Nature Genetics: doi: /ng Supplementary Figure 1

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1 Supplementary Figure 1 Frequencies of DQ2.5, DQ2.2, DQ8 and DQ7.5, the most common haplotypes in celiac disease cases. The map illustrates the differences among European countries and shows a clear gradient in the frequencies from north to south, especially for DQ2.5 and DQ7.5.

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3 Supplementary Figure 2 Association results for amino acids in HLA DQα1 and HLA DQβ1. (a) Amino acid position 74 in HLA DQβ1 showed the strongest association with celiac disease (P = 10 1,981 ). (b) Controlling for position 74 in HLA DQβ1, position 47 in HLA DQα1 was significantly associated with celiac disease (P = ). (c) Controlling for positions 74 in HLA DQβ1 and 47 in HLA DQα1, position 57 was significantly associated with celiac disease (P = ). (d) After controlling for positions 74 and 57 in HLA DQβ1 and 47 in HLA DQα1, position 25 in HLA DQα1 was significantly associated with celiac disease (P = 1.6 x 10 9 ). (e) After controlling for positions 74 and 57 in HLA DQβ1 and positions 47 and 25 in HLA DQα1, no amino acid position was significant (position 197 in HLA DQβ1, P > ). Gray arrows indicate the drop in association after conditional analysis.

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5 Supplementary Figure 3 Stepwise conditional analysis of the MHC HLA region under a conservative model, where HLA DQA1 and HLA DQB1 four digit alleles were included in the model to control for their effects. With this analysis, we identified five independent associations outside the HLA DQ and HLA DR loci. Each dot represents log 10 (P) of the variant, including SNPs, classical HLA alleles and amino acid polymorphisms encoded by the HLA genes.

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7 Supplementary Figure 4 Stepwise conditional analysis of the MHC HLA region under a relaxed model, with no adjustment for the effects of HLA DQ alleles. Each dot represents log 10 (P) of the variant, including SNPs, classical HLA alleles and amino acid polymorphisms encoded by the HLA genes.

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9 pplementary Figure 5 Histograms with r 2 post imputation for each of the populations analyzed in this study. The y axis (frequency) shows the number of variants analyzed, and the x axis shows imputation r 2.

10 Supplementary,Table,1./Description/of/samples/included/in/this/study. Population Sample Cases/ Controls Male(%) Female(%) λgc λgc1000 Netherlands (44.6) 1288(55.4) 1 1 Italy (26.2) 2034(72.8) 1 1 Poland (47.5) 557(52.5) 1 1 Spain (37.1) 588(62.8) 1 1 Spain (43.6) 438(51.1) 1 1 UK (38.4) 9849(61.6) Total (38.2) 14754(61.6)

11 Supplementary&Table&2.0Estimated0effects0of0haplotypes0of0HLA$DRB1,0HLA$DQA10and0HLA$DQB10on0susceptibility0to0CeD.0The0 haplotypes0were0constructed0based0on0phased0data0from0imputation.0for0each0haplotype,0the0multivariate0effect0is0given0as0an0 odds0ratio0(or),0taking0the0haplotype0dr15$dq60as0the0reference0(i.e0an0or0of01).0unadjusted0haplotype0frequencies0are0given0 for0cases0and0controls0in0all0samples. Freq.&Total&Sample Haplotype& classification subtype&dq Alleles OR =log10(p) Total Cases Controls DR3$DQ2 DQ2.5 HLA$DRB1* HLA$DQA1* HLA$DQB1* DR7$DQ2 DQ2.2 HLA$DRB1* HLA$DQA1* HLA$DQB1* DR4$DQ8 DQ8.1 HLA$DRB1* HLA$DQA1* HLA$DQB1* DR11$DQ7 DQ7.5 HLA$DRB1* HLA$DQA1* HLA$DQB1* DR15$DQ6 DQ6.2 HLA$DRB1* HLA$DQA1* HLA$DQB1* (Ref) DR12$DQ7 DQ7.5 HLA$DRB1* HLA$DQA1* HLA$DQB1* DR13$DQ6 DQ6.3 HLA$DRB1* HLA$DQA1* HLA$DQB1* DR1$DQ5 DQ5.1 HLA$DRB1* HLA$DQA1* HLA$DQB1* DR8$DQ4 DQ4.4 HLA$DRB1* HLA$DQA1* HLA$DQB1* DR14$DQ5 DQ5.3 HLA$DRB1* HLA$DQA1* HLA$DQB1* DR7$DQ9 DQ9.2 HLA$DRB1* HLA$DQA1* HLA$DQB1* DR4$DQ7 DQ7.3 HLA$DRB1* HLA$DQA1* HLA$DQB1*

12 Supplementary)Table)3.Frequencies0of0HLA$DRB1,0HLA$DQA10and0HLA$DQB10haplotypes0across0European0 populations.0the0haplotypes0were0constructed0based0on0phased0data0from0imputation. UK The)Netherlands Poland Spain Haplotype) subtype)dq classification Alleles Total Cases Controls Total Cases Controls Total Cases Controls Total Cases Controls Total Cases Controls DR3$DQ2 DQ2.5 HLA$DRB1* HLA$DQA1* HLA$DQB1* DR7$DQ2 DQ2.2 HLA$DRB1* HLA$DQA1* HLA$DQB1* DR4$DQ8 DQ8.1 HLA$DRB1* HLA$DQA1* HLA$DQB1* DR11$DQ7 DQ7.5 HLA$DRB1* HLA$DQA1* HLA$DQB1* DR15$DQ6 DQ6.2 HLA$DRB1* HLA$DQA1* HLA$DQB1* DR12$DQ7 DQ7.5 HLA$DRB1* HLA$DQA1* HLA$DQB1* DR13$DQ6 DQ6.3 HLA$DRB1* HLA$DQA1* HLA$DQB1* DR1$DQ5 DQ5.1 HLA$DRB1* HLA$DQA1* HLA$DQB1* DR8$DQ4 DQ4.4 HLA$DRB1* HLA$DQA1* HLA$DQB1* DR14$DQ5 DQ5.3 HLA$DRB1* HLA$DQA1* HLA$DQB1* DR7$DQ9 DQ9.2 HLA$DRB1* HLA$DQA1* HLA$DQB1* DR4$DQ7 DQ7.3 HLA$DRB1* HLA$DQA1* HLA$DQB1* Italy

13 Supplementary0Table04.EEstimatedEeffectsEofEhaplotypesEofEaminoEacidsEassociatedEinEHLANDQA1EandEHLANDQB1EwithEsusceptibilityEtoE CeD.ETheEhaplotypesEwereEconstructedEbasedEonEphasedEdataEfromEimputation.EForEeachEhaplotype,EtheEmultivariateEeffectEisEgivenEasEanE oddseratioe(or),etakingetheeaminoeacidehaplotypeethaterepresentsetheesubtypeedr15ndq6easetheereferencee(i.eeaneoreofe1).eunadjustede haplotypeefrequencieseareegiveneforecaseseandecontrolseineallesamples. Amino0acids0positions Frequency HLA9DQA1 HLA9DQB1 OR 9log10(p) subtype0dq Total Cases Controls Tyr Cys Ala Ala DQ2.5 Phe Lys Ala Ala DQ2.2 Tyr Gln Ala Glu DQ8.1 Tyr Cys Asp Glu DQ7.5 Tyr Arg Asp Glu (Ref) DQ6.2 Phe Arg Asp Glu DQ6.3 Tyr Arg Val Ser DQ5.1 Tyr Cys Asp Ser DQ4.4 Tyr Arg Asp Ser DQ5.3 Phe Lys Asp Glu DQ9.2 Tyr Gln Asp Glu DQ7.3

14 Supplementary;Table;5.BAssociationBresultsBforBtwoBstep;wiseBconditionalBmodels,BcalledBrelaxedBandB conservative.binbthebconservativebmodelbwebadjustedbabprioribforballbcommonbclassicalbhla;dqb4;digitb alleles.bvariantsbsharedbinbbothbthebconservativebandbrelaxedbmodelsbarebshownbinbbold.btheborsbforbtheb multiallelicbaminobacidbpositionsbwerebcalculatedbusingbthebmostbfrequentballelebasbreferenceb(ref*).b Conservative;(conditional;on;HLA-DQ) Stepwise Only;conditional;on;HLA-DQ Frequency Step Variant d.f. -log10(p) AIC OR -log10(p) AIC OR amino;acid Total Cases Controls Imputation;r 2 ref ref* Phe HLA-DPβ1;position; Tyr His HLA$B*08: rs rs HLA$B*39: Relaxed;model Stepwise Unconditional Frequency Step Variant d.f. -log10(p) AIC OR -log10(p) AIC OR amino;acid Total Cases Controls Imputation;r Arg ref* ref* Ala HLA;DRβ1BpositionB Gln Leu Glu ref* ref* Leu HLA;DQβ1BpositionB Arg Pro ref* ref* Phe HLA-DPβ1;position; Tyr His rs ; HLA$B*08: ref* ref* Tyr Leu HLA;DRβ1BpositionB Cys His Gly Arg ref* ref* Tyr HLA;DQβ1BpositionB Phe Leu rs ; Lys HLA;DQα1BpositionB ref* Gln ref* Arg rs rs HLA$B*39:

15 Supplementary,Table,6.#Heritability#calculations#using#different#using#different#prevalence#as#a#parameter.# h 2 #(SE) h 2 #(SE)#Liability#scale Model Observed#scale Prevalence#1% Prevalence#2% Prevalence#3% Classical#HLA>DQ#alleles#(4>digit) Independent#MHC#variants#outside#HLA>DQ Non>MHC#variants#(57#SNPs) Combined