Genome-wide association study identifies three loci ... · Genome-wide association study identifies three loci associated with melanoma risk D Timothy Bishop1, Florence Demenais2,

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.


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.


“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:


homozygotes


homozygotes

Alloftheaboveestimatesarebasedontheresultsofthegenome‐widestudyandthereplication

samplesexceptforrs1885120,whichwasnotgenotypedinthegenome‐widestudy.


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


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


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).


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.


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.


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.


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)


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.


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.


SupplementaryFigure3.Chromosome9p21.ThemapshowstherelativelocationsofMTAPtogetherwiththethreeSNPs(rs7023329,rs2218220andrs4636294)associatedwithmelanomariskinthisanalysis.ThesethreeSNPsarealsoassociatedwithnevusnumberinanaccompanyingmanuscript1.Further,multipleregressionanalysisshowedindependentcontributionsofSNPsoneithersideofCDKN2A,particularlyforrs7023329andrs1011970(SupplementaryTable4).Otherassociationsintheregionincluders10757278withcoronaryheartdisease4andrs10811661withtype2diabetes5


Documents

Genome-wide association study identifies three loci ... · Genome-wide association study identifies three loci associated with melanoma risk D Timothy Bishop1, Florence Demenais2,