Gene-Based Tests of Association 英文参考文献.docVIP

Gene-BasedTestsofAssociation HailiangHuang1,2,PritamChanda1,2,AlvaroAlonso3,JoelS.Bader1,2*,DanE.Arking4* 1Department ofBiomedicalEngineering,JohnsHopkinsUniversity,Baltimore,Maryland,UnitedStatesofAmerica, 2HighThroughputBiologyCenter,JohnsHopkins UniversitySchoolofMedicine,Baltimore,Maryland,UnitedStatesofAmerica,3DivisionofEpidemiologyandCommunityHealth,SchoolofPublicHealth,Universityof Minnesota,Minneapolis,Minnesota,UnitedStatesofAmerica,4McKusick-NathansInstituteofGeneticMedicine,JohnsHopkinsUniversitySchoolofMedicine,Baltimore, Maryland,UnitedStatesofAmerica Abstract Genome-wide association studies (GWAS) are now used routinely to identify SNPs associated with complex human phenotypes.Inseveralcases,multiplevariantswithinagenecontributeindependentlytodiseaserisk.Hereweintroducea novel Gene-WideSignificance(GWiS)testthatuses greedyBayesian modelselectiontoidentify theindependent effects withinagene,whicharecombinedtogenerateastrongerstatisticalsignal.Permutationtestsprovidep-valuesthatcorrect forthenumberofindependenttestsgenome-wideandwithineachgeneticlocus.Whenappliedtoadatasetcomprising2.5 millionSNPsinupto8,000individualsmeasuredforvariouselectrocardiography(ECG)parameters,thismethodidentifies morevalidatedassociationsthanconventionalGWASapproaches.Themethodalsoprovides,forthefirsttime,systematic assessments of the number of independent effects within a gene and the fraction of disease-associated genes housing multipleindependenteffects,observedat35%–50%oflociinourstudy.Thismethodcanbegeneralizedtootherstudy designs, retains power for low-frequency alleles, and provides gene-based p-values that are directly compatible for pathway-basedmeta-analysis. Citation: Huang H, Chanda P, Alonso A, Bader JS, Arking DE (2011) Gene-Based Tests of Association. PLoS Genet 7(7): e1002177. doi:10.1371/journal. pgen.1002177 Editor:MarkI.McCarthy,UniversityofOxford,UnitedKingdom ReceivedMay26,2010;AcceptedMay25,2011;PublishedJuly28,2011 Copyright: ? 2011 Bader et