00Physical attributes (height, eye color)Disease susceptibility (asthma, anxiety)Behavior (intelligence, personality)Life outcomes (income, children)Individual differencesPolygenic ModelPolygenic model: variation for a trait caused by a large number of individual genes, each inherited in a strict conformity to Mendel’s lawsMultifactorial model: many genes and many environmental factors also of small and equal effect Effects of many small factors combined > normal (Gaussian) distribution of trait values, according to the central limit theorem.The normal distribution is to be expected whenever variation is produced by the addition of a large number of effects, non-predominantThis holds quite oftenQuantitative traitsCentral Limit TheoremBody Mass Index vs “obesity”Blood pressure vs “hypertensive”Bone Mineral Density vs “fracture”Bronchial reactivity vs “asthma”Neuroticism vs “anxious/depressed”Reading ability vs “dyslexic”Aggressive behavior vs “delinquent”Continuous or Categorical ?unaffected affectedDisease liabilitySingle thresholdsevereDisease liabilityMultiple thresholdsmildnormal modMultifactorial Threshold Model of DiseaseImprecise phenotypePhenocopies / sporadic casesLow penetranceLocus heterogeneity/ polygenic effectsGenetically Complex DiseasesDisease PhenotypeCommonenvironmentMarker Gene1IndividualenvironmentPolygenicbackgroundGene2Gene3Linkage Linkagedisequilibrium Mode ofinheritance LinkageAssociation Complex Trait ModelCauses of Variationpre-1990estimation of ‘anonymous’ genetic and environmental components of phenotypic variationgenetic epidemiologic studiespost-1990identification of QTL’s: quantitative trait loci contributing to genetic variation of complex (quantitative) traitslinkage and association studiesStages of Genetic MappingAre there genes influencing this trait?Genetic epidemiological studiesWhere are those genes?Linkage analysisWhat are those genes?Association analysisPartitioning Variationphenotypic variance (VP) partitioned in genetic (VG) and environmental (VE)VP = VG + VEAssumptions: additivity & independence of genetic and environmental effectsheritability (h2): proportion of variance due to genetic influences (h2 = VG /VP)property of a group (not an individual), thus specific to a group in place & timeSources of
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