Genome-wide association study identifies three loci associated
with melanoma risk
D Timothy Bishop1, Florence Demenais2, Mark M Iles1, Mark Harland1, John C. Taylor1, Eve Corda2, 3,
Juliette Randerson-Moor1, Joanne F. Aitken4, Marie-Francoise Avril5, Esther Azizi6, Bert Bakker7,
Giovanna Bianchi-Scarrà8, Brigitte Bressac-de Paillerets9, Donato Calista10, Lisa A. Cannon-Albright11,
Thomas Chin-a-Woeng12, Tadeusz Dębniak13, Gilli Galore-Haskel6, Paola Ghiorzo8, Ivo Gut14, Johan
Hansson15, Marko Hocevar16, Veronica Höiom15, John L. Hopper17, Christian Ingvar18, Peter A. Kanetsky19,
Richard F. Kefford20, Maria Teresa Landi21, Julie Lang22, Jan Lubiński13, Rona Mackie23, Josep Malvehy24,
Graham J. Mann20, Nicholas G. Martin25, Grant W. Montgomery25, Frans A van Nieuwpoort26, Srdjan
Novakovic16, Håkan Olsson18, Susana Puig24, Marjan Weiss7, Wilbert van Workum12, Diana Zelenika14,
Kevin M Brown27, Alisa M. Goldstein21, Elizabeth M. Gillanders28, Anne Boland14, Pilar Galan29, David E.
Elder30, Nelleke A Gruis26, Nicholas K. Hayward25, G. Mark Lathrop14,3, Jennifer H Barrett1, Julia A
Newton Bishop1
Nature Genetics: doi:10.1038/ng.411
Supplementary Note: Quality Control details and GenoMEL membership
Quality control (QC) results
Call rate
We excluded 420 individuals (79.2% of the overall exclusions) whose single nucleotide polymorphism
(SNP) call rate was below 97% for the array on which the sample was genotyped. These individuals
predominantly came from the French controls (253 individuals – 60.2%).
Non-European Ancestry
In total 64 (1%) individuals (12.1% of the overall exclusions) were removed from subsequent analyses on
the basis of apparent non-European ancestry (35.9% or 23 individuals were from the French controls), with
a number of these subsequently confirmed with research records.
Sex and relatedness
Sexasinferredfromgenotypingdidnotmatchingreportedsex in 18 individuals (3.4% of the overall
exclusions). 28 samples (5.3% of the overall exclusions) were removed either because they were identical
to or estimated to be first-degree relatives of other samples. The majority of these were case-control pairs
and the control samples were removed from further analysis.
Overall QC
In total, 530 (8.9%) samples failed one of these QC criteria (more than half of them from the French control
set) and were excluded from subsequent analyses. Of the GenoMEL samples, 1539 cases and 979
GenoMEL controls passed all QC criteria; these were all genotyped at the Service XS laboratory in Leiden
(mean call rate 99.6%) apart from 537 cases genotyped at Centre National de Génotypage (CNG) in Paris
(mean call rate 99.1%). Of the other control sets, 1543 French controls and 1395 UK controls passed QC,
giving a total study size of 1539 cases and 3917 controls with a mean call rate of 98.7% (Supplementary
Table 1). Of the cases 1476 (96%) met the criteria defined to enhance for genetic risk.
Nature Genetics: doi:10.1038/ng.411
Falchi et al GWA study of nevus count variation
InanaccompanyingarticleFalchietal1reportagenome‐wideassociationstudyofnevuscount
variation.Asdescribedintheintroductiontothisreport,neviareamajorriskfactorformelanoma;
inparticularindividualswithincreasednumbersofneviareatincreasedriskofdeveloping
melanoma.TheFalchietalstudyreportsananalysisofunselectedUKtwinswhosenevuscounthas
beendeterminedbytrainedexaminers.Theirgenome‐widestudyidentifiestworegionscontaining
genesassociatedwithvariationinnevusnumberwhicharethenreplicatedinanAustralian
population.Oneoftheseregionsonchromosome9overlapswiththatdeterminedinthisstudy.
Thecombinationofthetwostudiessuggestthatthegeneticregionsonchromosomes9and22are
associatedwithnevuscountvariationandthisvariationinfluencestheriskofmelanoma.Toexamine
thishypothesisfurtherrequiresstudieswhichcombineparticipantinformationonmelanomaand
nevuscount.ForthisreasontheLeedscase‐controlstudywasexaminedtotestthesupportforthis
hypothesis.Theanalysisthereforeexaminesthecase‐controlstudysimplylookingatSNPsinthe
chromosome9regionwithandwithoutadjustmentfornevuscount.Thefindingssupportthe
speculationthatthegeneticregionpredominantlyinfluencesmelanomathroughnevuscount
variation.
IntermsofsamplestherearedifferencesinthenumbersofcasesandcontrolsreportedforGenoMEL
studyascomparedtoFalchietal.Thediscrepancyarisesbecausefortheanalysisofmelanomariskin
theFalchietalanalysistheLeedsstudyisregardedastestingthehypothesisoftheroleofnevi;this
analysisisbasedonallcasesandcontrols.IntheGenoMELstudywherethesamecase‐controlstudy
isusedtoreplicatetheriskofmelanomathereplicationcanonlyincludethoseindividualswhodid
notcontributetothegenome‐widephaseoftheanalysis.Thustherearefewerindividualsrecorded
intheGenoMELsectionoftheLeedscase‐controlstudythanintheFalchietalanalysis.
QQplot
Weproducedquantile‐quantileplots,usingtheresultsofthetrendtestfor287794SNPswitha
callrateofatleast97%andexcludingsomewithaverylowminorallelefrequency.Estimatesof
over‐dispersion2wereλ=1.14fortheunstratifiedanalysis,λ=1.06fortheanalysisstratifiedby
region,andλ=1.03fortheanalysisadjustedforregionandthefirstthreeprincipalcomponents(from
thePrincipalComponentsAnalysis(PCA)oftheGenoMELsamples).Theseresultssuggestthatthere
wasn’tagreatdealofstratificationinoursampleandthatwhatstratificationtherewas,was
adequatelycorrectedfor.
Nature Genetics: doi:10.1038/ng.411
“Geneticenrichment”ofreplicationsamples
Replicationcaseswerechosenpreferentiallytobegenetically‐enriched,categorisedashavingeither
(i)afamilyhistoryor(ii)multipleprimaries(withoutafamilyhistory),or(iii)onsetbeforetheageof
40years(intheabsenceofafamilyhistoryormultipleprimaries).AfewpersonsfromGenoMEL
groupsweregenotypedandsubsequentlyfoundnottohaveoneoftheriskcriterion(“Nocriterion”).
TheLeedscasesfromthecase‐controlstudywerenotselectedtosatisfythesecriteria.1149ofthe
casesand964ofthecontrolsinthereplicationsamplewerefromGenoMELand1163casesand903
controlswerefromtheLeedscase‐controlstudy.47%oftheGenoMELreplicationsampleswere
classifiedashavingafamilyhistory,25%ashavingmultipleprimarymelanoma,24%asbeingearly
onsetcasesand3%fulfillingnogeneticenrichmentcriteria.Ofthereplicationsamplesfromthe
Leedscase‐controlstudy10%hadafamilyhistory,2%multipleprimarymelanoma,15%earlyonset
and72%fulfillednogeneticenrichmentcriteria.
Genotypespecificrisk
Genotype‐specificrisksforthefivereplicatedlociinthisstudywereestimatedandlittleevidence
wasfoundfordeparturefromadditivity.Thegenotypespecificrisks(and95%confidenceintervals)
forthetopSNPsinourreplicatedregionsonchromsomes9,11and16are:
rs7023329(chromosome9):0.89[0.81,0.99]forheterozygotesand0.73[0.64,0.82]for
homozygotes
rs1393350(chromosome11)1.21[1.10,1.32]forheterozygotesand1.80[1.54,2.09]for
homozygotes
rs258322(chromosome16)1.70[1.53,1.89]forheterozygotesand2.42[1.74,3.37]for
homozygotes
For the two regions on chromsomes 20 and 22 we followed up on the basis of the findings of other studies
the genotype specific risks and 95% confidence intervals are:
rs1885120(chromosome20):1.75[1.46,2.09]forheterozygotesand1.34[0.67,2.68]for
homozygotes
rs2284063(chromosome22):0.81[0.71,0.93]forheterozygotesand0.68[0.55,0.84]for
homozygotes
Alloftheaboveestimatesarebasedontheresultsofthegenome‐widestudyandthereplication
samplesexceptforrs1885120,whichwasnotgenotypedinthegenome‐widestudy.
Nature Genetics: doi:10.1038/ng.411
GenoMEL Collaboration
AustralianMelanomaFamily Study: Graham J.Mann, JohnL.Hopper, JoanneF.Aitken,BruceK.
Armstrong,GrahamG.Giles,RichardF.Kefford,AnneCust,MarkJenkins
Barcelona:TheparticipantsofGenoMELinBarcelona:PaulaAguilera,CeliaBadenas,Cristina
Carrera,RemediosCervera,FranciscoCuellar,DanielGabriel,MelindaGonzalez,PabloIglesias,Josep
Malvehy,RosaMarti‐Laborda,MontseMila,ZigheOgbah,Joan‐AntonPuigButille,SusanaPuigand
OthermembersoftheMelanomaUnit:LlúciaAlós,AnaAncero,PedroArguís,AntonioCampo,
TeresaCastel,CarlosConill,JosePalou,RamonRull,MarceloSánchez,SergiVidal‐Sicart,Antonio
Vilalta,RamonVilella.
Brisbane:TheQueenslandstudyofMelanoma:EnvironmentalandGeneticAssociations(Q
MEGA)PrincipalInvestigatorsare:NicholasG.Martin,GrantW.Montgomery,DavidDuffy,David
Whiteman,StuartMacGregor,NicholasK.Hayward.TheAustralianCancerStudy(ACS)Principal
Investigatorsare:DavidWhiteman,PennyWebb,AdeleGreen,PeterParsons,DavidPurdie,
NicholasHayward.
EmiliaRomagna:MariaTeresaLandi,DonatoCalista,GiorgioLandi,PaolaMinghetti,Fabio
Arcangeli,PierAlbertoBertazzi
Genoa:GiovannaBianchi‐Scarrà,PaolaGhiorzo,LorenzaPastorino,WilliamBruno,LindaBattistuzzi,
SaraGliori,SaraGargiulo,SabinaNasti,PaolaQueirolo
Glasgow:RonaMackie,JulieLang
Leeds:JuliaANewtonBishop,PaulAffleck,JenniferHBarrett,DTimothyBishop,JaneHarrison,
MarkMIles,JulietteRanderson‐Moor,MarkHarland,JohnCTaylor,LindaWhittaker,Kairen
Kukalizch,SusanLeake,BiruteKarpavicius,SueHaynes,TriciaMack,MayChan,YvonneTaylor.
Leiden:DepartmentofDermatology,LeidenUniversityMedicalCentre:NellekeAGruis,FransA
vanNieuwpoort,CobyOut,ClasinevanderDrift,WilmaBergman,JaspervanderRhee,Geeskede
Kloe,LiesbethKoopmans,NicoleKukutsch,JanNicoBouwesBavinck.DepartmentofClinical
Genetics,CentreofHumanandClinicalGenetics,LeidenUniversityMedicalCentre:Bert
Bakker,MarianWeiss,JeanetterHuurne,Anne‐WilStelloo,TimSegboer.Departmentof
Dermatology,HAGAHospital,TheHague:HanvanderRhee.DepartmentofDermatology,
ReinierdeGraafGroep,Delft:MarcelBekkenk.DepartmentofDermatology,SintFranciscus
Gasthuis,Rotterdam:DyonSnels,MarinusvanPraag.DepartmentofDermatology,Ghent
Nature Genetics: doi:10.1038/ng.411
UniversityHospital,Ghent,Belgium:LieveBrochez&colleagues.DepartmentofDermatology,
St.RadboudUniversityMedicalCentre,Nijmegen:RianneGerritsen&colleagues.Departmentof
Dermatology,RijnlandHospital,Leiderdorp:MarianneCrijns&colleagues.Dutchpatient
organisation,StichtingMelanoom,Purmerend.TheNetherlandsFoundationforthedetection
ofHereditaryTumors,Leiden:HansVasen.
Lund:LundMelanomaStudyGroup:HåkanOlsson,ChristianIngvar,GöranJönsson,ÅkeBorg,
AnnaMåsbäck,LottaLundgren,KatjaBaeckenhorn,KariNielsen,AnitaSchmidtCasslén.
Paris:Marie‐FrançoiseAvril,BrigitteBressac‐dePaillerets,ValérieChaudru,NicolasChateigner,Eve
Corda,FabienneLesueur,MahautdeLichy,EveMaubec,HamidaMohamdi,MolfMoullec,Luc
Thomas,GilbertLenoir,FlorenceDemenaisandtheFrenchFamilyStudyGroupincludingthe
followingOncogeneticistsandDermatologists:PascaleAndry‐Benzaquen,BertrandBachollet,
FrédéricBérard,PascalineBerthet,FrançoiseBoitier,ValérieBonadona,Jean‐LouisBonafé,Jean‐
MarieBonnetblanc,FrédéricCambazard,OlivierCaron,FrédéricCaux,JacquelineChevrant‐Breton,
AgnèsChompret(deceased),StéphaneDalle,LilianeDemange,OlivierDereure,Martin‐XavierDoré,
Marie‐SylvieDoutre,CatherineDugast,LaurenceFaivre,FlorentGrange,PhilippeHumbert,Pascal
Joly,DelphineKerob,ChristineLasset,DominiqueLeroux,JulienLevang,DanLipsker,Sandrine
Mansard,LudovicMartin,TanguyMartin‐Denavit,ChristineMateus,Jean‐LoïcMichel,PatriceMorel,
LaurenceOlivier‐Faivre,Jean‐LucPerrot,CarolineRobert,SandraRonger‐Savle,BrunoSassolas,
PierreSouteyrand,DominiqueStoppa‐Lyonnet,PierreVabres,EvaWierzbicka.
Philadelphia:DavidElder,PeterKanetsky,PatriciaVanBelle,MichaelMing,NandiraMitra,Althea
Ruffin,LelloTesema,SaareneParossian.
Poland:TadeuszDębniak,JanLubiński,AnetaMirecka,SławomirErtmański
Slovenia:SrdjanNovakovic,MarkoHocevar,BarbaraPeric,PetraCerkovnik
Stockholm:VeronicaHöiom,JohanHansson,DianaLinden,RainerTuominen
Sydney:GrahamJ.Mann,RichardF.Kefford,HelenSchmid,ElizabethA.Holland.
TelAviv:EstherAzizi,GilliGalore‐Haskel,EitanFriedman,OrnaBaron‐Epel,AlonScope,Felix
Pavlotsky,EmanuelYakobson,IritCohen‐Manheim,YaelLaitman,RoniMilgrom,IrisShimoni,
EvgeniyaKozlovaa
Nature Genetics: doi:10.1038/ng.411
References
1. Falchi,M.etal.Genome‐wideassociationstudyidentifieslociat9p21and22q13associatedwithdevelopmentofcutaneousnevi.(ThisIssue).
2. Devlin,B.&Roeder,K.Genomiccontrolforassociationstudies.Biometrics55,997‐1004(1999).
3. Higgins,J.P.&Thompson,S.G.Quantifyingheterogeneityinameta‐analysis.StatMed21,1539‐58(2002).
4. Helgadottir,A.etal.Acommonvariantonchromosome9p21affectstheriskofmyocardialinfarction.Science316,1491‐3(2007).
5. Cauchi,S.etal.Postgenome‐wideassociationstudiesofnovelgenesassociatedwithtype2diabetesshowgene‐geneinteractionandhighpredictivevalue.PLoSONE3,e2031(2008).
Nature Genetics: doi:10.1038/ng.411
Supplementary Table 1. Description of cohorts included in genome-wide association study. In total samples from 1650 cases and 4336 controls were included in the genome-wide analysis. Summary information detailing samples contributed and genotyping laboratories is given for participating GenoMEL groups. Also listed are the numbers of samples genotyped, the numbers excluded after quality control, and the remaining numbers of cases and controls and their mean call rates. The numbers of each genetically-enriched case phenotype (family history, multiple primary melanoma or early onset) are given for those cases passing quality control. The genotyping laboratory is either SXS (ServiceXS, Leiden, The Netherlands), CNG (Centre National de Génotypage, Evry,France), or SAN (Sanger Centre, Cambridge, UK). Themean call rate is the average number of genotyped SNPs across allpersonsretainedintheanalysis.
Nature Genetics: doi:10.1038/ng.411
Supplementary Table 2. Detailed genome‐wide association results. The results of the Cochran‐Armitage trend test analysis across the genomeshowingtheresultsformultipleSNPswithp<10‐5andatleastonegenotyped(G)orimputed(Imp)SNPwithap‐valuelessthan5x10‐7.Resultsareshownforstratifiedanalysis(bygeographicalregion)andunstratifiedaswellasthe“minimump”(ietheminimumofthesetworesults).TheORistheper‐alleleoddsratio.ThecallrateistheproportionofpersonsgenotypedsuccessfullyforthisSNP.ForeachSNP,weincludetheminorallelefrequency(MAF),theHardy‐Weinbergequilibrium(HWE)p‐valueforallgenotypedcontrolsandthetestofthehomogeneityoftheminorallelefrequencyacrosspopulations.FortheimputatedSNPsthecallrateisrecordedasNA.WealsocomputedmeasuresofhomogeneityofORsacrossgeographicallocation.ThesewerebasedonthemeasuressuggestedbyHigginsandThompson3.QisCochran’stestforORhomogeneitybasedonachi‐squareddistributionwhileI2describesthepercentageoftotalstudyvarianceattributabletoheterogeneity.LowvaluesofI2areconsistentwithsamplingerror.
Nature Genetics: doi:10.1038/ng.411
SupplementaryTable3.Detailedreplicationresults. TheresultsoftheCochran‐ArmitagetrendtestanalysisofthereplicationsamplesforSNPsinregions identified in thegenome‐wideanalysis and chosen for follow‐up (SupplementaryTable2, chromosome2wasnot followedup).Results areshownforstratifiedanalysis(bygeographical location) for thereplicationsamples.Thetableshowstheresultsbyreplicationsampleset(GenoMELgenotyped at CNG or Leeds (genotyped in Leeds)), replication total (replication sets combined), and overall in combinationwith the genome‐wideanalysis. TheORistheper‐alleleoddsratio.Resultsmarkedwithadashsignwereeithernotattemptedortheassaydidnotworkinthegenotypinglaboratory.HWE is theHardy‐WeinbergEquilibriump‐value calculated for controls andMAF is theminor allele frequency in controls.We also listresultsforSNPsonchromosome20and22thathavebeenpreviouslyreportedtobeassociatedwithmelanoma(chromosome20inproximitytoASIPandchromosome22fornevibyFalchietal1).NotethatsomeSNPswerenotgenotypedinthegenome‐widesample,soresultsforthelasttwodatasetsisinsomecasesthesame.rs17305573andrs4911442werenotgenotypedintheGenoMELreplicationset.Analysesincludingandexcludingtheonenon‐Europeanpopulationwereconductedwithoutqualitativelychangingtheresults(seeSupplementaryInformation). NotethatforsomeSNPs,theminorallelediffers fromthatpresented inTable1andSupplementaryTable2; this reflects that theopposite strandhasbeenassayedbetween thegenome‐widearrayandthereplication(Taqman)technology.
Nature Genetics: doi:10.1038/ng.411
SupplementaryTable4.Multipointstepwiseregression.Thetophalfofthetableshowstheresultsofamultiplestepwiseregressionanalysis.WeappliedstepwiselogisticregressiontodeterminefromamongthemultipleSNPsonchromosomes9,11and16associatedwithmelanomarisk,thosewhichproducedthestrongestindependentassociations.Theseanalyseswereconductedindependentlybylocusandalsocombiningallregions. Thetableshowstheresultsforthecombinationofallgeneticregions,whicharequalitativelyidenticaltotheanalysesofeachgeneticregionseparately.Analysesare based on multiple logistic regression adjusting for geographical region. These analyses arerestricted to individuals with complete genotyping across all SNPs; inclusion of individuals withincomplete genotyping for each locusmade no difference except that for chromosome 9, in someanalyses rs4636294 replaced rs7023329 as the selected SNP. The table also lists the gene/genesclosesttotheSNP.ThestepnumberistheorderthattheSNPenteredthestepwisemodel.
Thebottomhalfofthetableshowstheresultsofaninvestigationoflocusxlocusinteraction.Resultsareshownfor logisticregressionanalysisadjusting forgeographical locationand includingthetopSNPfromeachofthe3replicatedregionsinthisstudy.Analysisinvolves4959personswithcomplete genotype information. The table shows the estimated effect sizes under the logisticregressionmodel,the95%confidenceintervaloftheestimateandthecorrespondingp‐value.Model1 includes pairwise interactions between each pair of SNPs; none of the interactions approachsignificance. ComparisonwithModel2,whichdoesnotincludeanyinteractions(similartothetophalfof the table), showsonlyamarginallypoorer fit (chi‐square test statistic from likelihoodratiotest=2.13with3df,p=0.55)indicatingthereisnoevidenceofdeviationfromindependenceoftheassociationwiththe3loci.
SNP(s) Chromosome(s) Position (bp) Gene Multiple
Regression: P to enter
Multiple regression:
P in final model
rs258322 16 88283404 CDK10 intron 8.3x10-15 2.8x10-7
rs1393350 11 88650694 TYR intron 2.6x10-7 1.8x10-7
rs4785763 16 88594437 Flanking 3'UTR of AFG3L1 5.3x10-7 1.9x10-8
rs8059973 16 88607035 Flanking 5'UTR of DBNDD1 5.3x10-7 4.4x10-7
rs7023329 9 21806528 MTAP intron 7.3x10-5 9.3x10-5
rs1011970 9 22052134 Flanking 5'UTR of CDKN2B 1.2x10-4 1.2x10-4
Model 1: including all 2-way
interactions Model 2: without any interaction
OR [Conf. Int] P OR [Conf. Int] P
rs7023329 9 0.83 [0.73, 0.95] 8.06x10-3 0.82 [0.75, 0.90] 4.65x10-5 rs1393350 11 1.24 [1.05, 1.48] 1.22x10-2 1.30 [1.18, 1.43] 2.16x10-7 rs258322 16 1.95 [1.50, 2.53] 5.77x10-7 1.75 [1.52, 2.01] 3.72x10-15
rs7023329 x rs1393350 9 and 11 1.04 [0.90, 1.19] 0.62 - -
rs7023329 x rs258322 9 and 16 0.88 [0.72, 1.07] 0.19 - -
rs1393350 x rs258322 11 and 16 1.03 [0.84, 1.28] 0.75 - -
Model log-likelihood (df) -2718.7 (df=11) -2719.8 (df=8) Likelihood-Ratio test of model 1 versus model 2 chi-squared (3 df) = 2.13 (p-value=0.55)
Nature Genetics: doi:10.1038/ng.411
SupplementaryFigure1.Anoverviewofstudydesignincludingthetwostagedesigninvolvingagenome‐widephasefollowedbyareplicationphaseinfurtherindependentsamples.SampleswereobtainedfromparticipatingGenoMELgroupsandincludedlikelygenetically‐enrichedcasesandcontrols.SamplesweregenotypedatSXS(ServiceXS,Leiden,TheNetherlands)andCNG(CentreNationaldeGénotypage,Paris,France).GenotypinginformationoncontrolswasobtainedfromtheWTCCC(UK)andfromCNG(Paris)toincreasethepowerofthestudy.Followingqualitycontrol(QC)whichinvolvedexcludingsamplesonthebasisoftheirlikelynon‐Europeanancestryandsampleswithlowcallrates,statisticalanalysisinvolvingbothstratifiedandunstratifiedmethodswasconductedtoidentifyregionsputativelycontainingmelanomasusceptibilitygenes.Follow‐upinthereplicationphaseincludedfurtherGenoMELcasesandcontrolsandpopulation‐basedcasesandcontrolsfromLeedswhichhadnotbeengenotypedinthegenome‐widephase.
Nature Genetics: doi:10.1038/ng.411
SupplementaryFigure2.Estimationofgeographicaloriginfromprincipalcomponents.A)Plotoffittedvaluesafterregressinglatitudeandlongitudeofcentresonfirsttwoprincipalcomponents(PC1andPC2).ResultsshownforstudydataafterQC,excludingthosesamplesdeclaredtobenon‐European.GenoMELcentresindicatedbycolour:Leeds(brown),Leiden(orange),Stockholm(grey),Lund(magenta),Paris(black),Barcelona(lightgreen),Genoa(red),Emilia‐Romagna(darkblue),Brisbane(darkgreen),Sydney&AMFS(reportedas“Sydney”here,lightblue).B)PrincipalComponentsforthegenome‐widestudyandHapMap.Plotoffirsttwoprincipalcomponentsfromanalysisofstudydata(afterQC)combinedwithHapMapdata.EthnicityofHapMapsamplesindicatedbycolour:Africa(YRI)inmagenta,Japan(JPT)inblue,China(CHB)ingreenandEurope(CEU)inred.Studysamplesdeclaredtobenon‐European(GenoMELoutliers)arecolouredorangeandthoselaterconfirmedtobeofnon‐Europeanethnicityfromrecordsindicatedby‘+’.TheremainingGenoMELstudysamplesassumedtobeofEuropeanoriginarecolouredblack.
Nature Genetics: doi:10.1038/ng.411
SupplementaryFigure3.Chromosome9p21.ThemapshowstherelativelocationsofMTAPtogetherwiththethreeSNPs(rs7023329,rs2218220andrs4636294)associatedwithmelanomariskinthisanalysis.ThesethreeSNPsarealsoassociatedwithnevusnumberinanaccompanyingmanuscript1.Further,multipleregressionanalysisshowedindependentcontributionsofSNPsoneithersideofCDKN2A,particularlyforrs7023329andrs1011970(SupplementaryTable4).Otherassociationsintheregionincluders10757278withcoronaryheartdisease4andrs10811661withtype2diabetes5
Nature Genetics: doi:10.1038/ng.411