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1、EuropeanJournalofHumanGenetics(2010)18,111117&2010MacmillanPublishersLimitedAllrightsreserved1018-4813/10$32.00www.nature.com/ejhgARTICLEGeneandpathway-basedsecond-waveanalysisofgenome-wideassociationstudiesGangPeng1,LiLuo2,HoicheongSiu1,YunZhu1,PengfeiHu1,ShengjunHong1,J
2、inyingZhao3,XiaodongZhou4,JohnDReveille4,LiJin1,ChristopherIAmos5andMomiaoXiong*,2Despitethegreatsuccessofgenome-wideassociationstudies(GWAS)inidentificationofthecommongeneticvariantsassociatedwithcomplexdiseases,thecurrentGWAShavefocusedonsingle-SNPanalysis.However,single
3、-SNPanalysisoftenidentifiesonlyafewofthemostsignificantSNPsthataccountforasmallproportionofthegeneticvariantsandoffersonlyalimitedunderstandingofcomplexdiseases.Toovercometheselimitations,weproposegeneandpathway-basedassociationanalysisasanewparadigmforGWAS.Asaproofofconcep
4、t,weperformedacomprehensivegeneandpathway-basedassociationanalysisof13publishedGWAS.OurresultsshowedthattheproposednewparadigmforGWASnotonlyidentifiedthegenesthatincludesignificantSNPsfoundbysingle-SNPanalysis,butalsodetectednewgenesinwhicheachsingleSNPconferredasmalldiseas
5、erisk;however,theirjointactionswereimplicatedinthedevelopmentofdiseases.TheresultsalsoshowedthatthenewparadigmforGWASwasabletoidentifybiologicallymeaningfulpathwaysassociatedwiththediseases,whichwereconfirmedbyagene-set-richanalysisusinggeneexpressiondata.EuropeanJournalof
6、HumanGenetics(2010)18,111117;doi:10.1038/ejhg.2009.115;publishedonline8July2009Keywords:genome-wideassociationstudies;geneandpathway-basedanalysis;complexdiseases;combiningP-values;gene-setenrichmentanalysisINTRODUCTIONThird,attemptingtounderstandandinterpretanumberofsign
7、ificantGenome-wideassociationstudies(GWAS)areemergingasamajorSNPswithoutanyunifyingbiologicalthemecanbechallengingandtooltoidentifydiseasesusceptibilitylociandhavebeensuccessfuldemanding.SNPsandgenescarryouttheirfunctionsthroughindetectingtheassociationofanumberofSNPswithc
8、omplexintricatepathwaysofreactionsandinteractions.Thefunctionofdiseases.112However,testingonlyfo
