Failure to Replicate a Genetic Association May Provide Important Clues About Genetic Architecture 英文参考文献.docVIP

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Failure to Replicate a Genetic Association May Provide Important Clues About Genetic Architecture 英文参考文献.doc

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Failure to Replicate a Genetic Association May Provide Important Clues About Genetic Architecture 英文参考文献

FailuretoReplicateaGeneticAssociationMayProvide ImportantCluesAboutGeneticArchitecture CaseyS.Greene1,NadiaM.Penrod1,ScottM.Williams2,JasonH.Moore1,2,3,4,5,6* 1Department of Genetics, Dartmouth College, Lebanon, New Hampshire, United States of America, 2Vanderbilt University, Center for Human Genetics, Nashville, Tennessee,UnitedStatesofAmerica,3DepartmentofCommunityandFamilyMedicine,DartmouthMedicalSchool,Lebanon,NewHampshire,UnitedStatesofAmerica, 4DepartmentofComputerScience,UniversityofNewHampshire,Lebanon,NewHampshire,UnitedStatesofAmerica,5DepartmentofComputerScience,Universityof Vermont,Burlington,Vermont,UnitedStatesofAmerica,6TranslationalGenomicsResearchInstitute,Phoenix,Arizona,UnitedStatesofAmerica Abstract Replication has become the gold standard for assessing statistical results from genome-wide association studies. Unfortunatelythisreplicationrequirementmaycauserealgeneticeffectstobemissed.Arealresultcanfailtoreplicatefor numerousreasonsincludinginadequatesamplesizeorvariabilityinphenotypedefinitionsacrossindependentsamples.In genome-wideassociationstudiestheallelefrequenciesofpolymorphismsmaydifferduetosamplingerrororpopulation differences. We hypothesize that some statistically significant independent genetic effects may fail to replicate in an independent dataset when allele frequencies differ and the functional polymorphism interacts with one or more other functional polymorphisms. To test this hypothesis, we designed a simulation study in which case-control status was determinedby twointeractingpolymorphisms withheritabilitiesrangingfrom0.025to0.4withreplicationsamplesizes rangingfrom400to1600individuals.Weshowthatthepowertoreplicatethestatisticallysignificantindependentmain effectofonepolymorphismcandropdramaticallywithachangeofallelefrequencyoflessthan0.1atasecondinteracting polymorphism.Wealsoshowthatdifferencesinallelefrequencycanresultinareversalofalleliceffectswhereaprotective allele becomes a risk factor in replication studies. These re