Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Fallin,L3a 6/23/2002 slide#,*,Fudan Genetic Workshop 2005,Genetic Epidemiology in Populations,Yin Yao,yyao,jhsph.edu,Genetic Association Studies:,Studies with Unrelated Individuals,Fudan Genetic Workshop 2005Ge,Fudan Genetic Workshop,Jan 04 2005,Assessing risk for disease due to specific alleles/genotypes,Contrast direct/indirect genetic association studies,Discuss genetic models,Tests and estimates of association between alleles/genotypes and disease,Designs to be used,Fudan Genetic Workshop,Jan 04,Learning Objectives for This Lecture,Applications for genetic association analyses,Direct versus indirect association,Indirect association:marker-based disease association,Exploits LD between markers and unobserved disease variants,Examples of direct and indirect association studies,Study designs for direct and marker-based(LD)association,Learning Objectives for This L,Genetic Association Studies in Epidemiology,Applications:,Fine mapping,Candidate gene effects,Whole genome scan,Gene environment effects,Drug response modification,Genetic Association Studies in,Genetic Association Studies in Epidemiology,Common Designs:,Cross-sectional,Case-control,Cohort,Clinical Trial(drug response hypothesis is really a case-control),Case-family(trios,sibs,extended families),Case-only,Genetic Association Studies in,Learning Objectives for This Lecture,Applications for association analyses,Direct versus indirect association,Indirect association:marker-based association,Exploits LD,Examples of direct and indirect association studies,Study designs for direct and marker-based(LD)association,Learning Objectives for This L,Direct method,Testing whether a particular allele is a disease-predisposing(causative)allele,exposure status directly measured,Genetic epidemiology studies,two different concepts,.GACTAAGGCCC CCGTTCAAGGAA.,C/T,APOE gene on c19,Eg:A particular APOE allele(e4)changes protein isoform,Genotype that particular site for association study,Direct methodGenetic epidemiol,2.LD Mapping(indirect method),exposure status not directly measured,Rely on markers correlated with true exposure status,This correlation is due to linkage disequilibrium,Genetic epidemiology studies,two different concepts,.GACTAAGGCCC CCGTTCAAGGA CCTG.,C/T,A/G,APOE gene on c19,Eg:Genotype a nearby,genetic marker,among study participants,Rely on correlation(LD)between these alleles to detect association!,2.LD Mapping(indirect meth,Direct Tests,Test for association between observed genotypes and disease outcome,Case,Control,Total,CC,a,b,m1,CT,c,d,m2,TT,e,f,m3,Total,n,d,n,h,N,CC,C,CCG,CC,C,CCG,CC,C,CCG,CC,T,CCG,CC,T,CCG,CC,T,CCG,Directly measure potentially predisposing alleles,Direct TestsTest for associati,Indirect Tests,Test for association between,marker,genotypes and disease outcome,Marker,Case,Control,Total,AA,a,b,m1,AG,c,d,m2,GG,e,f,m3,Total,n,d,n,h,N,CC,?,CCGC,A,G,CC,?,CCGC,A,G,Use,marker genotypes,as surrogate for,functional genotype,by exploiting any correlation between,C,and,A,CC,?,CCGC,A,G,CC,?,CCGC,G,G,CC,?,CCGC,G,G,CC,?,CCGC,G,G,Indirect TestsTest for associa,Direct,Method:Candidate Allele Testing,Must know potentially functional polymorphisms,SNPs may offer set of candidate loci for this method,Eg,look at non-synonymous cSNPs(those in coding regions that are likely to be functional),Note:,Assuming disease is caused by(relatively)common alleles,Common disease-common variant hypothesis,This hypothesis is controversial,If genome-wide project:multiple comparisons-30,000 genes.,Even if only one functional locus/gene tested,very high number of false+s due to chance,Direct Method:Candidate Allel,Indirect,Method:,LD,Gene Mapping,General idea:,Exploit the phenomenon of linkage disequilibrium(LD)between alleles of closely linked markers,to identify genetic regions associated with disease status.,i.e.,Exploit LD-induced,correlation,between observed marker alleles and potentially unobserved disease alleles,.GACTAAGGCCC CCGTTCAAGGA CCTG.,C/T,A/G,Rely on correlation(LD)between these alleles to detect association!,Indirect Method:LD Gene Mappi,Indirect Association Studies in Epidemiology,Applications:,Localization(what is the best estimate of the disease gene location?),Fine mapping,Whole genome scan,Candidate gene effects,Gene environment effects,Drug response modification,Indirect Association Studies i,Localization,Localization,Indirect Association Studies in Epidemiology,Applications:,Localization(what is the best estimate of the disease gene location?),Fine mapping,Whole genome scan,Candidate gene effects,Gene environment effects,Drug response modification,Indirect Association Studies i,Source:Uhl et al,2001.AJHG 69:1290-1300.,Source:Uhl et al,2001.AJHG,Indirect Association Studies in Epidemiology,Applications:,Localization(what is the best estimate of the disease gene location?),Fine mapping,Whole genome scan,Candidate gene effects,Gene en