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RESEARCHARTICLE Subtypes of Native American ancestry and leading causes of death: Mapuche ancestry- specific associations with gallbladder cancer risk in Chile JustoLorenzoBermejo1☯*,FelixBoekstegers1☯,RosaGonza´lezSilos1, KatherineMarcelain2,PabloBaezBenavides2,CarolBarahonaPonce1,2,BettinaMu¨ller3, CatterinaFerreccio4,5,JillKoshiol6,ChristineFischer7,BarbaraPeil1,JanetSinsheimer8, a1111111111 MacarenaFuentesGuajardo9,10,OlgaBarajas11,RolandoGonzalez-Jose12, a1111111111 GabrielBedoya13,MariaCa´tiraBortolini14,SamuelCanizales-Quinteros15,CarlaGallo16, a1111111111 AndresRuizLinares10,FranciscoRothhammer9 a1111111111 1 StatisticalGeneticsGroup,InstituteofMedicalBiometryandInformatics,UniversityofHeidelberg, a1111111111 Heidelberg,Germany,2 ProgramofHumanGenetics,InstituteofBiomedicalSciences,MedicalFaculty, UniversityofChile,SantiagodeChile,Chile,3 InstitutoNacionaldelCa´ncerdeChile,SantiagodeChile, Chile,4 SchoolofMedicine,PontificiaUniversidadCato´licadeChile,SantiagodeChile,Chile,5 Advanced CenterforChronicDiseases,SantiagodeChile,Chile,6 InfectionsandImmunoepidemiologyBranch, DivisionofCancerEpidemiologyandGenetics,NationalCancerInstitute,Bethesda,Maryland,United StatesofAmerica,7 InstituteofHumanGenetics,UniversityofHeidelberg,Heidelberg,Germany, OPENACCESS 8 BiomathematicsandHumanGeneticsDepartments,DavidGeffenSchoolofMedicineatUCLA,Los Citation:LorenzoBermejoJ,BoekstegersF, Angeles,California,UnitedStatesofAmerica,9 InstitutodeAltaInvestigacio´n,Tarapaca´University,Arica, Gonza´lezSilosR,MarcelainK,BaezBenavidesP, Chile,10 DepartmentofGenetics,EvolutionandEnvironment,andUCLGeneticsInstitute,University BarahonaPonceC,etal.(2017)SubtypesofNative CollegeLondon,London,UnitedKingdom,11 DepartmentofInternalMedicine,UniversityHospitalof UniversityofChile,SantiagodeChile,Chile,12 CentroNacionalPatago´nico,PuertoMadryn,Argentina, Americanancestryandleadingcausesofdeath: 13 LaboratoriodeGene´ticaMolecular,FacultaddeCienciasExactasyNaturales,UniversidaddeAntioquia, Mapucheancestry-specificassociationswith Medell´ın,Colombia,14 DepartamentodeGene´tica,InstitutodeBiociênciasUniversidadeFederaldoRio gallbladdercancerriskinChile.PLoSGenet13(5): GrandedoSul,PuertoAlegre,Brazil,15 UnidaddeGeno´micadePoblacionesAplicadaalaSalud,Facultad e1006756.https://doi.org/10.1371/journal. deQu´ımica,UniversidadNacionalAuto´nomadeMe´xico,CiudaddeMe´xico,Me´xico,16 Laboratoriosde pgen.1006756 Investigacio´nyDesarrollo,FacultaddeCienciasyFilosof´ıa,UniversidadPeruanaCayetanoHeredia,Lima, Peru´ Editor:SarahA.Tishkoff,Universityof Pennsylvania,UNITEDSTATES ☯Theseauthorscontributedequallytothiswork. Received:December23,2016 *[email protected] Accepted:April11,2017 Published:May25,2017 Abstract Copyright:Thisisanopenaccessarticle,freeofall LatinAmericansarehighlyheterogeneousregardingthetypeofNativeAmericanancestry. copyright,andmaybefreelyreproduced, distributed,transmitted,modified,builtupon,or Considerationofspecificassociationswithcommondiseasesmayleadtosubstantial otherwiseusedbyanyoneforanylawfulpurpose. advancesinunravelingofdiseaseetiologyanddiseaseprevention. TheworkismadeavailableundertheCreative HereweinvestigatepossibleassociationsbetweenthetypeofNativeAmericanancestry CommonsCC0publicdomaindedication. andleadingcausesofdeath.Afteranaggregate-datastudybasedongenome-widegeno- DataAvailabilityStatement:Estimatedancestry typedatafrom1805admixedChileansand639,789deaths,wevalidateanidentifiedassoci- proportionsanddemographicdataareavailable throughwww.biometrie.uni-heidelberg.de/ ationwithgallbladdercancerrelyingonindividualdatafrom64gallbladdercancerpatients, StatisticalGenetics/Software_and_Data.Allother withandwithoutafamilyhistory,and170healthycontrols.NativeAmericanproportions relevantdataarewithinthepaperandits weremarkedlyunderestimatedwhenthetwomaintypesofNativeAmericanancestryin SupportingInformationfiles. Chile,originatedfromtheMapucheandAymaraindigenouspeoples,werecombined Funding:Thisstudywasfinanciallysupportedby together.ConsiderationofthetypeofNativeAmericanancestrywascrucialtoidentifydis- theGermanFederalMinistryofEducationand easeassociations.NativeAmericanancestryshowednoassociationwithgallbladder Research(BMBF,grant01DN15021),Germany’s PLOSGenetics|https://doi.org/10.1371/journal.pgen.1006756 May25,2017 1/23 OriginofNativeAmericanancestryandmortality ExcellenceInitiativeofHeidelbergUniversitywithin cancermortality(P=0.26).Bycontrast,each1%increaseintheMapucheproportion theprogram“Mobilita¨tsmaßnahmenimRahmen representeda3.7%increasedmortalityriskbygallbladdercancer(95%CI3.1–4.3%, internationalerForschungskooperationen2015- P=6×10−27).Individual-dataresultsandextensivesensitivityanalysesconfirmedtheasso- 16”,thesupportprogram“StiftungenundPreise” oftheRuprecht-Karls-Universita¨tHeidelberg,the ciationbetweenMapucheancestryandgallbladdercancer.IncreasingMapucheproportions DeutscheForschungsgemeinschaftandthe werealsoassociatedwithanincreasedmortalityduetoasthmaand,interestingly,witha Ruprecht-Karls-Universita¨tHeidelbergwithinthe decreasedmortalitybydiabetes.Themortalityduetoskin,bladder,larynx,bronchusand fundingprogramOpenAccessPublishing,andthe lungcancersincreasedwithincreasingAymaraproportions.Describedmethodsshouldbe GermanResearchFoundation(DFG,grantLO 2061/1).Samplecollectionandstoragewas consideredinfuturestudiesonhumanpopulationgeneticsandhumanhealth.Complemen- supportedbytheBiobankofUniversityofChile. taryindividual-basedstudiesareneededtoapportionthegeneticandnon-geneticcompo- JSSispartiallyfundedbyUSANIHGrant nentsofassociationsidentifiedrelyingonaggregate-data. GM053275.Thisworkwaspartiallysupportedby generalfundsfromtheIntramuralResearch ProgramoftheNationalInstitutesofHealth, NationalCancerInstitute,DivisionofCancer EpidemiologyandGenetics(DCEG)andtheOffice Authorsummary ofResearchonWomen’sHealth(ORWH).The fundershadnoroleinstudydesign,datacollection AlotofattentionhasbeenpaidtoLatinoheterogeneityrelatedtoindividualproportions andanalysis,decisiontopublish,orpreparationof ofNativeAmerican,EuropeanandAfricanancestry.TheimportanceofthetypeofNative themanuscript. Americanancestryforhealth,however,hashardlybeenstudied.Hereweexamined Competinginterests:Theauthorshavedeclared geneticdatafrom2,039admixedChileanstoinvestigatepossibleassociationsbetweentop thatnocompetinginterestsexist. causesofdeathandthetwomajortypesofNativeAmericanancestryinChile.Ourfind- ingsdemonstratethenecessityofsuitablesurrogatesforancestryestimationwhichmirror theactualcompositionofthestudypopulation,andtheadvantageofconsideringfine- scaleLatinoheterogeneityforunravelingofdiseaseetiologyandpersonalizedhealthcare. Introduction DifferencesindiseaseprevalencebetweenLatinosandotherpopulationsarewellestablished. LatinAmericansandLatinoAmericansshowingeneralhigherincidenceratesofgallbladder andstomachcancer,asthmaanddiabetes,andlowerincidencesofbreastandprostatecancer thannon-HispanicWhitesandAfricanAmericans[1–10].Recentlymuchattentionhasbeen paidtodifferencesindiseasesusceptibilityaccordingtotheindividualproportionsofNative American,EuropeanandAfricanancestry[11,12].Onaverage,ColombiansandPuerto RicanshavehigherpercentagesofAfricanancestrythanMexicansandChileans,andthis potentiallytranslatesintodifferentialdiseaserisks,withimportantimplicationstohealthpol- icy[13].Thisarticlefocusesonafinerlevelofgeneticheterogeneity,namelyonthetypeof NativeAmericanancestry.EveniftwopersonsfromMexicoandChilehaveidenticalNative Americanproportions,letsayequalto50%,theirNativeAmericanproportionsoriginatefrom differentnativepeoples,potentiallyresultinginunequaldiseasesusceptibilitiesandpreva- lences.Sofar,LatinoheterogeneityrelatedtothetypeofNativeAmericanancestryisnotcon- sideredindiseasepreventionandmanagementprograms.Presentresultsmaycontributeto changingthissituation. ThegenomeofmodernChileansistheresultofgeneticadmixturebetweenNativeAmeri- cansfromtwomajorindigenouspeoples,theMapucheandtheAymara,Spaniardswho reachedChileinthemid-sixteenthcentury,Africanslaveswhoarrivedinseventeenthcentury, andsubsequentmigrationsinthenineteenthandtwentiethcenturies,mainlyfromEurope. RecentpublicationsongeneticvariabilityinChilehighlighttherelevanceofexaminingNative Americanancestrytounderstandpopulationhistory[13–16].Basedongenotypedatafrom PLOSGenetics|https://doi.org/10.1371/journal.pgen.1006756 May25,2017 2/23 OriginofNativeAmericanancestryandmortality 313Chileans,Eyheramendyetal.confirmedpreviouslyreportedlargercontributionsofEuro- peanmenandNativeAmericanwomen,andattributedtheincreasedNativeAmericanpro- portionintheSouthofthecountrytothelateoccupationofthisterritorybynon-indigenous immigrants[14].ThepredominanceofNativeAmericanancestryinthesouthofChilewas corroboratedbyRuiz-Linaresetal.,whoutilized1561Chileangenotypestoinvestigatethe geographicvariationinancestryinalargeLatinAmericanstudy[13]. Thegoalofthepresentstudyismarkedlydifferent.Wefocushereontherelationship betweentopcausesofmortalityandthetwomaintypesofNativeAmericanancestryinChile. Weconductfirstanaggregate-datastudybasedon1805subjects,andthenvalidateanidenti- fiedassociationbetweenMapucheancestryandgallbladdercancerusingindividualdatafrom 64patientsand170healthycontrolswithandwithoutafamilyhistory.Intotal,thepresent studyreliesongenome-widesinglenucleotidepolymorphismdatafrom2,039admixedChi- leansand639,789country-wideregistereddeathsbetween2005and2011.Itaimstoillustrate theneedtoconsiderfine-scaleLatinoheterogeneitytoadvanceintheunderstandingofdisease etiology,andtopersonalizehealthcare.Ourinvestigationbenefitedfrom1)thegeographyof Chile,acountrywithover4,300kmfromnorthtosouthbutonly200kmfromeasttowest whichshowslargeregionaldifferencesindisease-specificmortalityrates,2)thegeneticarchi- tectureofChileanswhichislargelycomposedofEuropeanandNativeAmericanancestryand presentsalow(3%)Africancomponent,and3)theclearseparationofthetwoinvestigated subcomponentsofNativeAmericanancestrywhichvariesgreatlyfromNortherntoSouthern Chile. Results Fig1Ashowsresultsfromageneticprincipalcomponentanalysis(PCA)ofindividualsusedin theaggregate-datastudyusing64samplesfromtheAmericasintheHumanGenomeDiversity Project(HGDP)assurrogatesofNativeAmericanancestry.Thefirstprincipalcomponent explainedaround3%ofgeneticvariabilityanddistinguishedAfricansfromnon-Africans,the secondprincipalcomponentexplainedabout1.5%ofvariabilityandseparatedtheEuropean andNativeAmericanancestrycomponents.Fig1BshowsPCAresultsrelyingonMapuche andAymaraindividualsassurrogatesofthetwolargestindigenouspeoplesinChile.Thefirst andthirdprincipalcomponentsbasedonHGDPareplottedinFig1C,analogousresultsusing MapucheandAymarareferenceindividualsareshowninFig1D.Thethirdprincipalcompo- nentexplained0.3%ofgeneticvariabilityandseparatedtheMapuchefromtheAymaraNative Americansubcomponents.AlargergeneticvariabilitywasobservedintheMapuchecompared totheAymarareferencegroup(dotdispersioninFig1Band1D). MapucheandAymaraindividualsshowedthelowestgeneticdistanceamongallfourrefer- encegroups(Weir&Cockerham’sFst=0.038).AccordingtoADMIXTURErecommenda- tions,thelargenumberofSNPsavailable(morethan300,000afterqualitycontroland mergingwithreferenceindividuals)wasmorethansufficienttoestimateancestryproportions [17].Fig1EshowsthecorrelationbetweenNativeAmericanproportionsestimatedusing HGDP,andthesumofMapucheandAymaraproportionswhenfourreferencegroups(Afri- can,European,MapucheandAymara)wereconsidered.Thecorrelationbetweenthesumof MapucheandAymaraproportions,andthesumofthetwocorrespondingNativeAmerican proportionswhenthenumberofancestralpopulationswassettofourinanunsupervised ADMIXTUREanalysiswiththreereferencepanels(African,EuropeanandHGDP)isshown inFig1F.Irrespectiveoftheadmixtureestimationmethod(un/supervised)andtheassumed numberofancestralpopulations(three/four),useofHDGPinsteadofMapucheandAymara referenceindividualsresultedinanunderestimationoftheNativeAmericanancestry PLOSGenetics|https://doi.org/10.1371/journal.pgen.1006756 May25,2017 3/23 OriginofNativeAmericanancestryandmortality Fig1.Geneticprincipalcomponentanalysesofindividualsusedintheaggregate-datastudyto investigatetherelationshipbetweenthetypeofNativeAmericanancestryanddisease-specific mortalityrisks(panelsA-D),andscatterplotsofestimatedNativeAmericanproportionsusing differentreferenceindividualsassurrogatesofNativeAmericanancestry:9Mapucheand9Aymara referenceindividualsversussamplesfromtheAmericansintheHumanGenomeDiversityProject, supervisedADMIXTUREanalysis(panelE)andunsupervisedADMIXTUREanalysiswithfour ancestralpopulations(panelF). https://doi.org/10.1371/journal.pgen.1006756.g001 PLOSGenetics|https://doi.org/10.1371/journal.pgen.1006756 May25,2017 4/23 OriginofNativeAmericanancestryandmortality componentinindividualswithalargeMapucheproportion,andanunderestimationofthe overallNativeAmericanancestry,representedbythesumofMapucheandAymarapropor- tions.SupplementaryS2FigdepictsthehighcorrelationbetweenNativeAmericanpropor- tionsestimatedusingHGDPandproportionestimatesthatreliedonthecombinedsetof MapucheandAymaraindividualsinasinglegroup. Table1showstheestimatedaverageNativeAmerican(HDGPreference),Mapucheand Aymaraancestrycomponentsintheaggregate-datastudy,andpossibleancestrydifferencesby age,gender,educationallevel,socioeconomicstatus,salaryandeachofthe15Chileanregions. CompleteresultsforAfricanandEuropeanproportionsareavailableassupplementarymate- rial.ThemeanNativeAmericanancestrycomponentinthe1805individualsfromthepresent aggregate-datastudyamountedto40%(95%CI37%-43%).Thisproportionwassmallerthan thesumofaverageMapuche(40%,95%CI37%-42%)andAymara(8%,95%CI4%-12%)pro- portions,confirmingthenecessityofsuitablesurrogatesforancestryestimationwhichreflect theactualcompositionofthestudypopulation.TheaverageEuropeanandAfricanpercent- agesestimatedusingfourreferencegroupswere49%(95%CI47%-52%)and3%(95%CI2%- 3%),respectively.IncreasingNativeAmericanancestrywasassociatedwithalowersocioeco- nomicstatus,andthelargestNativeAmericanproportionswerefoundinthenorthandinthe southofChile(Fig2).TheoverallpicturewasmarkedlydifferentwhentheMapucheand AymarasubcomponentsofNativeAmericanancestrywereseparated.Malesincludedinthe aggregate-datastudyshoweda2%largerMapuchecomponentthanparticipatingwomendue tothelargerproportionofmenenrolledfromthesouthcomparedtowomen.Increasing Mapucheancestryassociatedwithalowereducationallevelandwithalowersocioeconomic status.Forexample,theaverageMapuchecomponentwas40%-6%=34%intheABC1group (highmiddleclass),comparedto40%intheD/Estrata(semi-andun-skilledmanualoccupa- tions,unemployedandlowestgradeoccupations).Mapucheancestryshowedlargeregional differences,withthehighestproportion(54%)intheDelosR´ıos,andthelowestpercentage (30%)intheDeAricayParinacotaregions(Fig2).Oppositeresultswerenoticedforthe Aymaraancestrycomponent.Malesincludedintheaggregate-datastudyshoweda2%lower Aymaracomponentthanwomen.Aymaraancestrydifferencesbyeducationallevelandsocio- economicstatusdidnotreachstatisticalsignificance.ThehighestAymaracomponentwas foundintheDeAricayParinacota(29%)andDeTarapaca´(28%)regions,andthelowestpro- portion(6%)intheDelosR´ıosregion. InadditiontoregionalestimatesofAfrican,European,NativeAmerican,Mapucheand Aymaraancestrycomponents,Fig2showsregionalmortalityratesduetogallbladdercancer inChile.ThecorrelationbetweenMapucheproportionsandgallbladdercancermortalityrates wasstriking.Table2providesestimatesofthestrengthofassociationbetweenthetwoleading causesofdeathinChile—diseasesofthecirculatorysystemandneoplasms—andNativeAmer- ican,MapucheandAymaraproportions.Correspondingresultsforallinvestigateddiseasecat- egories,AfricanandEuropeanancestrycomponentsareprovidedassupplementarymaterial. Sincearound500ICD10-categorieswereinvestigated,thefollowingdescriptionofaggregate- dataresultshighlightsassociationswithprobabilityvaluesunder0.05/500=0.0001.Theneces- sityofseparatingtheMapucheandtheAymarasubcomponentsduetopossiblemaskingof contraryeffectswasevident.Forexample,NativeAmericanancestrydidnotshowevidenceof associationwithmortalitybymultiplevalvediseases(P=0.98),buta1%increaseinMapuche ancestrytranslatedintoa5.7%increasedriskofdeathduetodiseasesinthiscategory (P=2×10−6).IncreasingMapucheancestrywasalsoassociatedwithincreasingmortalityrisks duetoatrialfibrillationandflutter,hypertensiveheartdisease,sequelaeofcerebrovasculardis- easeandmyocardialinfarction,andwithadecreasingriskofdeathbyothercerebrovascular diseases.IncreasingAymaraancestryassociatedwithalowermortalityriskduetothemajority PLOSGenetics|https://doi.org/10.1371/journal.pgen.1006756 May25,2017 5/23 OriginofNativeAmericanancestryandmortality Table1. EstimatedaverageNativeAmerican,MapucheandAymaraproportions,anddifferencesintheancestrycomponentsbyageclass,gen- der,educationallevel,socioeconomicstatus,salaryandregion. Variable Level N NativeAmerican(HGDP) Mapuche Aymara Pval Estimate 95% CI Pval Estimate 95% CI Pval Estimate 95% CI Intercept Reference 1805 <0.0001 0.40 0.37 0.43 <0.0001 0.40 0.37 0.42 <0.0001 0.08 0.04 0.12 Ageclass <24years 398 0.40 0.00 -0.02 0.03 0.05 -0.01 -0.03 0.01 0.09 0.01 -0.01 0.04 24years–26years 454 Ref. Ref. Ref. 27years–32years 486 -0.01 -0.03 0.01 0.01 0.00 0.03 -0.02 -0.05 0.00 >32years 467 -0.01 -0.03 0.02 0.00 -0.02 0.02 -0.01 -0.04 0.02 Gender Female 709 0.40 Ref. 0.003 Ref. 0.04 Ref. Male 1096 -0.01 -0.02 0.01 0.02 0.01 0.03 -0.02 -0.04 0.00 Educational Primary/secondary 1283 0.17 Ref. 0.03 Ref. 0.93 Ref. level school Technical 56 0.00 -0.04 0.05 -0.01 -0.04 0.02 0.01 -0.05 0.06 University/postgrade 466 -0.02 -0.04 0.00 -0.02 -0.03 -0.01 0.00 -0.03 0.02 Socio- E/D 495 0.0003 -0.01 -0.03 0.02 0.004 0.00 -0.01 0.02 0.26 -0.01 -0.04 0.02 economic C3 501 Ref. Ref. Ref. status C2 150 -0.04 -0.07 -0.01 -0.02 -0.04 0.01 -0.02 -0.06 0.02 ABC1 32 -0.12 -0.18 -0.07 -0.06 -0.11 -0.02 -0.07 -0.14 0.00 Missing 627 -0.01 -0.04 0.02 0.02 0.00 0.04 -0.03 -0.06 0.01 Salary <350000$ 197 0.35 0.03 0.00 0.06 0.003 0.00 -0.03 0.02 0.20 0.03 -0.01 0.07 350000–450000$ 233 0.01 -0.02 0.03 0.02 -0.01 0.04 -0.01 -0.04 0.03 450000$+ 515 Ref. Ref. Ref. Missing 860 0.00 -0.02 0.03 -0.03 -0.05 -0.01 0.02 -0.01 0.06 Region DeAricay 794 <0.0001 0.14 0.12 0.16 <0.0001 -0.10 -0.11 -0.08 <0.0001 0.21 0.18 0.23 Parinacota DeTarapaca´ 69 0.13 0.09 0.17 -0.10 -0.13 -0.07 0.20 0.15 0.25 DeAntofagasta 85 0.09 0.06 0.13 -0.07 -0.10 -0.05 0.14 0.10 0.19 DeAtacama 25 0.06 0.00 0.12 -0.05 -0.09 0.00 0.09 0.01 0.17 DeCoquimbo 25 0.07 0.01 0.13 0.00 -0.05 0.04 0.07 -0.01 0.14 DeValpara´ıso 97 0.01 -0.03 0.04 -0.02 -0.05 0.01 0.02 -0.02 0.06 Metropolitanade 312 Ref. Ref. Ref. Santiago DelLibertadorGral. 35 0.00 -0.06 0.05 -0.01 -0.05 0.03 0.00 -0.06 0.07 BernardoO´Higgins DelMaule 67 0.00 -0.04 0.04 0.01 -0.02 0.04 -0.01 -0.06 0.04 DelBiob´ıo 158 0.02 -0.01 0.05 0.04 0.02 0.06 -0.01 -0.05 0.03 DeLaAraucan´ıa 71 0.09 0.05 0.13 0.11 0.08 0.14 0.00 -0.05 0.05 DeLosR´ıos 24 0.10 0.03 0.16 0.14 0.09 0.19 -0.02 -0.10 0.06 DeLosLagos 30 0.07 0.02 0.13 0.11 0.07 0.15 -0.01 -0.09 0.06 DeAise´ndelGral. 8 0.08 -0.03 0.19 0.12 0.03 0.20 -0.01 -0.15 0.12 CarlosIba´ñezdel Campo DeMagallanesyde 5 0.06 -0.07 0.20 0.06 -0.04 0.16 0.02 -0.15 0.19 laAnta´rticaChilena Pval:Globalprobabilityvalue,CI:confidenceinterval;Boldrepresentsassociated95%confidenceintervalswhichdonotincludezero https://doi.org/10.1371/journal.pgen.1006756.t001 ofdiseasesofthecirculatorysystem.TheadvantageofseparatingtheMapucheandAymara ancestrysubcomponentswasalsoobviousforneoplasms.Forexample,NativeAmerican ancestrydidnotshowanyassociationwithgallbladdercancermortality(P=0.26).Bycontrast, a1%increaseintheMapucheproportionrepresenteda3.7%increasedmortalityrisk PLOSGenetics|https://doi.org/10.1371/journal.pgen.1006756 May25,2017 6/23 OriginofNativeAmericanancestryandmortality Fig2.MapswithaverageregionalAfrican,European,NativeAmerican,AymaraandMapucheproportions,andregional mortalityratesduetogallbladdercancerinChile. https://doi.org/10.1371/journal.pgen.1006756.g002 (P=6×10−27),anda1%increaseinAymaraancestrytranslatedintoa2.7%lowerriskofdeath duetogallbladdercancer.IncreasingMapucheancestrywasassociatedwithanincreasing mortalityduetogallbladder,esophagusandstomachcancers,malignantneoplasmswithout specificationofsiteandmyelodysplasticsyndromes,andwithadecreasingriskofbladder,lar- ynx,skin,andbronchusandlungcancers.OppositeassociationswerenoticedforAymara ancestry,e.g.themortalityriskduetoskin,bladder,larynx,bronchusandlungcancers increasedwithincreasingAymaraproportions. Standardizedmortalityratiosfordiseasesoftherespiratoryanddigestivesystems,andfor endocrine,nutritionalandmetabolicdiseasesby1%increaseintheNativeAmerican,Mapu- cheandAymaraproportionsareprovidedinTable3.Forexample,a1%increaseintheMapu- cheproportiontranslatedintoa4.7%increasedmortalityriskduetoasthma,butalsowitha -1.3%mortalityriskbydiabetes. Resultsfromthestepwiseforwardmodelselectiontoidentifythemostsignificantlyassoci- atedancestrycomponentsareshowninFig3.NativeAmericanancestrywasnotselectedfor anydisease.Mapucheancestryshowedthemostsignificantassociationswithmortalityrates dueto12ICD10-diseasecategories,includingasthmaandgallbladdercancer,andtheAymara componentwasselectedfor19categories.Nomodelselectionresultedinthesimultaneous inclusionofboththeMapucheandtheAymaraproportions. PanelsA-CinFig4showresultsfromanexploratorygeneticprincipalcomponentanalysis ofgenotypesofindividualsincludedinthevalidationstudy.Inagreementwithresultsbased onaggregate-data,thefirstprincipalcomponent(7.1%ofgeneticvariability)distinguished Africanfromnon-Africanancestry,thesecondprincipalcomponent(2.7%ofvariability) separatedEuropeanandNativeAmericanancestrycomponents,andthethirdprincipal PLOSGenetics|https://doi.org/10.1371/journal.pgen.1006756 May25,2017 7/23 OriginofNativeAmericanancestryandmortality Table2. Totalnumberofdeathsandstandardizedmortalityratios(SMR)duetodiseasesofthecirculatorysystemandtoneoplasmsby1% increaseintheNativeAmerican(HGDP),MapucheandAymaraproportions. ICD Description Deaths NativeAmerican(HGDP) Mapuche Aymara Pval SMR 95% CI Pval SMR 95% CI Pval SMR 95% CI Diseasesofthecirculatorysystem I08 Multiplevalvediseases 596 0.98 1.000 0.962 1.041 210−6 1.057 1.034 1.081 0.0009 0.950 0.922 0.979 I10 Essentialprimaryhypertension 7054 0.0003 0.975 0.962 0.988 0.004 1.012 1.004 1.020 210−5 0.981 0.973 0.990 I11 Hypertensiveheartdisease 12654 0.0009 0.979 0.968 0.991 710−7 1.018 1.011 1.026 210−8 0.978 0.970 0.985 I21 Myocardialinfarction 40828 0.0006 0.985 0.977 0.994 310−7 1.013 1.008 1.018 510−9 0.985 0.980 0.990 I48 Atrialfibrillationandflutter 5487 0.18 0.991 0.978 1.004 310−10 1.025 1.017 1.032 810−8 0.976 0.968 0.985 I63 Cerebralinfarction 4316 610−6 1.049 1.028 1.071 0.05 1.014 1.000 1.028 0.39 1.006 0.993 1.019 I64 Stroke,notspecifiedashaemorrhageor 18939 10−6 0.979 0.971 0.987 0.0005 1.009 1.004 1.015 210−8 0.985 0.979 0.990 infarction I67 Othercerebrovasculardiseases 5712 0.0007 0.969 0.952 0.987 10−6 0.974 0.964 0.984 0.11 1.008 0.998 1.019 I69 Sequelaeofcerebrovasculardisease 11879 0.002 0.985 0.976 0.994 910−8 1.015 1.010 1.020 410−9 0.983 0.977 0.988 Neoplasms C15 Malignantneoplasmofesophagus 4878 0.0005 0.975 0.961 0.989 510−13 1.031 1.023 1.039 910−14 0.963 0.954 0.972 C16 Malignantneoplasmofstomach 22285 0.03 0.991 0.983 0.999 210−26 1.024 1.020 1.027 410−20 0.978 0.973 0.982 C23 Malignantneoplasmofgallbladder 9641 0.26 1.007 0.995 1.020 610−27 1.037 1.031 1.043 10−11 0.973 0.965 0.980 C32 Malignantneoplasmoflarynx 954 0.01 1.032 1.007 1.058 510−7 0.958 0.943 0.974 10−7 1.036 1.023 1.050 C34 Malignantneoplasmofbronchusandlung 17633 210−5 1.033 1.018 1.048 310−15 0.965 0.957 0.973 310−17 1.032 1.025 1.039 C44 Otherandunspecifiedmalignantneoplasm 1262 510−5 1.057 1.029 1.085 210−6 0.961 0.946 0.977 310−9 1.041 1.027 1.054 ofskin C62 Malignantneoplasmoftestis 677 0.003 0.966 0.945 0.988 0.003 1.020 1.007 1.033 710−5 0.970 0.956 0.985 C67 Malignantneoplasmofbladder 2817 0.001 1.041 1.016 1.067 310−9 0.957 0.943 0.970 210−10 1.039 1.028 1.051 C68 Malignantneoplasmofotherand 137 0.01 1.093 1.021 1.170 410−6 0.896 0.856 0.938 710−7 1.080 1.049 1.113 unspecifiedurinaryorgans C80 Malignantneoplasmwithoutspecificationof 5338 0.36 1.006 0.993 1.018 810−14 1.027 1.021 1.034 10−6 0.980 0.973 0.988 site D46 Myelodysplasticsyndromes 684 0.95 0.999 0.964 1.035 210−6 1.053 1.032 1.075 0.0006 0.952 0.926 0.979 Boldrepresentsassociatedprobabilityvaluesunder0.0001 https://doi.org/10.1371/journal.pgen.1006756.t002 component(0.4%ofgeneticvariability)mirroredtheMapuche-Aymaraancestryaxis.The genotypesofsomeindividualswhodevelopedgallbladdercancer(GBC,filleddots)were markedlyclose/similartothegenotypesofMapuchereferenceindividuals.Hazardratiosesti- matedinthevalidationstudyareshowninTable4.Thevalidationcollectiveincluded186 womenand48menwhoshowedsimilarrisksofbeingdiagnosedwithgallbladdercancer (P=0.66).Each1%increaseintheMapucheproportiontranslatedintoa2%increasedriskof beingdiagnosedwithgallbladdercancer(P=0.04).Takingintoaccountfamilystructureand integratingtheChileangallbladdercancerincidenceratesinaCoxproportionalhazardssur- vivalmodel,asimplementedintheMendelsoftware,resultedinahazardratioequalto1.02 (P=0.05). Sensitivityanalysesidentifiednooutlierswithnoticeableinfluenceonregionalestimatesof theancestrycomponents;outlierplotsareprovidedassupplementarymaterial.Useofresam- plingtechniquestoaccountforthedifferentialnumberofindividualsperregionintheaggre- gate-datastudyshowedamarginalimpactontheestimatedstandardizedmortalityratiofor gallbladdercancer;theincreasedmortalityriskper1%Mapucheproportionestimatedby resamplingwas3.3%(95%CI2.5to4.1%). PLOSGenetics|https://doi.org/10.1371/journal.pgen.1006756 May25,2017 8/23 OriginofNativeAmericanancestryandmortality Table3. Totalnumberofdeathsandstandardizedmortalityratios(SMR)duetorespiratory,digestiveandendocrinediseasesby1%increasein theNativeAmerican(HGDP),MapucheandAymaraproportions. ICD Description Deaths NativeAmerican(HGDP) Mapuche Aymara Pval SMR 95% CI Pval SMR 95% CI Pval SMR 95% CI Diseasesoftherespiratorysystem J18 Pneumonia,unspecifiedorganism 23265 0.001 0.984 0.975 0.994 410−8 1.016 1.011 1.022 10−9 0.981 0.975 0.987 J44 Otherchronicobstructivepulmonary 18427 0.006 0.988 0.980 0.997 10−6 1.012 1.007 1.017 10−7 0.986 0.981 0.991 disease J45 Asthma 1383 0.14 0.981 0.957 1.006 510−10 1.047 1.032 1.061 10−7 0.950 0.932 0.968 J62 Pneumoconiosisduetodustcontaining 616 0.54 1.022 0.953 1.095 310−7 0.891 0.854 0.930 0.0002 1.064 1.031 1.099 silica J69 Pneumonitisduetosolidsandliquids 1499 0.008 0.963 0.936 0.990 0.001 1.026 1.010 1.042 810−5 0.962 0.944 0.980 J84 Otherinterstitialpulmonarydiseases 7697 10−6 1.030 1.018 1.043 510−11 0.975 0.968 0.982 410−15 1.026 1.020 1.032 Diseasesofthedigestivesystem K70 Alcoholicliverdisease 10828 0.10 0.990 0.978 1.002 10−10 1.023 1.017 1.030 10−8 0.977 0.970 0.985 K74 Fibrosisandcirrhosisofliver 9957 910−5 1.019 1.010 1.029 10−13 0.978 0.973 0.984 10−15 1.021 1.016 1.026 K76 Otherdiseasesofliver 5581 0.56 0.996 0.982 1.010 10−7 0.979 0.971 0.986 0.0004 1.014 1.006 1.021 Endocrine,nutritionalandmetabolicdiseases E14 Unspecifieddiabetesmellitus 12490 0.10 0.993 0.984 1.002 210−6 0.987 0.982 0.993 0.009 1.007 1.002 1.012 E46 Unspecifiedprotein-caloriemalnutrition 2819 0.01 1.019 1.004 1.035 0.001 0.985 0.975 0.994 910−5 1.017 1.008 1.025 E88 Otherandunspecifiedmetabolicdisorders 276 0.07 1.058 0.996 1.124 510−5 0.928 0.896 0.962 410−5 1.058 1.030 1.087 Boldrepresentsassociatedprobabilityvaluesunder0.0001 https://doi.org/10.1371/journal.pgen.1006756.t003 ExclusionofvariantsoflikelyEuropeandescentinMapuchereferenceindividualsinorder toartificiallyincreasetheminimumNativeAmericanproportiondecreasedtheaverageMapu- chepercentageintheaggregate-datastudyfrom40%to37%;thecorrespondingprincipal componentanalysisplotscanbefoundinthesupplementarymaterial.Theartificialincrease Fig3.Venndiagramwithresultsfromastepwiseforwardmodelselectiontoidentifytheancestrycomponentsshowingthe mostsignificantassociationswithdisease-specificmortalityrates.Mapucheancestry(reddish)showedthemostsignificant associationswithmortalityratesdueto12ICD10-diseasecategoriesandtheAymaracomponent(inblue)wasselectedfor19 categories. https://doi.org/10.1371/journal.pgen.1006756.g003 PLOSGenetics|https://doi.org/10.1371/journal.pgen.1006756 May25,2017 9/23 OriginofNativeAmericanancestryandmortality Fig4.Geneticprincipalcomponentanalysesofindividualsusedinthevalidationstudytoinvestigatetherelationship betweenMapucheproportionsandgallbladdercancerrisk,usingMapucheandAymaraindividualsassurrogatesofthe twolargestindigenouspeoplesinChile(panelsA-C).Gallbladdercancercasesarerepresentedbyblackdotsandunaffected subjectsbygreydots.Fig4Drepresentsthepedigreesofthefourfamiliesincludedinthevalidationstudy(Gallbladdercancercases genotypedinthestudyarerepresentedbyblackdots,unaffectedgenotypedsubjectsbygreydots,non-genotypedgallbladder cancercasesbyreddotsandunaffectednon-genotypedsubjectsbyemptycircles). https://doi.org/10.1371/journal.pgen.1006756.g004 oftheNativeAmericanproportioninMapuchereferenceindividualsresultedinastronger relationshipbetweenMapucheancestryandmortalityduetogallbladdercancerbasedon aggregateddata(4.1%increasedmortalityriskper1%increaseintheMapuchepercentage), anditshowednoeffectonthehazardratiosestimatedinthevalidationstudy. Inclusionofhospitalizationratesduetocholecystectomyasadditionalexplanatoryvariable inamultiplePoissonregressionmodelresultedina3.0%increasedmortalityriskduetogall- bladdercancer(95%CI2.3to3.7%)per1%increaseintheMapuchepercentage. Asabovementioned,partofthevalidationcollective–aroundhalfofthedataset–wasprevi- ouslyinvestigatedbyKoshioletal.anditdidnotincludeaffectedfamilies[18].Theaverage Mapucheproportioninthissubsetofthevalidationcollectiveamounted47%,andthecorre- spondinghazardratioforgallbladdercancerper1%increaseintheMapucheproportionwas 1.026.Thesecondhalfofthevalidationcollectivewasnewlyrecruitedanditincludedthefour familiesdepictedinFig4D.TheaverageMapucheproportioninthesecondsubsetofthevali- dationstudywaslower(40%),andthecorrespondinghazardratiowashigher(1.035)thanin thecompletevalidationcollective.Althoughthedifferencebetweenhazardratiosinthesecond PLOSGenetics|https://doi.org/10.1371/journal.pgen.1006756 May25,2017 10/23

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Chile, originated from the Mapuche and Aymara indigenous peoples, were the actual composition of the study population, and the advantage of . and European ancestry components are provided as supplementary material.
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Chile, originated from the Mapuche and Aymara indigenous peoples, were the actual composition of the study population, and the advantage of . and European ancestry components are provided as supplementary material.

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