Supplementary Material Replication of signals from recent genome-wide association studies of Crohn disease

identifies new disease loci for ulcerative colitis

Andre Franke1,*, Tobias Balschun1,*, Tom H. Karlsen2, Jürgen Hedderich3, Sandra May1,

Tim Lu3, Dörthe Schuldt1,4, Susanna Nikolaus4, Philip Rosenstiel1, Michael Krawczak3,

Stefan Schreiber1,4,†

1 Institute for Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany 2 Medical Department, Rikshospitalet University Hospital, Oslo, Norway 3 Institute of Medical Informatics and Statistics, Christian-Albrechts-University, Kiel,

Germany 4 Department of General Internal Medicine, University Hospital Schleswig-Holstein,

Christian-Albrechts-University, Kiel, Germany

* These authors contributed equally to the work.

† To whom correspondence should be addressed:

Prof. Dr. Stefan Schreiber (s.schreiber@mucosa.de)

Institute for Clinical Molecular Biology and

Department of General Internal Medicine

Christian-Albrechts-University Kiel

Schittenhelmstr. 12

D-24105 Kiel, Germany

Tel.: +49-431-597-4138

Fax.: +49-431-597-1842

Supplementary Methods Patient Recruitment

All patients were recruited in Germany, either at the Department of General Internal Medicine of

the Christian-Albrechts-University Kiel, the Charité University Hospital Berlin, through local

outpatient services, or nationwide with the support of the German Crohn and Colitis Foundation.

Patients and controls overlapped to a small extent with samples that have been used in previous

studies 1-5. Clinical, radiological, histological, and endoscopic (i.e. type and distribution of lesions)

examinations were required to unequivocally confirm the diagnosis of ulcerative colitis (UC) or

Crohn disease (CD) 6, 7. Healthy German control individuals were obtained from the PopGen

biobank 8. Written, informed consent was obtained from all study participants and all protocols

were approved by the institutional ethical review committees of the participating centres.

SNP Selection and Genotyping

Fifty-three SNPs were selected for genotyping, drawn from one of the following four categories:

Category 1: All six variants replicated by Rioux and colleagues 9

Category 2: The 12 replicated follow-up SNPs of the WTCCC study 10, 11, including the IRGM

(n=2), NKX2-3 (n=1), and PTPN2 (n=1) lead SNPs

Category 3: All 25 SNPs of the WTCCC study for which allele frequencies were similar

(“converging”) with that in other diseases, as described in the manuscript.

Category 4: Ten SNPs of moderate association in the WTCCC study (see supplementary Table 7c

of reference 12) where the affected locus was found of pathophysiological relevance

to the extent that genotyping in independent populations was warranted.

For fine mapping the IRGM, NKX2-3, and PTPN2 gene region, respectively, an additional 26, 29,

and 34 SNPs were selected utilizing HapMap data of individuals with European ancestry (minor

allele frequency >1%, pairwise r2 >0.8, pHWE >0.05, less than two Mendelian errors) and de Bakkers

tagging algorithm 13 as implemented in Haploview 14.

Ligation-based SNPlex™ genotyping 15, 16 was performed as previously described 3. In brief, 100

nanograms of whole genome amplified (GE Healthcare Life Sciences, Buckinghamshire, UK) DNA

were dried overnight in TwinTec hardshell 384well plates (Eppendorf, Hamburg, Germany) at room

temperature. Genotyping was subsequently performed on these plates using the SNPlex™

chemistry (Applied Biosystems, Foster City, USA) on an automated platform with TECAN

Freedom EVO and 384well TEMO liquid handling robots (TECAN, Männedorf, Switzerland).

Genotype assignments were manually confirmed by visual inspection with the Genemapper 4.0

(Applied Biosystems) software. All process data were written to, and administered by a previously

described database-driven laboratory information management system (LIMS) 17.

Statistical Analyses

Single-marker association analyses, transmission disequilibrium tests, permutation tests, calculation

of pairwise LD, and SNP selection were performed using Haploview 4.0RC2 14. Graphical

summaries of LD were created using GOLD 1.0 18. Possible marker-marker interactions and

subphenotype associations were assessed for statistical significance by means of logistic regression

analysis with forward selection, as implemented in the R statistical analysis software 19. Genotypes

of all variants were coded numerically by the carriership status for the risk allele (0=non-carrier,

1=carrier), except for NOD2 where genotypes were classified according to the number of mutations

present. Power calculations were carried out using PS Power and Sample Size 2.130 20. At the 5%

significance level, and assuming a frequency of the disease-associated allele of at least 20% in

controls, our UC and CD samples provided a pre-hoc power of >80% to replicate an odds ratio of

1.3 or higher. Nominal p-values of the case-control analysis were adjusted for multiple testing using

Bonferroni correction. Corrections of p-values for IRGM, NKX2-2, and PTPN2 markers were

performed on a gene-wise (or, for the remaining 47 SNPs, pool-wise) basis, considering each

candidate gene as an independent hypothesis. Corresponding correction factors were nIRGM=28,

nNKX2-3=30, nPTPN2=35, and nRest=47.

Quality control

Duplicate or related samples were identified and excluded from the analyses, using algorithms

implemented in the above mentioned LIMS 17. However, no specific genotyping was conducted to

“ID” tag the DNA samples. All genotyped SNPs were polymorphic, had less than six Mendelian

errors, and were found to be in Hardy-Weinberg equilibrium (pHWE>0.01) in controls. All sample-

wise call rates and the separate call rates in the healthy controls, UC, and CD cases exceeded 90%.

Of the 49 remaining SNPs that were genotyped, only rs10801047 (category 2, failed genotyping)

and rs7081330 (category 3, pHWE<0.01; [pHWE <0.05 in the WTCCC controls]) did not meet the

above quality criteria and were therefore excluded from the analysis.

References 1 Croucher, P.J. et al. Eur J Hum Genet 11, 6-16 (2003). 2 Hampe, J. et al. Am J Hum Genet 64, 808-816 (1999). 3 Hampe, J. et al. Nat Genet 39, 207-211 (2007). 4 Stoll, M. et al. Nat Genet 36, 476-480 (2004). 5 Franke, A. et al. PLoS ONE 2, e691 (2007). 6 Lennard-Jones, J.E. Scand J Gastroenterol Suppl 170, 2-6; discussion 16-19 (1989). 7 Truelove, S.C. et al. Gut 17, 192-201 (1976). 8 Krawczak, M. et al. Community Genet 9, 55-61 (2006). 9 Rioux, J.D. et al. Nature genetics 39, 596-604 (2007). 10 WTCCC Nature 447, 661-678 (2007). 11 Parkes, M. et al. Nat Genet 39, 830-832 (2007). 12 Nature 447, 661-678 (2007). 13 de Bakker, P.I. et al. Nature genetics 37, 1217-1223 (2005). 14 Barrett, J.C. et al. Bioinformatics 21, 263-265 (2005). 15 De la Vega, F.M. et al. Mutat Res 573, 111-135 (2005). 16 Tobler, A.R. et al. J Biomol Tech 16, 398-406 (2005). 17 Teuber, M. et al. Journal of the Association for Laboratory Automation 10, 43-47 (2005). 18 Abecasis, G.R. et al. Bioinformatics 16, 182-183 (2000). 19 Team, R.D.C. R Foundation for Statistical Computing, Vienna, Austria (2007). 20 Dupont, W.D. et al. Controlled Clin Trials 18, (1997).

Supplementary Table 1: SNPs that were sigificantlly associated with UC, CD, or IBD but that did

not withstand multiple testing. Association testing results for the IL23R, IBD5, and NOD2 variants

are listed at the end of the table (see next page) for benchmarking. Detailed results and genotype

counts of all SNPs under study are shown in Supplementary Table 2 online.

SRC: original source of SNP association (1=Rioux et al. 1; 2=WTCCC main manuscript 2, 3;

3=WTCCC “converged” SNPs 3; 4=WTCCC supplement 2); A1: nucleotide of allele 1; allele

frequencies of A1 are given as observed in our control sample (RUAFA1), in previously reported

controls (GUAFA1), in previously reported CD samples (GAAFA1), and in our panel of CD patients

(RAAFA1); PHENO: disease phenotype; pnom.: nominal p-value from an allele-based case-control

comparison with 1 degree of freedom; OR: odds ratio for carriership of the rarer allele; 95%CI:

95% confidence interval of OR; nominal p-values <0.05 are highlighted in bold type

SRC SNP ID Chr. Locus A1 RUAFA1 GUAFA1 GAAFA1 PHENO RAAFA1 Pnom. OR 95% CI OTA pTDT

CD 0.865 0.013 0.83 0.71-0.96 C 0.68

1 rs224136 10q21.2 gene desert C 0.845 0.809 0.866 UC 0.855 0.30 0.90 0.76-1.07 C 0.10

IBD 0.861 0.025 0.85 0.75-0.97 C 0.15

CD 0.333 0.031 1.07 0.94-1.22 C 0.79

1 rs4821544 22q12.3 NCF4 C 0.309 0.333 0.397 UC 0.328 0.13 1.14 0.98-1.32 C 0.65

IBD 0.331 0.027 1.10 0.97-1.24 C 0.61

CD 0.665 0.043 0.92 0.81-1.05 C 0.039

3 rs11205760 1p33 FAF1 C 0.643 0.649 0.693 UC 0.669 0.039 0.93 0.80-1.08 C 0.87

IBD 0.667 0.017 0.93 0.82-1.04 C 0.10

CD 0.842 0.024 0.84 0.73-0.97 C 0.19

3 rs1363670 5q33.3 AK097548 C 0.822 0.830 0.862 UC 0.844 0.025 0.79 0.67-0.93 C 0.15

IBD 0.843 0.008 0.82 0.72-0.93 C 0.051

CD 0.808 0.025 0.86 0.75-0.99 C 0.015

3 rs6908425 6p22.3 CDKAL1 C 0.787 0.770 0.810 UC 0.809 0.050 0.85 0.72-0.99 C 0.67

IBD 0.808 0.012 0.86 0.76-0.97 C 0.040

CD 0.929 0.026 1.24 1.01-1.51 A 0.45

3 rs12529198 6p25.1 LYRM4 A 0.942 0.947 0.926 UC 0.939 0.54 1.10 0.87-1.39 A 0.14

IBD 0.933 0.067 1.19 0.99-1.42 A 0.12

CD 0.941 0.048 0.85 0.69-1.03 A 0.63

3 rs9895062 17p13.1 STX8 A 0.929 0.952 0.934 UC 0.945 0.022 0.80 0.64-1.02 G 0.75

IBD 0.942 0.012 0.83 0.69-0.99 A 0.89

CD 0.281 0.010 0.87 0.76-0.99 T 0.46

4 rs7869487 9q32 TNFSF15 C 0.308 0.314 0.273 UC 0.297 0.42 0.98 0.85-1.14 T 0.52

IBD 0.287 0.031 0.91 0.81-1.02 T 0.33

CD 0.276 0.0047 0.85 0.75-0.97 G 0.24

4 rs6011040 20q13.33 ARFRP1 A 0.307 0.332 0.291 UC 0.274 0.0076 0.87 0.74-1.01 G 0.061

IBD 0.275 0.0011 0.86 0.76-0.96 G 0.032

SRC SNP ID Chr. Locus A1 RUAFA1 GUAFA1 GAAFA1 PHENO RAAFA1 Pnom. OR 95% CI OTA pTDT

rs11209026 Arg381Gln

CD 0.03 3.65x10-12 0.45 0.36-0.57 G 0.0012

- 1p31.3 IL23R A 0.07 - - UC 0.04 3.97x10-6 0.55 0.42-0.72 G 0.0097

IBD 0.03 1.58x10-13 0.49 0.40-0.60 G 0.000038

IGR2063_b1

CD 0.47 2.44x10-11 1.45 1.26-1.67 G 0.000045

- 5q31 IBD5 G 0.40 - - UC 0.45 0.000079 1.25 1.06-1.47 G 0.069

IBD 0.47 6.89x10-11 1.37 1.21-1.55 G 0.000013

rs2066844 Arg702Trp

„SNP8“

CD 0.11 4.02x10-21 2.35 1.93-2.86 T 1.10x10-8

- 16q12.1 NOD2 T 0.05 - - UC 0.05 0.91 0.99 0.76-1.29 C 0.21

IBD 0.08 8.14x10-12 1.81 1.50-2.19 T 0.000022

rs2066845 Gly908Arg „SNP 12“

CD 0.05 4.33x10-15 3.23 2.35-4.45 G 0.00020

- 16q12.1 NOD2 G 0.01 - - UC 0.02 0.055 1.46 0.97-2.19 G 0.35

IBD 0.04 1.63x10-10 2.56 1.88-3.49 G 0.00020

rs2066847 Leu1007fs „SNP 13“

CD 0.15 4.96x10-63 4.44 3.61-5.47 1 3.15x10-28

- 16q12.1 NOD2 C 0.04 - - UC 0.03 0.13 0.80 0.58-1.09 2 0.42

IBD 0.11 2.62x10-34 2.91 2.38-3.57 1 2.82x10-23

Supplementary Table 2: Summary of association results for the (A) IRGM, (B) NKX2-3, (C) PTPN2 gene, respectively, and (D) all other tested loci with

UC and CD, respectively. Chromosomal positions in base pairs (bp) correspond to NCBI build 36 (March 2006). Dist. [kb]: inter-marker distance in

kilobases [kb]; A1/A2: nucleotides of allele 1/2; 11/12/22: genotype counts for homozygotes A1, heterozygotes and homozygotes A2, respectively;

CR: SNP call rate; AFA1: allele frequencies of A1; pCCA: p-value from an allele-based case-control comparison; Bonf. pCCA: p-value after Bonferroni

correction; OR: odds ratio for carriership of the rarer allele; 95% CI: 95% confidence interval of OR; T:U: number of transmissions vs. nontransmissions;

OTA: overtransmitted allele; pTDT: p-value of transmission disequilibrium test; Source: original publication of SNP (1.0=Rioux et al.; 1.1=WTCCC main

manuscript; 1.2=WTCCC converged frequency SNPs; 1.3=WTCCC supplement). Significant p-values (p<0.05) are highlighted by green shading.

Established susceptibility loci are highlighted in blue and lead SNPs from the WTCCC manuscript are printed in red.

(A) IRGM Controls CD UC

# dbSNP ID Pos. [bp] Dist. [kb] A1 A2 11/12/22 CR AFA1 11/12/22 CR AFA1 pCCA Bonf. pCCA OR 95% CI T:U OTA pTDT 11/12/22 CR AFA1 pCCA Bonf. pCCA OR 95% CI T:U OTA pTDT

1 rs6868496 150,131,464 C T 458/877/454 0.98 0.501 447/913/467 0.99 0.495 0.59 >0.99 1.06 0.91-1.23 222:208 T 0.50 263/519/298 0.98 0.4838 0.21 >0.99 1.07 0.90-1.27 213:177 T 0.068

2 rs12653083 150,138,140 6.68 C T 1643/115/6 0.97 0.964 1627/176/6 0.98 0.948 0.0010 0.028 1.52 1.20-1.93 40:36 C 0.65 922/78/4 0.91 0.957 0.23 >0.99 1.22 0.88-1.68 34:24 T 0.19

3 rs1144651 150,147,343 9.20 G T 8/169/1623 0.99 0.051 8/153/1672 0.99 0.046 0.30 >0.99 0.88 0.71-1.11 50:42 T 0.40 1/80/1014 0.99 0.0374 0.014 0.39 0.73 0.56-0.96 40:31 T 0.29

4 rs13361189 150,203,580 56.24 C T 8/234/1447 0.93 0.074 24/325/1453 0.97 0.104 1.27E-05 3.55E-04 1.44 1.21-1.73 80:57 C 0.049 11/162/888 0.96 0.0867 0.081 >0.99 1.17 0.95-1.45 77:67 C 0.40

5 rs17111376 150,207,092 3.51 C T 10/239/1534 0.98 0.073 25/327/1441 0.97 0.105 1.38E-06 3.86E-05 1.51 1.26-1.80 85:58 C 0.024 16/163/826 0.91 0.0972 0.0030 0.084 1.34 1.07-1.69 74:64 C 0.39

6 rs10065172 150,208,191 1.10 C T 1549/241/9 0.99 0.928 1471/336/24 0.99 0.895 7.94E-07 2.22E-05 1.52 1.27-1.81 85:60 T 0.038 917/169/12 1.00 0.9121 0.026 0.74 1.23 1.00-1.51 78:71 T 0.57

7 rs11949556 150,209,994 1.80 A C 1435/342/24 0.99 0.892 1337/446/45 0.99 0.853 6.83E-07 1.91E-05 1.44 1.24-1.69 113:91 C 0.12 847/230/18 0.99 0.8785 0.095 >0.99 1.16 0.97-1.39 101:83 C 0.18

8 rs11957134 150,211,143 1.15 A G 9/230/1563 0.99 0.069 21/317/1498 0.99 0.098 9.25E-06 2.59E-04 1.47 1.23-1.76 79:59 A 8.87E-02 11/152/932 0.99 0.0795 0.13 >0.99 1.14 0.92-1.42 74:67 A 0.56

9 rs6869426 150,213,197 2.05 C T 438/899/462 0.99 0.493 397/936/498 0.99 0.472 0.074 >0.99 0.93 0.80-1.07 241:202 T 6.39E-02 273/531/280 0.98 0.4968 0.82 >0.99 0.99 0.84-1.18 211:190 C 0.29

10 rs4958847 150,219,780 6.58 A G 24/339/1436 0.99 0.108 45/448/1337 0.99 0.147 3.95E-07 1.11E-05 1.46 1.25-1.70 113:93 A 0.16 17/229/846 0.99 0.1204 0.12 >0.99 1.15 0.96-1.38 99:86 A 0.34

11 rs1000113 150,220,269 0.49 C T 1561/231/9 0.99 0.931 1497/316/21 0.99 0.902 1.28E-05 3.59E-04 1.46 1.22-1.75 80:59 T 7.49E-02 927/155/11 0.99 0.919 0.088 >0.99 1.17 0.94-1.45 74:67 T 0.56

12 rs1150153 150,227,130 6.86 A G 1720/80/0 0.99 0.978 1770/69/1 0.99 0.981 0.39 >0.99 0.85 0.61-1.18 23:17 A 0.34 1058/34/0 0.99 0.9844 0.077 >0.99 0.69 0.46-1.04 25:18 A 0.29

13 rs1428555 150,237,584 10.45 A G 9/240/1548 0.99 0.072 25/337/1471 0.99 0.106 4.09E-07 1.14E-05 1.53 1.28-1.83 84:60 A 0.046 12/164/910 0.98 0.0866 0.041 >0.99 1.20 0.98-1.48 74:69 A 0.68

14 rs11747270 150,239,060 1.48 A G 1550/238/9 0.99 0.929 1476/332/25 0.99 0.896 6.50E-07 1.82E-05 1.52 1.27-1.81 87:62 G 0.041 917/163/12 0.99 0.9144 0.043 >0.99 1.20 0.97-1.48 73:68 G 0.67

15 rs10041072 150,239,835 0.78 C T 9/242/1553 0.99 0.072 25/335/1473 0.99 0.105 6.55E-07 1.83E-05 1.52 1.27-1.81 87:61 C 0.033 12/166/912 0.99 0.0872 0.035 0.99 1.21 0.98-1.49 76:68 C 0.51

16 rs1150154 150,250,852 11.02 C T 1742/66/0 1.00 0.982 1782/56/0 0.99 0.985 0.32 >0.99 0.83 0.58-1.19 22:14 C 0.18 1070/31/0 1.00 0.9859 0.23 >0.99 0.77 0.50-1.18 17:15 C 0.72

17 rs6579806 150,251,277 0.43 C T 1549/243/9 0.99 0.928 1470/334/25 0.99 0.895 1.31E-06 3.66E-05 1.50 1.26-1.79 86:60 T 0.031 917/170/12 1.00 0.9117 0.029 0.81 1.22 0.99-1.50 81:72 T 0.47

18 rs12653571 150,254,567 3.29 C T 3/119/1673 0.99 0.035 6/141/1694 1.00 0.042 0.14 >0.99 1.18 0.92-1.52 43:34 T 0.31 1/68/1026 0.99 0.032 0.57 >0.99 0.92 0.68-1.26 26:22 C 0.56

19 rs4958427 150,258,780 4.21 C T 1433/343/24 0.99 0.891 1334/447/46 0.99 0.853 5.24E-07 1.47E-05 1.45 1.24-1.69 113:95 T 0.21 843/234/18 0.99 0.8767 0.071 >0.99 1.18 0.98-1.41 101:85 T 0.24

20 rs1277603 150,260,755 1.98 C T 732/827/236 0.99 0.638 769/865/193 0.99 0.658 0.083 >0.99 0.95 0.83-1.08 199:186 T 0.51 489/460/134 0.98 0.6639 0.046 >0.99 0.83 0.72-0.97 219:154 C 8.00E-04

21 rs2290989 150,262,977 2.22 C T 3/122/1684 1.00 0.035 6/140/1698 1.00 0.041 0.17 >0.99 1.17 0.91-1.50 42:35 T 0.43 1/70/1029 1.00 0.0327 0.63 >0.99 0.94 0.69-1.27 27:22 C 0.48

22 rs7724036 150,265,001 2.02 C T 1510/269/10 0.98 0.919 1455/346/27 0.99 0.891 3.47E-05 9.70E-04 1.39 1.17-1.65 83:65 T 0.14 869/179/13 0.96 0.9034 0.034 0.95 1.20 0.98-1.47 86:70 T 0.20

23 rs1947773 150,265,144 0.14 A T 3/98/1599 0.94 0.031 6/125/1647 0.96 0.039 0.069 >0.99 1.26 0.96-1.65 43:24 T 0.19 1/52/990 0.95 0.0259 0.32 >0.99 0.85 0.60-1.20 21:21 - >0.99

24 rs1382319 150,278,081 12.94 C G 360/881/561 0.99 0.444 372/928/526 0.99 0.458 0.24 >0.99 1.12 0.97-1.29 231:198 C 0.11 233/506/341 0.98 0.45 0.67 >0.99 0.98 0.83-1.15 215:185 G 0.13

25 rs1478388 150,278,308 0.23 A G 360/876/560 0.99 0.444 375/930/527 0.99 0.459 0.25 >0.99 1.12 0.97-1.29 233:197 A 0.083 233/512/339 0.98 0.4511 0.62 >0.99 1.00 0.85-1.17 215:187 G 0.16

26 rs17800886 150,289,732 11.42 C G 1526/259/12 0.99 0.921 1477/331/24 0.99 0.897 3.00E-04 0.0084 1.35 1.14-1.61 87:61 G 0.033 894/186/12 0.99 0.9038 0.021 0.59 1.25 1.02-1.53 78:62 G 0.18

27 rs11167525 150,291,871 2.14 A G 562/879/358 0.99 0.557 527/931/373 0.99 0.542 0.21 >0.99 1.13 0.98-1.30 236:198 G 0.068 334/508/230 0.97 0.5485 0.54 >0.99 1.01 0.85-1.18 218:179 A 0.050

28 rs6579814 150,292,698 0.83 G T 725/827/230 0.98 0.639 734/889/197 0.98 0.648 0.45 >0.99 1.02 0.89-1.16 199:187 T 0.54 456/414/135 0.91 0.6593 0.14 >0.99 0.82 0.69-0.98 207:157 G 0.0088

(B) NKX2-3 Controls CD UC

# dbSNP ID Pos. [bp] Dist. [kb] A1 A2 11/12/22 CR AFA1 11/12/22 CR AFA1 pCCA Bonf. pCCA OR 95% CI T:U OTA pTDT 11/12/22 CR AFA1 pCCA Bonf. pCCA OR 95% CI T:U OTA pTDT

1 rs7077930 101,223,564 A C 917/739/151 0.99 0.712 911/752/154 0.98 0.708 0.70 >0.99 1.03 0.90-1.17 171:167 C 0.83 546/452/86 0.98 0.7122 0.99 >0.99 1.02 0.88-1.18 170:166 C 0.83

2 rs12355928 101,237,541 13.98 C T 1228/527/53 1.00 0.825 1302/481/51 0.99 0.841 0.062 >0.99 0.86 0.75-0.99 115:112 C 0.84 756/291/32 0.98 0.8355 0.29 >0.99 0.90 0.77-1.06 113:110 C 0.84

3 rs9665572 101,240,338 2.80 A C 115/725/968 1.00 0.264 135/707/997 0.99 0.266 0.92 >0.99 0.97 0.85-1.11 171:166 A 0.79 73/466/564 1.00 0.2772 0.30 >0.99 1.09 0.94-1.27 165:156 A 0.62

4 rs10883353 101,246,098 5.76 A G 1520/274/20 1.00 0.914 1475/348/23 1.00 0.893 0.0046 0.14 1.30 1.09-1.53 83:82 G 0.94 872/222/9 1.00 0.8913 0.0050 0.15 1.37 1.13-1.66 85:81 G 0.76

5 rs10883365 101,277,754 31.66 A G 493/934/356 0.98 0.538 440/907/476 0.99 0.490 4.03E-05 0.0012 1.21 1.04-1.40 240:221 G 0.38 245/528/315 0.99 0.4678 2.44E-07 7.31E-06 1.31 1.10-1.56 250:163 G 1.86E-05

6 rs7899176 101,279,113 1.36 C T 86/670/1045 0.99 0.234 93/627/1099 0.98 0.224 0.31 >0.99 0.91 0.79-1.04 152:147 T 0.77 47/378/665 0.99 0.2165 0.14 >0.99 0.89 0.76-1.03 157:124 T 0.049

7 rs1548964 101,279,643 0.53 C G 361/954/502 1.00 0.461 486/914/438 0.99 0.513 8.09E-06 2.43E-04 1.23 1.06-1.43 242:218 C 0.26 316/533/247 0.99 0.5315 1.57E-07 4.71E-06 1.32 1.10-1.57 262:175 C 3.16E-05

8 rs11190140 101,281,583 1.94 C T 503/941/351 0.99 0.542 440/905/478 0.99 0.490 8.87E-06 2.66E-04 1.22 1.05-1.42 237:222 T 0.48 230/521/305 0.96 0.4645 1.33E-08 3.99E-07 1.39 1.16-1.67 251:167 T 3.98E-05

9 rs7903232 101,288,792 7.21 C G 28/419/1343 0.99 0.133 38/390/1398 0.99 0.128 0.51 >0.99 0.92 0.79-1.07 103:99 C 0.78 19/229/825 0.97 0.1244 0.37 >0.99 0.90 0.76-1.08 91:90 C 0.94

10 rs4919345 101,294,307 5.52 C G 280/897/613 0.99 0.407 240/835/757 0.99 0.359 2.75E-05 8.25E-04 0.74 0.65-0.85 219:187 G 0.11 145/490/455 0.99 0.3578 2.00E-04 0.0060 0.73 0.62-0.85 214:172 G 0.033

11 rs10786559 101,298,880 4.57 C G 132/771/914 1.00 0.285 124/670/1050 1.00 0.249 6.00E-04 0.018 0.77 0.67-0.87 181:150 G 0.088 71/386/640 0.99 0.2407 2.00E-04 0.0060 0.72 0.62-0.84 198:136 G 7.00E-04

12 rs11814750 101,304,281 5.40 C T 1399/374/21 0.99 0.884 1472/346/25 1.00 0.893 0.25 >0.99 0.89 0.76-1.05 88:84 C 0.76 790/202/17 0.91 0.8831 0.95 >0.99 0.98 0.81-1.18 83:72 T 0.38

13 rs10786560 101,305,156 0.88 A G 100/670/1036 0.99 0.241 131/677/1034 1.00 0.255 0.19 >0.99 1.05 0.92-1.20 166:164 A 0.91 64/434/590 0.99 0.2583 0.13 >0.99 1.14 0.98-1.32 159:120 A 0.020

14 rs2902288 101,314,355 9.20 C G 30/426/1343 0.99 0.135 30/393/1415 0.99 0.123 0.13 >0.99 0.88 0.76-1.02 104:89 G 0.28 13/228/854 0.99 0.116 0.036 >0.99 0.83 0.70-0.99 97:90 G 0.61

15 rs1360522 101,315,787 1.43 A G 154/783/866 0.99 0.303 135/694/1009 0.99 0.262 1.00E-04 0.0030 0.76 0.66-0.86 190:160 G 0.11 71/419/598 0.99 0.2578 2.00E-04 0.0060 0.76 0.65-0.88 202:143 G 0.0015

16 rs7091572 101,317,841 2.05 C T 163/839/815 1.00 0.320 145/722/972 0.99 0.275 2.44E-05 7.33E-04 0.73 0.64-0.83 193:152 T 0.027 94/420/585 1.00 0.2766 6.00E-04 0.018 0.72 0.62-0.84 200:149 T 0.0063

17 rs12268645 101,318,008 0.17 G T 914/750/148 1.00 0.711 951/751/142 1.00 0.719 0.43 >0.99 0.95 0.84-1.09 194:179 T 0.44 578/446/75 1.00 0.7288 0.14 >0.99 0.91 0.79-1.06 173:159 G 0.44

18 rs12241254 101,319,148 1.14 C T 1302/466/32 0.99 0.853 1325/478/33 0.99 0.852 0.87 >0.99 1.01 0.88-1.17 129:109 C 0.19 794/278/20 0.99 0.8544 0.88 >0.99 0.98 0.83-1.16 120:102 C 0.23

19 rs4919352 101,319,957 0.81 C T 576/897/334 0.99 0.567 600/873/360 0.99 0.566 0.87 >0.99 0.96 0.84-1.11 212:193 C 0.35 339/549/205 0.99 0.5613 0.65 >0.99 1.04 0.89-1.23 207:189 T 0.37

20 rs4601693 101,322,029 2.07 A T 2/160/1655 1.00 0.045 7/199/1642 1.00 0.058 0.016 0.47 1.28 1.03-1.59 54:33 A 0.024 1/126/976 1.00 0.0579 0.029 0.87 1.33 1.04-1.70 55:42 A 0.19

21 rs12414093 101,324,224 2.20 A G 1178/579/60 1.00 0.808 1290/500/58 1.00 0.833 0.0040 0.12 0.80 0.69-0.91 151:118 A 0.044 740/326/34 1.00 0.8209 0.21 >0.99 0.90 0.76-1.05 136:111 A 0.11

22 rs883942 101,329,335 5.11 C G 110/652/1040 0.99 0.242 125/646/1062 0.99 0.244 0.85 >0.99 0.99 0.87-1.13 156:144 G 0.49 63/418/611 0.99 0.2491 0.56 >0.99 1.07 0.92-1.25 147:131 G 0.34

23 rs7896866 101,329,818 0.48 A C 143/785/886 1.00 0.295 140/775/916 0.99 0.288 0.51 >0.99 0.95 0.84-1.09 186:171 C 0.43 94/459/545 1.00 0.2946 0.97 >0.99 0.97 0.83-1.13 166:160 C 0.74

24 rs4919355 101,332,092 2.27 C T 811/826/178 1.00 0.674 839/812/183 0.99 0.679 0.67 >0.99 0.96 0.84-1.09 187:171 C 0.40 512/472/119 1.00 0.6782 0.72 >0.99 0.93 0.80-1.08 181:165 C 0.39

25 rs918117 101,332,571 0.48 C G 1668/145/1 1.00 0.960 1676/157/9 1.00 0.953 0.18 >0.99 1.12 0.89-1.42 41:36 C 0.57 1001/100/0 1.00 0.9546 0.37 >0.99 1.14 0.87-1.49 40:34 G 0.49

26 rs878940 101,333,016 0.45 C T 1074/643/89 0.99 0.773 1065/654/102 0.98 0.764 0.41 >0.99 1.04 0.91-1.19 159:141 T 0.30 629/406/58 0.99 0.7612 0.33 >0.99 1.08 0.93-1.26 156:148 C 0.65

27 rs17493485 101,333,870 0.85 C T 58/524/1229 1.00 0.177 64/530/1254 1.00 0.178 0.95 >0.99 1.00 0.87-1.14 130:121 T 0.57 32/345/726 1.00 0.1852 0.46 >0.99 1.09 0.93-1.27 127:113 T 0.37

28 rs6584294 101,335,214 1.34 A G 536/893/376 0.99 0.544 584/899/358 1.00 0.561 0.15 >0.99 0.91 0.79-1.05 207:200 A 0.73 328/550/213 0.99 0.5527 0.50 >0.99 0.98 0.83-1.15 205:194 G 0.58

29 rs1035210 101,335,409 0.20 A T 1169/428/56 0.91 0.837 1262/482/60 0.98 0.833 0.64 >0.99 1.04 0.90-1.21 126:114 T 0.44 693/297/31 0.93 0.8242 0.22 >0.99 1.15 0.97-1.36 116:103 T 0.38

30 rs6584295 101,335,461 0.05 C T 725/835/237 0.99 0.636 675/909/244 0.99 0.618 0.11 >0.99 1.16 1.01-1.32 202:197 T 0.80 420/538/129 0.99 0.6339 0.85 >0.99 1.08 0.92-1.26 193:189 C 0.84

(C) PTPN2 Controls CD UC

# dbSNP ID Pos. [bp] Dist. [kb] A1 A2 11/12/22 CR AFA1 11/12/22 CR AFA1 pCCA Bonf. pCCA OR 95% CI T:U OTA pTDT 11/12/22 CR AFA1 pCCA Bonf. pCCA OR 95% CI T:U OTA pTDT

1 rs12966571 12,726,042 A G 41/404/1355 0.99 0.135 32/422/1374 0.99 0.133 0.79 >0.99 1.01 0.86-1.17 109:98 G 0.44 14/233/836 0.98 0.1205 0.14 >0.99 0.91 0.76-1.09 98:83 G 0.26

2 rs1893212 12,726,491 0.45 A G 1323/458/34 1.00 0.855 1336/458/42 0.99 0.852 0.74 >0.99 1.01 0.87-1.17 111:101 G 0.49 801/273/23 0.99 0.8546 1.00 >0.99 0.99 0.83-1.17 105:94 A 0.44

3 rs2186940 12,732,809 6.32 C T 90/605/1111 0.99 0.217 90/597/1145 0.99 0.212 0.55 >0.99 0.96 0.84-1.09 153:128 T 0.14 64/340/682 0.98 0.2155 0.81 >0.99 0.94 0.80-1.10 138:136 C 0.90

4 rs16939788 12,734,692 1.88 C T 973/623/87 0.93 0.763 930/664/102 0.92 0.744 0.062 >0.99 1.13 0.99-1.30 140:121 T 0.24 550/393/62 0.91 0.7428 0.15 >0.99 1.12 0.94-1.34 137:134 C 0.86

5 rs10460003 12,737,012 2.32 C T 1421/301/17 0.96 0.904 1407/362/24 0.97 0.886 0.012 0.41 1.23 1.04-1.46 69:68 T 0.93 783/211/11 0.91 0.8842 0.036 >0.99 1.27 1.03-1.57 84:70 C 0.26

6 rs16939801 12,737,129 0.12 C T 1410/357/26 0.99 0.886 1401/394/25 0.98 0.878 0.28 >0.99 1.10 0.94-1.29 90:89 T 0.94 843/219/15 0.98 0.8844 0.80 >0.99 1.03 0.86-1.24 78:77 T 0.94

7 rs888264 12,740,377 3.25 A C 739/786/249 0.98 0.638 708/828/258 0.97 0.625 0.26 >0.99 1.10 0.96-1.26 192:184 C 0.68 367/486/152 0.91 0.6071 0.031 >0.99 1.25 1.05-1.49 170:167 A 0.87

8 rs17655374 12,740,758 0.38 C T 204/767/820 0.99 0.328 167/793/859 0.98 0.310 0.11 >0.99 0.95 0.83-1.08 187:179 C 0.68 90/447/534 0.97 0.2927 0.0097 0.34 0.86 0.74-1.00 162:147 T 0.39

9 rs2105665 12,752,045 11.29 A G 615/857/326 0.99 0.580 634/868/326 0.99 0.584 0.71 >0.99 0.98 0.86-1.12 212:208 G 0.85 381/533/165 0.98 0.6001 0.12 >0.99 0.95 0.81-1.11 188:179 A 0.64

10 rs12458131 12,761,159 9.11 G T 1473/308/16 0.99 0.905 1460/358/14 0.99 0.895 0.14 >0.99 1.16 0.98-1.37 84:82 G 0.88 875/191/11 0.98 0.9011 0.56 >0.99 1.05 0.87-1.28 68:67 T 0.93

11 rs2847266 12,763,338 2.18 A G 935/705/141 0.98 0.723 918/752/146 0.98 0.713 0.31 >0.99 1.09 0.95-1.24 169:156 G 0.47 530/409/100 0.94 0.7069 0.20 >0.99 1.06 0.91-1.24 172:125 G 0.0064

12 rs2542151 12,769,947 6.61 G T 41/464/1274 0.98 0.154 58/514/1223 0.97 0.176 0.010 0.36 1.18 1.02-1.36 111:99 G 0.41 35/313/657 0.91 0.1905 0.0013 0.046 1.33 1.11-1.59 122:91 G 0.034

13 rs2542157 12,777,247 7.30 G T 302/826/675 0.99 0.397 284/916/636 0.99 0.404 0.56 >0.99 1.12 0.98-1.29 225:200 G 0.23 161/533/401 0.99 0.3904 0.72 >0.99 1.04 0.89-1.22 203:171 T 0.098

14 rs2542170 12,790,820 13.57 A G 373/870/560 0.99 0.448 314/901/610 0.99 0.419 0.010 0.36 0.89 0.78-1.03 236:201 G 0.094 185/526/358 0.97 0.4191 0.027 0.95 0.89 0.76-1.05 202:180 G 0.26

15 rs8088256 12,803,201 12.38 A G 51/483/1260 0.99 0.163 42/474/1306 0.98 0.153 0.24 >0.99 0.93 0.81-1.08 124:117 G 0.65 26/257/780 0.96 0.1453 0.076 >0.99 0.86 0.72-1.01 113:98 G 0.30

16 rs973767 12,810,057 6.86 A G 1195/539/65 0.99 0.814 1240/535/57 0.99 0.823 0.31 >0.99 0.94 0.82-1.08 134:126 A 0.62 730/308/32 0.97 0.8262 0.22 >0.99 0.92 0.78-1.08 117:109 A 0.59

17 rs2847281 12,811,593 1.54 C T 285/848/666 0.99 0.394 264/881/680 0.99 0.386 0.48 >0.99 0.99 0.87-1.13 218:206 C 0.56 147/518/407 0.97 0.3787 0.22 >0.99 0.95 0.82-1.12 208:160 T 0.012

18 rs10502416 12,812,702 1.11 G T 989/572/93 0.91 0.771 1032/585/78 0.92 0.781 0.31 >0.99 0.96 0.83-1.10 121:94 G 0.066 608/352/45 0.91 0.7801 0.48 >0.99 0.96 0.80-1.17 82:81 G 0.94

19 rs683351 12,823,458 10.76 G T 1/60/1737 0.99 0.017 2/48/1787 0.99 0.014 0.29 >0.99 0.80 0.54-1.16 13:11 G 0.68 2/29/1046 0.98 0.0153 0.59 >0.99 0.85 0.55-1.31 13:12 T 0.84

20 rs3826556 12,831,406 7.95 C G 1690/117/0 0.99 0.968 1697/129/3 0.99 0.963 0.28 >0.99 1.13 0.87-1.46 28:20 G 0.25 998/79/1 0.98 0.9624 0.26 >0.99 1.17 0.87-1.58 30:30 - >0.99

21 rs674222 12,838,349 6.94 C G 285/841/657 0.98 0.396 264/881/675 0.98 0.387 0.48 >0.99 0.99 0.87-1.14 220:209 C 0.60 144/502/399 0.95 0.378 0.20 >0.99 0.94 0.81-1.11 200:155 G 0.017

22 rs487273 12,843,458 5.11 G T 1234/434/34 0.94 0.853 1246/479/54 0.96 0.835 0.038 >0.99 1.13 0.98-1.31 95:95 - >0.99 737/290/35 0.96 0.8305 0.033 >0.99 1.16 0.98-1.37 105:98 T 0.62

23 rs908579 12,881,550 38.09 A T 189/748/866 0.99 0.312 184/727/913 0.99 0.300 0.31 >0.99 0.93 0.81-1.05 190:180 T 0.60 112/454/514 0.98 0.3139 0.88 >0.99 1.02 0.87-1.18 175:164 A 0.55

24 rs4797710 12,883,018 1.47 C G 882/740/175 0.99 0.697 932/711/178 0.98 0.707 0.31 >0.99 0.92 0.80-1.04 187:181 C 0.75 510/448/105 0.96 0.6905 0.67 >0.99 1.04 0.89-1.21 181:161 G 0.28

25 rs4616352 12,888,134 5.12 C T 960/697/124 0.98 0.735 950/707/150 0.98 0.721 0.21 >0.99 1.05 0.92-1.20 179:174 T 0.79 565/374/65 0.91 0.7487 0.32 >0.99 0.91 0.77-1.08 153:122 C 0.062

26 rs8090005 12,888,759 0.63 A G 13/284/1378 0.92 0.093 22/302/1363 0.91 0.103 0.16 >0.99 1.11 0.93-1.32 63:49 G 0.19 384/540/179 1.00 0.0875 0.60 >0.99 0.91 0.71-1.16 67:65 G 0.86

27 rs8083335 12,892,446 3.69 A G 13/293/1470 0.98 0.090 22/310/1482 0.98 0.098 0.25 >0.99 1.08 0.91-1.28 73:62 G 0.34 10/144/838 0.90 0.0827 0.39 >0.99 0.89 0.72-1.10 69:66 G 0.80

28 rs11080612 12,911,361 18.92 C T 963/702/118 0.98 0.737 1033/680/103 0.98 0.756 0.075 >0.99 0.89 0.78-1.02 158:140 C 0.30 590/398/69 0.96 0.7465 0.48 >0.99 0.93 0.80-1.09 171:153 C 0.32

29 rs12326918 12,912,549 1.19 A G 58/542/1212 1.00 0.182 66/539/1228 0.99 0.183 0.92 >0.99 0.99 0.86-1.14 135:127 G 0.62 30/313/747 0.99 0.1711 0.32 >0.99 0.93 0.79-1.09 112:110 G 0.89

30 rs7242343 12,914,117 1.57 A G 2/99/1708 1.00 0.029 2/120/1708 0.99 0.034 0.20 >0.99 1.20 0.92-1.58 31:17 A 0.043 1/63/1023 0.99 0.0299 0.72 >0.99 1.07 0.77-1.47 26:23 A 0.67

31 rs6505770 12,916,278 2.16 C T 497/887/390 0.98 0.530 550/863/379 0.97 0.548 0.13 >0.99 0.87 0.76-1.01 220:203 C 0.41 300/509/238 0.95 0.5296 0.99 >0.99 0.96 0.81-1.14 198:195 T 0.88

32 rs7234619 12,916,654 0.38 C T 761/834/201 0.99 0.656 738/851/228 0.98 0.640 0.16 >0.99 1.08 0.94-1.23 205:194 T 0.58 470/456/134 0.96 0.6585 0.87 >0.99 0.92 0.79-1.08 200:167 C 0.085

Controls CD UC

# dbSNP ID Pos. [bp] Dist. [kb] A1 A2 11/12/22 CR AFA1 11/12/22 CR AFA1 pCCA Bonf. pCCA OR 95% CI T:U OTA pTDT 11/12/22 CR AFA1 pCCA Bonf. pCCA OR 95% CI T:U OTA pTDT

33 rs8088752 12,919,767 3.11 C T 405/929/445 0.98 0.489 429/926/460 0.98 0.492 0.84 >0.99 0.98 0.85-1.15 216:205 T 0.59 236/492/282 0.92 0.4772 0.40 >0.99 0.86 0.72-1.02 201:187 T 0.48

34 rs8083393 12,920,125 0.36 A G 135/694/976 0.99 0.267 146/725/956 0.99 0.278 0.29 >0.99 1.07 0.94-1.22 182:175 G 0.71 79/420/591 0.99 0.2651 0.93 >0.99 1.00 0.86-1.16 173:145 G 0.12

35 rs7229406 12,924,111 3.99 C T 527/842/291 0.91 0.571 532/844/290 0.90 0.573 0.88 >0.99 0.99 0.85-1.15 153:150 C 0.86 384/540/179 1.00 0.5926 0.19 >0.99 0.87 0.72-1.06 126:122 T 0.80

(D) Other loci Controls CD UC

# Source Locus dbSNP ID Chr. Pos. [bp] A1 A2 11/12/22 CR AFA1 11/12/22 CR AFA1 pCCA Bonf. pCCA OR 95% CI T:U OTA pTDT 11/12/22 CR AFA1 pCCA Bonf. pCCA OR 95% CI T:U OTA pTDT

1 1 ATG16L1 rs2241880 2 233,965,368 C T 500/909/384 0.99 0.532 647/872/299 0.98 0.596 5.82E-08 2.74E-06 0.70 0.61-0.81 243:165 C 1.00E-04 342/509/226 0.98 0.5539 0.12 >0.99 0.84 0.71-0.99 199:195 T 0.84

2 1 - rs16853571 4 41,594,058 A C 1566/200/8 0.98 0.939 1606/201/12 0.98 0.938 0.88 >0.99 1.00 0.81-1.22 51:45 C 0.54 930/104/6 0.94 0.9442 0.44 >0.99 0.89 0.70-1.14 46:44 A 0.83

3 1 - rs224136 10 64,140,681 C T 1272/481/38 0.99 0.845 1369/429/32 0.99 0.865 0.013 0.59 0.83 0.71-0.96 109:103 C 0.68 792/266/24 0.98 0.8549 0.30 >0.99 0.90 0.76-1.07 119:95 C 0.10

4 1 - rs11617463 13 74,229,094 A C 20/273/1481 0.98 0.088 17/270/1531 0.98 0.084 0.55 >0.99 0.96 0.80-1.14 70:61 C 0.43 11/175/892 0.98 0.0914 0.67 >0.99 1.06 0.86-1.29 71:49 C 0.045

5 1 FLJ44299 rs8050910 16 83,696,674 G T 336/879/567 0.98 0.435 314/916/597 0.99 0.423 0.26 >0.99 0.96 0.83-1.10 223:215 T 0.70 215/508/351 0.97 0.4367 0.92 >0.99 0.96 0.82-1.13 180:179 T 0.96

6 1 NCF4 rs4821544 22 35,583,003 C T 162/754/831 0.96 0.309 225/757/829 0.98 0.333 0.031 >0.99 1.07 0.94-1.22 181:176 C 0.79 107/493/478 0.98 0.3279 0.13 >0.99 1.14 0.98-1.32 155:147 C 0.65

7 2 - rs12035082 1 171,165,000 C T 241/854/684 0.98 0.376 323/887/632 1.00 0.416 4.00E-04 0.019 1.20 1.05-1.37 212:212 - >0.99 142/536/417 0.99 0.3744 0.93 >0.99 1.01 0.87-1.18 195:169 T 0.17

8 2 3p21.31 rs9858542 3 49,676,987 A G 137/684/957 0.98 0.269 211/759/854 0.99 0.324 5.06E-07 2.38E-05 1.32 1.16-1.51 205:157 A 0.012 127/440/505 0.97 0.3237 1.25E-05 5.90E-04 1.31 1.13-1.53 186:133 A 0.0030

9 2 5p13.1 rs17234657 5 40,437,266 G T 39/426/1315 0.98 0.142 83/554/1210 1.00 0.195 1.33E-09 6.25E-08 1.49 1.29-1.72 132:105 G 0.080 24/315/755 0.99 0.1659 0.012 0.55 1.27 1.08-1.50 128:91 G 0.012

10 2 5p13.1 rs9292777 5 40,473,705 C T 249/830/705 0.98 0.372 172/830/818 0.98 0.323 8.67E-06 4.08E-04 0.80 0.70-0.91 233:177 T 0.0057 140/501/453 0.99 0.3569 0.24 >0.99 0.92 0.79-1.08 195:178 T 0.38

11 2 5q31.1 rs10077785 5 131,829,057 C T 1087/620/89 0.99 0.778 1220/540/77 0.99 0.811 4.00E-04 0.019 0.78 0.68-0.89 151:126 C 0.13 705/342/48 0.99 0.8 0.046 >0.99 0.85 0.73-0.99 131:128 C 0.85

12 2 - rs6887695 5 158,755,223 C G 145/711/923 0.98 0.281 188/838/815 1.00 0.330 7.99E-06 3.75E-04 1.36 1.19-1.55 197:183 C 0.47 117/459/511 0.99 0.3188 0.0026 0.12 1.22 1.04-1.41 175:155 C 0.27

13 2 FLJ45139 rs2836754 21 39,213,610 C T 694/860/226 0.98 0.632 699/878/255 0.99 0.621 0.37 >0.99 1.04 0.91-1.18 208:186 T 0.27 420/518/149 0.99 0.6247 0.62 >0.99 1.01 0.87-1.18 182:177 T 0.79

14 3 - rs2484676 1 50,645,260 A T 532/844/398 0.98 0.538 511/905/404 0.98 0.529 0.48 >0.99 1.10 0.95-1.27 222:220 T 0.92 284/545/244 0.97 0.5186 0.16 >0.99 1.19 1.00-1.41 193:165 T 0.14

15 3 FAF1 rs11205760 1 50,946,918 C T 756/795/243 0.99 0.643 811/828/202 1.00 0.665 0.043 >0.99 0.92 0.81-1.05 218:177 C 0.039 479/504/109 0.99 0.6694 0.039 >0.99 0.93 0.80-1.08 168:165 C 0.87

16 3 - rs4506508 1 77,028,924 A C 1129/580/74 0.98 0.796 1156/612/72 0.99 0.795 0.90 >0.99 1.02 0.89-1.17 147:146 A 0.95 720/344/35 1.00 0.8116 0.15 >0.99 0.91 0.78-1.07 135:118 C 0.29

17 3 POU2F1 rs2814036 1 165,494,922 A G 1/72/1707 0.98 0.021 2/73/1770 1.00 0.021 0.97 >0.99 0.99 0.71-1.38 16:15 G 0.86 1/35/1061 0.99 0.0169 0.30 >0.99 0.79 0.53-1.19 22:10 G 0.034

18 3 - rs17419032 1 199,265,154 C T 947/713/123 0.98 0.731 1069/657/111 0.99 0.761 0.0039 0.18 0.81 0.71-0.93 193:147 C 0.013 657/367/70 0.99 0.7683 0.0017 0.080 0.75 0.65-0.88 175:138 C 0.037

19 3 - rs363617 2 74,772,200 C T 34/403/1357 0.99 0.131 31/413/1399 1.00 0.129 0.73 >0.99 0.98 0.84-1.14 101:100 T 0.94 19/263/821 1.00 0.1362 0.59 >0.99 1.06 0.90-1.27 93:90 C 0.82

20 3 LCT rs2322659 2 136,272,129 C T 920/721/142 0.98 0.718 933/751/143 0.99 0.716 0.86 >0.99 1.02 0.90-1.16 182:172 T 0.60 553/443/89 0.98 0.7138 0.69 >0.99 1.03 0.89-1.20 192:166 C 0.17

21 3 FLJ44290 rs9870678 3 57,497,990 A G 616/894/275 0.98 0.596 662/849/327 0.99 0.591 0.70 >0.99 0.94 0.82-1.07 213:191 A 0.27 394/522/175 0.99 0.6004 0.74 >0.99 0.94 0.80-1.10 204:177 G 0.17

22 3 - rs1462651 3 149,236,246 C T 1315/428/41 0.98 0.857 1333/480/27 0.99 0.855 0.80 >0.99 1.07 0.92-1.23 113:106 T 0.64 799/256/36 0.99 0.8497 0.47 >0.99 1.02 0.86-1.21 102:97 T 0.72

23 3 - rs9993022 4 59,606,282 C T 1657/114/1 0.98 0.967 1733/114/3 1.00 0.968 0.96 >0.99 0.98 0.75-1.27 29:23 T 0.41 1032/62/0 0.99 0.9717 0.35 >0.99 0.87 0.63-1.19 22:22 - >0.99

24 3 AK097548 rs1363670 5 158,716,689 C G 1196/549/44 0.98 0.822 1305/505/40 1.00 0.842 0.024 >0.99 0.84 0.73-0.97 136:115 C 0.19 790/277/33 1.00 0.8441 0.025 >0.99 0.79 0.67-0.93 116:95 C 0.15

25 3 C6orf85 rs17309827 6 3,378,317 G T 251/850/687 0.98 0.378 230/794/817 1.00 0.341 0.0010 0.047 0.78 0.69-0.90 245:187 T 0.0053 149/485/457 0.99 0.3588 0.15 >0.99 0.87 0.74-1.01 195:171 T 0.21

26 3 LYRM4 rs12529198 6 5,096,246 A G 1589/189/9 0.98 0.942 1603/232/15 1.00 0.929 0.026 >0.99 1.24 1.01-1.51 60:52:00 A 0.45 970/130/3 1.00 0.9385 0.54 >0.99 1.10 0.87-1.39 59:44:00 A 0.14

Controls CD UC

# Source Locus dbSNP ID Chr. Pos. [bp] A1 A2 11/12/22 CR AFA1 11/12/22 CR AFA1 pCCA Bonf. pCCA OR 95% CI T:U OTA pTDT 11/12/22 CR AFA1 pCCA Bonf. pCCA OR 95% CI T:U OTA pTDT

27 3 CDKAL1 rs6908425 6 20,836,710 C T 1106/612/76 0.99 0.787 1201/585/63 1.00 0.808 0.025 >0.99 0.86 0.75-0.99 161:120 C 0.015 722/338/42 1.00 0.8085 0.050 >0.99 0.85 0.72-0.99 135:128 C 0.67

28 3 - rs6927210 6 138,117,846 C T 476/894/410 0.98 0.519 458/922/461 1.00 0.499 0.11 >0.99 1.10 0.94-1.27 234:229 C 0.82 286/526/282 0.99 0.5018 0.22 >0.99 1.03 0.87-1.22 204:196 C 0.69

29 3 - rs946227 6 138,124,455 C T 692/829/260 0.98 0.621 739/849/248 0.99 0.634 0.28 >0.99 0.94 0.83-1.08 219:217 C 0.92 437/506/153 0.99 0.6296 0.53 >0.99 0.96 0.82-1.12 196:181 T 0.44

30 3 - rs1558043 7 19,946,298 C G 1335/398/24 0.97 0.873 1429/355/27 0.98 0.887 7.69E-02 >0.99 0.85 0.73-0.99 90:79 C 0.40 766/201/20 0.90 0.8779 0.58 >0.99 0.91 0.75-1.09 66:51 G 0.17

31 3 - rs12704036 7 147,889,094 C T 869/749/164 0.98 0.698 911/761/163 0.99 0.704 0.60 >0.99 0.97 0.85-1.10 209:187 C 0.27 524/459/102 0.98 0.6945 0.76 >0.99 1.02 0.88-1.19 169:152 C 0.34

32 3 - rs4871612 8 126,609,769 C T 1165/550/65 0.98 0.809 1198/566/66 0.99 0.809 0.98 >0.99 1.00 0.87-1.15 154:120 C 0.040 688/356/40 0.98 0.7989 0.34 >0.99 1.09 0.93-1.28 135:129 C 0.71

33 3 CCNY rs3936503 10 35,589,263 A G 156/781/851 0.98 0.306 241/806/793 0.99 0.350 5.76E-05 0.0027 1.20 1.05-1.37 210:174 A 0.066 147/481/462 0.99 0.3555 8.90E-05 0.0042 1.23 1.06-1.44 177:149 A 0.12

34 3 U10 rs10761659 10 64,115,570 A G 355/906/514 0.98 0.455 313/876/647 0.99 0.409 8.25E-05 0.0039 0.75 0.65-0.86 235:199 G 0.084 198/513/377 0.99 0.4177 0.0052 0.24 0.77 0.65-0.90 208:178 G 0.13

35 3 GPC5 rs1931047 13 92,087,164 C T 2/59/1716 0.98 0.018 2/64/1780 1.00 0.018 0.82 >0.99 1.04 0.73-1.49 18:12 T 0.27 1/44/1046 0.99 0.0211 0.36 >0.99 1.21 0.82-1.79 17:10 C 0.18

36 3 HERC2 rs916977 15 26,186,959 A G 20/340/1428 0.98 0.106 33/408/1393 0.99 0.129 0.0024 0.11 1.26 1.07-1.47 107:102 G 0.73 29/268/802 1.00 0.1483 3.32E-06 1.56E-04 1.46 1.23-1.75 87:66 A 0.090

37 3 STX8 rs9895062 17 9,311,348 A G 1542/222/15 0.98 0.929 1635/205/7 1.00 0.941 0.048 >0.99 0.85 0.69-1.03 57:52:00 A 0.63 974/119/1 0.99 0.9447 0.022 >0.99 0.80 0.64-1.02 46:43:00 G 0.75

38 4 ATCL8 rs7547331 1 17,963,516 C T 245/809/718 0.98 0.367 240/826/751 0.98 0.359 0.56 >0.99 0.97 0.85-1.11 212:207 C 0.81 138/502/431 0.97 0.3632 0.81 >0.99 1.01 0.87-1.18 163:162 T 0.96

39 4 - rs7807268 7 147,888,981 C G 498/880/403 0.98 0.527 534/886/424 1.00 0.530 0.82 >0.99 0.96 0.83-1.10 234:222 G 0.57 313/549/223 0.98 0.5415 0.29 >0.99 0.96 0.81-1.14 188:169 G 0.31

40 4 - rs7869487 9 116,620,735 C T 171/762/859 0.99 0.308 141/754/949 1.00 0.281 0.010 0.49 0.87 0.76-0.99 187:173 T 0.46 87/481/534 1.00 0.2972 0.42 >0.99 0.98 0.85-1.14 182:170 T 0.52

41 4 - rs6601764 10 3,852,542 C T 344/874/568 0.98 0.437 353/901/585 0.99 0.437 0.99 >0.99 1.00 0.87-1.15 227:219 C 0.70 196/544/349 0.99 0.4298 0.58 >0.99 0.99 0.84-1.16 206:189 T 0.39

42 4 STAT3 rs744166 17 37,767,727 C T 300/896/595 0.99 0.418 289/898/658 1.00 0.400 0.13 >0.99 0.90 0.78-1.03 219:212 T 0.74 147/521/431 1.00 0.3708 5.00E-04 0.024 0.77 0.66-0.90 200:173 T 0.16

43 4 - rs4362447 17 73,545,157 C T 821/773/191 0.98 0.677 839/781/218 0.99 0.669 0.49 >0.99 1.01 0.89-1.16 209:194 T 0.45 476/477/133 0.98 0.6579 0.13 >0.99 1.10 0.94-1.28 177:163 C 0.45

44 4 RSHL1 rs8111071 19 50,999,246 A G 1452/309/17 0.98 0.904 1498/341/9 1.00 0.903 0.91 >0.99 1.04 0.88-1.23 78:75 A 0.81 902/178/7 0.99 0.9117 0.30 >0.99 0.91 0.75-1.11 78:50 A 0.013

45 4 NFATC2 rs880324 20 49,487,597 A G 89/590/1105 0.98 0.215 83/626/1138 1.00 0.214 0.95 >0.99 1.02 0.89-1.16 153:150 A 0.86 53/370/672 0.99 0.2174 0.87 >0.99 1.02 0.88-1.19 135:129 A 0.71

46 4 ARFRP1 rs6011040 20 61,807,850 A G 169/756/856 0.98 0.307 136/743/957 0.99 0.276 0.0047 0.22 0.85 0.75-0.97 185:163 G 0.24 69/455/559 0.98 0.2738 0.0076 0.36 0.87 0.74-1.01 171:138 G 0.061

47 4 FLJ45139 rs2836753 21 39,213,057 C T 693/864/226 0.98 0.631 701/885/256 1.00 0.621 0.34 >0.99 1.04 0.91-1.19 213:193 T 0.32 420/524/150 0.99 0.6234 0.55 >0.99 1.02 0.87-1.19 183:175 T 0.67

Supplementary Table 3: Demographic and disease characteristics of Crohn disease patients that

were used in this study and in the genotype-subphenotype analysis (see Supplementary Table 4).

The subphenotype distribution reflects the expected distribution seen in clinical trials 4. For UC the

median age of onset was 26 years, the median age 40, and the sample consisted of 57.2% females.

No subphenotype analysis was conducted for UC. The control sample was age- and sex-matched.

n=1850 Crohn disease patients

Median age at diagnosis 21

Median age at time of recruitment 38

Females 68.0%

Family history of IBD 20.1%

Smoking at diagnosis 40.5%

Location

17.4% Ileal

15.6% Colonic

67.0% Ileocolonic

Extra intestinal manifestations 34.6% Skin

73.1% Joint (incl. arthralgia)

Fistulae 15.8%

Stenoses 68.3%

Colon resection 29.1%

Supplementary Table 4: Results of tests for statistical interactions with the known CD loci

(NOD2 (rs2066844/Arg702Trp, rs2066845/Gly908Arg, rs2066847/Leu1007fs), the 5p13.1

region (rs1992660 and rs1992662), IL23R (rs11209026/Arg381Gln), ATG16L1

(rs2241880/T300A), DLG5 (rs1248696/Arg30Gln), and the IBD5 region (tagging SNP

IGR2063_b1 5, 6) and of the subphenotype analysis (including early age of onset, family

history, smoking status, disease location [colonic, ileal, ileocolonic], extra intestinal

manifestations, fistulising or stenotic behaviour) are shown. All novel variants (n=20) that had

a significant nominal p-value in the case-control association analysis for CD were included.

Nominal p-values are shown for the logistic regression analysis. None of the tests remained

significant after correcting for multiple testing.

dbSNP ID #1 Subphenotype OR dbSNP ID #2 P-valuers10761659 5p13.1_rs1992660 0.9421rs10761659 5p13.1_rs1992662 0.3969rs10761659 ATG16L1_rs2241880 0.0912rs10761659 Colonic 0.1815rs10761659 DLG5_rs1248696 0.5584rs10761659 Early age of onset 0.4843rs10761659 Extra intestinal manifestations 0.2570rs10761659 Family history of IBD 0.4004rs10761659 Fistulae 0.8520rs10761659 Gender 0.1312rs10761659 IBD5_IGR2063_b1 0.3414rs10761659 IL23R_rs11209026 0.5616rs10761659 Ileal 0.4059rs10761659 Ileocolonic 0.8267rs10761659 NOD2_status 0.5539rs10761659 Smoking 0.9997rs10761659 Stenoses 0.9146rs10883365 5p13.1_rs1992660 0.0285rs10883365 5p13.1_rs1992662 0.1095rs10883365 ATG16L1_rs2241880 0.1031rs10883365 Colonic 0.3440rs10883365 DLG5_rs1248696 0.0861rs10883365 Early age of onset 0.1427rs10883365 Extra intestinal manifestations 0.5737rs10883365 Family history of IBD 0.5579rs10883365 Fistulae 0.3883rs10883365 Gender 0.5916rs10883365 IBD5_IGR2063_b1 0.1144rs10883365 IL23R_rs11209026 0.9925rs10883365 Ileal 0.4857rs10883365 Ileocolonic 0.1919rs10883365 NOD2_status 0.6870rs10883365 Smoking 0.3037rs10883365 Stenoses 0.0284rs11205760 5p13.1_rs1992660 0.6340rs11205760 5p13.1_rs1992662 0.1932rs11205760 ATG16L1_rs2241880 0.5117rs11205760 Colonic 0.1547rs11205760 DLG5_rs1248696 0.3264rs11205760 Early age of onset 0.0691rs11205760 Extra intestinal manifestations 0.0262rs11205760 Family history of IBD 0.7231rs11205760 Fistulae 0.0242rs11205760 Gender 0.8256rs11205760 IBD5_IGR2063_b1 0.7871rs11205760 IL23R_rs11209026 0.6433rs11205760 Ileal 0.3256rs11205760 Ileocolonic 0.7558rs11205760 NOD2_status 0.9685rs11205760 Smoking 0.6323rs11205760 Stenoses 0.5001rs12035082 5p13.1_rs1992660 0.0915rs12035082 5p13.1_rs1992662 0.5426rs12035082 ATG16L1_rs2241880 0.7798rs12035082 Colonic 0.4366rs12035082 DLG5_rs1248696 0.7724rs12035082 Early age of onset 0.5448

rs12035082 Extra intestinal manifestations 0.3740rs12035082 Family history of IBD 0.5281rs12035082 Fistulae 0.5077rs12035082 Gender 0.6289rs12035082 IBD5_IGR2063_b1 0.3452rs12035082 IL23R_rs11209026 0.2012rs12035082 Ileal 0.5770rs12035082 Ileocolonic 0.8649rs12035082 NOD2_status 0.9547rs12035082 Smoking 0.8393rs12035082 Stenoses 0.0154rs12529198 5p13.1_rs1992660 0.9428rs12529198 5p13.1_rs1992662 0.9697rs12529198 ATG16L1_rs2241880 0.4672rs12529198 Colonic 0.5828rs12529198 DLG5_rs1248696 0.9784rs12529198 Early age of onset 0.1654rs12529198 Extra intestinal manifestations 0.9278rs12529198 Family history of IBD 0.9911rs12529198 Fistulae 0.7392rs12529198 Gender 0.0271rs12529198 IBD5_IGR2063_b1 0.0142rs12529198 IL23R_rs11209026 NArs12529198 Ileal 0.2226rs12529198 Ileocolonic 0.1769rs12529198 NOD2_status 0.9716rs12529198 Smoking 0.2022rs12529198 Stenoses 0.0963rs13361189 5p13.1_rs1992660 0.1494rs13361189 5p13.1_rs1992662 0.3346rs13361189 ATG16L1_rs2241880 0.6132rs13361189 Colonic 0.7159rs13361189 DLG5_rs1248696 0.0102rs13361189 Early age of onset 0.2978rs13361189 Extra intestinal manifestations 0.1783rs13361189 Family history of IBD 0.5963rs13361189 Fistulae 0.1096rs13361189 Gender 0.9467rs13361189 IBD5_IGR2063_b1 0.3865rs13361189 IL23R_rs11209026 0.2141rs13361189 Ileal 0.2920rs13361189 Ileocolonic 0.2265rs13361189 NOD2_status 0.9582rs13361189 Smoking 0.0213rs13361189 Stenoses 0.0438rs1363670 5p13.1_rs1992660 0.6914rs1363670 5p13.1_rs1992662 0.7949rs1363670 ATG16L1_rs2241880 0.4404rs1363670 Colonic 0.7401rs1363670 DLG5_rs1248696 0.5154rs1363670 Early age of onset 0.0566rs1363670 Extra intestinal manifestations 0.1412rs1363670 Family history of IBD 0.0091rs1363670 Fistulae 0.7585rs1363670 Gender 0.7945rs1363670 IBD5_IGR2063_b1 0.9030rs1363670 IL23R_rs11209026 0.4629rs1363670 Ileal 0.9122

rs1363670 Ileocolonic 0.6783rs1363670 NOD2_status 0.2248rs1363670 Smoking 0.2387rs1363670 Stenoses 0.3492rs17309827 5p13.1_rs1992660 0.8722rs17309827 5p13.1_rs1992662 0.3746rs17309827 ATG16L1_rs2241880 0.8614rs17309827 Colonic 0.0997rs17309827 DLG5_rs1248696 0.4687rs17309827 Early age of onset 0.9886rs17309827 Extra intestinal manifestations 0.5119rs17309827 Family history of IBD 0.4128rs17309827 Fistulae 0.4381rs17309827 Gender 0.6733rs17309827 IBD5_IGR2063_b1 0.4065rs17309827 IL23R_rs11209026 0.0278rs17309827 Ileal 0.7661rs17309827 Ileocolonic 0.3411rs17309827 NOD2_status 0.5354rs17309827 Smoking 0.0332rs17309827 Stenoses 0.5452rs17419032 5p13.1_rs1992660 0.6319rs17419032 5p13.1_rs1992662 0.2140rs17419032 ATG16L1_rs2241880 0.6548rs17419032 Colonic 0.5237rs17419032 DLG5_rs1248696 0.1076rs17419032 Early age of onset 0.0422rs17419032 Extra intestinal manifestations 0.6562rs17419032 Family history of IBD 0.2525rs17419032 Fistulae 0.1567rs17419032 Gender 0.8567rs17419032 IBD5_IGR2063_b1 0.6283rs17419032 IL23R_rs11209026 0.2116rs17419032 Ileal 0.0889rs17419032 Ileocolonic 0.3095rs17419032 NOD2_status 0.5383rs17419032 Smoking 0.6162rs17419032 Stenoses 0.7545rs224136 5p13.1_rs1992660 0.7498rs224136 5p13.1_rs1992662 0.9707rs224136 ATG16L1_rs2241880 0.0735rs224136 Colonic 0.3514rs224136 DLG5_rs1248696 0.5879rs224136 Early age of onset 0.2206rs224136 Extra intestinal manifestations 0.8736rs224136 Family history of IBD 0.9922rs224136 Fistulae 0.7499rs224136 Gender 0.4421rs224136 IBD5_IGR2063_b1 0.5631rs224136 IL23R_rs11209026 0.6075rs224136 Ileal 0.2238rs224136 Ileocolonic 0.1056rs224136 NOD2_status 0.9697rs224136 Smoking 0.2533rs224136 Stenoses 0.2098rs2542151 5p13.1_rs1992660 0.6523rs2542151 5p13.1_rs1992662 0.2213rs2542151 ATG16L1_rs2241880 0.7696

rs2542151 Colonic 0.7735rs2542151 DLG5_rs1248696 0.8262rs2542151 Early age of onset 0.9642rs2542151 Extra intestinal manifestations 0.9286rs2542151 Family history of IBD 0.8539rs2542151 Fistulae 0.8703rs2542151 Gender 0.5242rs2542151 IBD5_IGR2063_b1 0.8461rs2542151 IL23R_rs11209026 0.8281rs2542151 Ileal 0.7724rs2542151 Ileocolonic 0.8484rs2542151 NOD2_status 0.1562rs2542151 Smoking 0.9244rs2542151 Stenoses 0.8418rs3936503 5p13.1_rs1992660 0.7897rs3936503 5p13.1_rs1992662 0.1498rs3936503 ATG16L1_rs2241880 0.3791rs3936503 Colonic 0.7370rs3936503 DLG5_rs1248696 0.4679rs3936503 Early age of onset 0.0915rs3936503 Extra intestinal manifestations 0.0110rs3936503 Family history of IBD 0.8536rs3936503 Fistulae 0.8971rs3936503 Gender 0.5427rs3936503 IBD5_IGR2063_b1 0.1409rs3936503 IL23R_rs11209026 0.1788rs3936503 Ileal 0.4454rs3936503 Ileocolonic 0.1993rs3936503 NOD2_status 0.8737rs3936503 Smoking 0.3824rs3936503 Stenoses 0.4832rs4821544 5p13.1_rs1992660 0.3664rs4821544 5p13.1_rs1992662 0.4887rs4821544 ATG16L1_rs2241880 0.1160rs4821544 Colonic 0.5376rs4821544 DLG5_rs1248696 0.4586rs4821544 Early age of onset 0.0488rs4821544 Extra intestinal manifestations 0.3269rs4821544 Family history of IBD 0.0115rs4821544 Fistulae 0.9898rs4821544 Gender 0.8485rs4821544 IBD5_IGR2063_b1 0.6562rs4821544 IL23R_rs11209026 0.0488rs4821544 Ileal 0.5840rs4821544 Ileocolonic 0.3219rs4821544 NOD2_status 0.8015rs4821544 Smoking 0.4001rs4821544 Stenoses 0.9976rs4958847 5p13.1_rs1992660 0.1604rs4958847 5p13.1_rs1992662 0.8013rs4958847 ATG16L1_rs2241880 0.4435rs4958847 Colonic 0.9135rs4958847 DLG5_rs1248696 0.0402rs4958847 Early age of onset 0.3309rs4958847 Extra intestinal manifestations 0.7322rs4958847 Family history of IBD 0.5955rs4958847 Fistulae 0.1129rs4958847 Gender 0.6935

rs4958847 IBD5_IGR2063_b1 0.1610rs4958847 IL23R_rs11209026 0.0239rs4958847 Ileal 0.3122rs4958847 Ileocolonic 0.2943rs4958847 NOD2_status 0.9644rs4958847 Smoking 0.4537rs4958847 Stenoses 0.0932rs6011040 5p13.1_rs1992660 0.3745rs6011040 5p13.1_rs1992662 0.1061rs6011040 ATG16L1_rs2241880 0.6782rs6011040 Colonic 0.7708rs6011040 DLG5_rs1248696 0.7012rs6011040 Early age of onset 0.4748rs6011040 Extra intestinal manifestations 0.4103rs6011040 Family history of IBD 0.6416rs6011040 Fistulae 0.0049rs6011040 Gender 0.6513rs6011040 IBD5_IGR2063_b1 0.3587rs6011040 IL23R_rs11209026 0.5088rs6011040 Ileal 0.3974rs6011040 Ileocolonic 0.4729rs6011040 NOD2_status 0.2162rs6011040 Smoking 0.4923rs6011040 Stenoses 0.2479rs6887695 5p13.1_rs1992660 0.9012rs6887695 5p13.1_rs1992662 0.3864rs6887695 ATG16L1_rs2241880 0.4973rs6887695 Colonic 0.9325rs6887695 DLG5_rs1248696 0.3856rs6887695 Early age of onset 0.1157rs6887695 Extra intestinal manifestations 0.1491rs6887695 Family history of IBD 0.5160rs6887695 Fistulae 0.8178rs6887695 Gender 0.0444rs6887695 IBD5_IGR2063_b1 0.7511rs6887695 IL23R_rs11209026 0.2005rs6887695 Ileal 0.6795rs6887695 Ileocolonic 0.6431rs6887695 NOD2_status 0.8110rs6887695 Smoking 0.0416rs6887695 Stenoses 0.7172rs6908425 5p13.1_rs1992660 0.6848rs6908425 5p13.1_rs1992662 0.3853rs6908425 ATG16L1_rs2241880 0.1603rs6908425 Colonic 0.6425rs6908425 DLG5_rs1248696 0.4222rs6908425 Early age of onset 0.2801rs6908425 Extra intestinal manifestations 0.5481rs6908425 Family history of IBD 0.9895rs6908425 Fistulae 0.5129rs6908425 Gender 0.4663rs6908425 IBD5_IGR2063_b1 0.4280rs6908425 IL23R_rs11209026 0.2856rs6908425 Ileal 0.2315rs6908425 Ileocolonic 0.1610rs6908425 NOD2_status 0.9595rs6908425 Smoking 0.4690rs6908425 Stenoses 0.5198

rs7869487 5p13.1_rs1992660 0.8442rs7869487 5p13.1_rs1992662 0.5298rs7869487 ATG16L1_rs2241880 0.1751rs7869487 Colonic 0.7996rs7869487 DLG5_rs1248696 0.8799rs7869487 Early age of onset 0.8562rs7869487 Extra intestinal manifestations 0.9208rs7869487 Family history of IBD 0.1128rs7869487 Fistulae 0.8489rs7869487 Gender 0.2984rs7869487 IBD5_IGR2063_b1 0.0670rs7869487 IL23R_rs11209026 0.8952rs7869487 Ileal 0.0448rs7869487 Ileocolonic 0.1504rs7869487 NOD2_status 0.1005rs7869487 Smoking 0.3860rs7869487 Stenoses 0.5981rs916977 5p13.1_rs1992660 0.0263rs916977 5p13.1_rs1992662 0.6131rs916977 ATG16L1_rs2241880 0.7023rs916977 Colonic 0.8131rs916977 DLG5_rs1248696 0.5289rs916977 Early age of onset 0.8978rs916977 Extra intestinal manifestations 0.2713rs916977 Family history of IBD 0.6913rs916977 Fistulae 0.0232rs916977 Gender 0.7686rs916977 IBD5_IGR2063_b1 0.4637rs916977 IL23R_rs11209026 0.2366rs916977 Ileal 0.4377rs916977 Ileocolonic 0.4202rs916977 NOD2_status 0.1589rs916977 Smoking 0.5847rs916977 Stenoses 0.7577rs9895062 5p13.1_rs1992660 0.4364rs9895062 5p13.1_rs1992662 0.9603rs9895062 ATG16L1_rs2241880 0.4381rs9895062 Colonic 0.9262rs9895062 DLG5_rs1248696 0.9518rs9895062 Early age of onset 0.5484rs9895062 Extra intestinal manifestations 0.9270rs9895062 Family history of IBD 0.9900rs9895062 Fistulae 0.9663rs9895062 Gender 0.6802rs9895062 IBD5_IGR2063_b1 NArs9895062 IL23R_rs11209026 0.4945rs9895062 Ileal 0.8241rs9895062 Ileocolonic 0.7764rs9895062 NOD2_status 0.9639rs9895062 Smoking 0.9797rs9895062 Stenoses 0.4401

Supplementary Figure 1: Regional plot of disease association and LD structure for the (A) IRGM

and (B) PTPN2 gene. For a description of the different panels of the diagram see Figure 1 of the

main manuscript. Filled circles correspond to the lead variants of the original GWAS. Detailed

analysis results are given in Supplementary Table 2 online.

(A) IRGM

(B) PTPN2

Supplementary Figure 2: Forest plots of odds ratios (ORs) including 95% confidence intervals for

all genotyped GWAS lead SNPs. The meta-analysis has been conducted using the results of this

study and the respective GWAS (including replication data when available). ORs in diagram (A)

correspond to the variants listed in Table 1 of the main manuscript. Diagram (B) displays the ORs

of all remaining (non-replicating in the German CD panel) SNPs (see Supplementary Table 1

online). The ORs for carriership of the rare allele are shown. The four different SNP categories are

described in the Supplementary Methods online.

ORI: OR in the original study. For category 1 SNPs, neither confidence intervals, nor genotype

counts were listed in the work of Rioux and colleagues, not allowing the inclusion in the meta-

analysis. For category 2 SNPs, genotypes of the case panels WTCD (1747 GWAS cases)/RCD

(1182 replication CD cases) and control panels WTU1 (2938 GWAS controls)/RU (2024 replication

controls) were combined (for detailed description of panels see original publication of Parkes et al.)

and for category 3 only WTCD/RCD with WTU1. For category 4, only genotypes of panels WTCD

and WTU1 were used; CD: German Crohn disease patient panel (1850 cases/1817 healthy

controls); Combined: ORs for combined sample, i.e. ORI+CD.

(A)

(B)

References 1 Rioux, J.D. et al. Nat Genet 39, 596-604 (2007). 2 WTCCC Nature 447, 661-678 (2007). 3 Parkes, M. et al. Nat Genet 39, 830-832 (2007). 4 Schreiber, S. et al. N Engl J Med 357, 239-250 (2007). 5 Rioux, J.D. et al. Nat Genet 29, 223-228 (2001). 6 Fisher, S.A. et al. Hum Mutat 27, 778-785 (2006).