Mouse Genome-Wide Association Mapping Needs Linkage Analysis to Avoid False-Positive Loci 英文参考文献.docVIP

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Mouse Genome-Wide Association Mapping Needs Linkage Analysis to Avoid False-Positive Loci 英文参考文献.doc

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Mouse Genome-Wide Association Mapping Needs Linkage Analysis to Avoid False-Positive Loci 英文参考文献

MouseGenome-WideAssociationMappingNeeds LinkageAnalysistoAvoidFalse-PositiveLoci GiacomoManenti1,AntonellaGalvan1,AngelaPettinicchio1,GaiaTrincucci1,ElenaSpada2,AnnaZolin2, SilvanoMilani2,AnnaGonzalez-Neira3,TommasoA.Dragani1* 1Department of Experimental Oncology and Laboratories, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, 2Istituto di Statistica Medica e Biometria ‘‘GA Maccacaro’’,Universita` diMilano,Milan,Italy,3GenotypingUnit(CeGen),CNIO,Madrid,Spain Abstract We carried out genome-wide association (GWA) studies in inbred mouse strains characterized for their lung tumor susceptibility phenotypes (spontaneous or urethane-induced) with panels of 12,959 (13K) or 138,793 (140K) single- nucleotidepolymorphisms(SNPs).Abovethestatisticalthresholds,wedetectedonlySNPrs3681853onChromosome5,two SNPs in the pulmonary adenoma susceptibility 1 (Pas1) locus, and SNP rs4174648 on Chromosome 16 for spontaneous tumorincidence,urethane-inducedtumorincidence,andurethane-inducedtumormultiplicity,respectively,withthe13K SNPpanel,butonlythePas1locuswiththe140KSNPpanel.Haplotypeanalysiscarriedoutinthelatterpaneldetectedfour additionalloci.LocireportedinpreviousGWAstudiesfailedtoreplicate.Genome-widegeneticlinkageanalysisinurethane- treated(BALB/c6C3H/He)F2,(BALB/c6SWR/J)F2,and(A/J6C3H/He)F2miceshowedthatPas1,butnoneoftheotherloci detectedpreviouslyorhereinbyGWA,hadasignificanteffect.TheLasc1gene,identifiedbyGWAasafunctionalelement (Nat.Genet.,38:888–95,2006),showednogeneticeffectsinthetwoindependentintercrossmousepopulationscontaining bothalleles,norwasitexpressedinmousenormallungorlungtumors.OurresultsindicatethatGWAstudiesinmouse inbredstrainscansufferahighrateoffalse-positiveresultsandthatsuchanapproachshouldbeusedinconjunctionwith classicallinkagemappingingeneticcrosses. Citation:ManentiG,GalvanA,PettinicchioA,TrincucciG,SpadaE,etal.(2009)MouseGenome-WideAssociationMappingNeedsLinkageAnalysistoAvoid False-PositiveLoci.PLoSGenet5(1):e1000331.doi:10.1371/journal.pgen.