Genetic Association Mapping via Evolution-Based Clustering of Haplotypes 英文参考文献.docVIP

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Genetic Association Mapping via Evolution-Based Clustering of Haplotypes 英文参考文献.doc

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Genetic Association Mapping via Evolution-Based Clustering of Haplotypes 英文参考文献

GeneticAssociationMapping viaEvolution-BasedClustering ofHaplotypes Ioanna Tachmazidou1*,Claudio J.Verzilli2,Maria DeIorio1 1Department of Epidemiology andPublic Health, Imperial College London, United Kingdom, 2 Department ofEpidemiologyand Population Health, London School of HygieneandTropicalMedicine,UnitedKingdom Multilocusanalysisofsinglenucleotidepolymorphismhaplotypesisapromisingapproachtodissectingthegenetic basisofcomplexdiseases.Weproposeacoalescent-basedmodelforassociationmappingthatpotentiallyincreases thepowertodetectdisease-susceptibilityvariantsingeneticassociationstudies.TheapproachusesBayesianpartition modelling to cluster haplotypes with similar disease risks by exploiting evolutionary information. We focus on candidategeneregionswithdenselyspacedmarkersandmodelchromosomalsegmentsinhighlinkagedisequilibrium therein assumingaperfect phylogeny. Tomakethis assumptionmore realistic,we split thechromosomal region of interest into sub-regions or windows of high linkage disequilibrium. The haplotype space is then partitioned into disjointclusters,withinwhichthephenotype–haplotypeassociationisassumedtobethesame.Forexample,incase- controlstudies,weexpectchromosomalsegmentsbearingthecausalvariantonacommonancestralbackgroundtobe morefrequentamongcasesthancontrols,givingrisetotwoseparatehaplotypeclusters.Thenoveltyofourapproach arisesfromthefactthatthedistanceusedforclusteringhaplotypeshasanevolutionaryinterpretation,ashaplotypes are clustered according to the time to their most recent common ancestor. Our approach is fully Bayesian and we developaMarkovChainMonteCarloalgorithmtosampleefficientlyoverthespaceofpossiblepartitions.Wecompare theproposedapproachtobothsingle-markeranalysesandrecentlyproposedmulti-markermethodsandshowthat theBayesianpartitionmodelling performssimilarly in localizing thecausalallele whileyielding lowerfalse-positive rates.Also,themethodiscomputationallyquickerthanothermulti-markerapproaches.Wepresentanapplicationto realgenotyped