Table S1: Relative CRC risk (RR) of overweight, smoking and alcohol consumption (from published meta-analyses)

Risk factor / RR (95% CI) / Reference
Overweight / Men / 1.24§ (1.20-1.28) / Harriss et al. 2009
Women / 1.09§ (1.05-1.13) / Harriss et al. 2009
Smoking / Smoker vs. non-smoker / 1.18 (1.11-1.25) / Botteri et al. 2008
Alcohol consumption / Moderate vs. non-drinking / 1.21 (1.13-1.28) / Fedirko et al. 2011
Heavy vs. non-drinking / 1.52 (1.27-1.81) / Fedirko et al. 2011

§per 5 kg/m2 increase in BMI

Table S2: G×E interactionsin CRC with p<10-4 in stage I

Environmental factor/Locus / Stage I / Stage II
Unadjusted / Unadjusted / Sex- and age-adjusted
SNP / Region spanned by clumping SNPs§ / Minor / MAF / # clumping / # clumping / # clumping
allele / OR / p / SNPs with / OR / p / SNPs with / OR / p / SNPs with / Pc
p<0.01 / p<0.05 / p<0.05
Overweight
rs11211604 / chr1:48251342..48318689 (67kb) / T / 0.24 / 2.48 / 2.5×10-5 / 10 / 0.97 / 0.905 / 0 / 0.98 / 0.944 / 0 / 0.955
rs4839497 / chr1:116372354..116658478 (286kb) / A / 0.06 / 4.63 / 7.4×10-5 / 118 / 1.10 / 0.821 / 0 / 1.07 / 0.884 / 0 / 0.951
rs12034493 / chr1:206960216..206969339 (9kb) / A / 0.24 / 0.36 / 1.0×10-5 / 7 / 1.41 / 0.155 / 0 / 1.63 / 0.055 / 0 / 0.544
rs12474326 / chr2:4544875..4579292 (34kb) / C / 0.38 / 2.11 / 7.6×10-5 / 18 / 0.72 / 0.105 / 0 / 0.80 / 0.294 / 0 / 0.930
rs6753034 / chr2:108936355..108946178 (9kb) / T / 0.45 / 2.13 / 4.8×10-5 / 8 / 0.83 / 0.408 / 0 / 0.92 / 0.729 / 0 / 0.951
rs2358499 / chr2:206516665..206541927 (25kb) / C / 0.42 / 0.50 / 9.2×10-5 / 14 / 0.86 / 0.455 / 0 / 0.83 / 0.393 / 0 / 0.944
rs10171821 / chr2:206516979..206544302 (27kb) / A / 0.50 / 0.48 / 1.2×10-5 / 11 / 0.86 / 0.430 / 0 / 0.87 / 0.510 / 0 / 0.944
rs11678440 / chr2:206544665..206554114 (9kb) / T / 0.49 / 2.38 / 7.7×10-6 / 7 / 0.89 / 0.589 / 0 / 0.97 / 0.905 / 0 / 0.951
rs2708150 / chr2:214115506..214235826 (120kb) / C / 0.32 / 2.21 / 2.0×10-5 / 21 / 1.26 / 0.293 / 0 / 1.27 / 0.291 / 0 / 0.930
rs13013336 / chr2:214129546..214298668 (169kb) / C / 0.36 / 2.04 / 7.4×10-5 / 21 / 1.40 / 0.133 / 0 / 1.34 / 0.202 / 0 / 0.899
rs6747293 / chr2:214236393..214575924 (339kb) / T / 0.33 / 2.25 / 5.0×10-6 / 171 / 1.31 / 0.206 / 0 / 1.31 / 0.225 / 0 / 0.903
rs11915371 / chr3:70449028..70593081 (144kb) / C / 0.21 / 2.61 / 6.0×10-5 / 119 / 1.31 / 0.279 / 0 / 1.28 / 0.348 / 0 / 0.941
rs62246017 / chr3:71481192..71628286 (147kb) / A / 0.31 / 2.30 / 4.5×10-6 / 92 / 1.09 / 0.688 / 0 / 1.11 / 0.659 / 0 / 0.951
chr5:157374590 / chr5:157360570..157387092 (26kb) / T / 0.14 / 3.86 / 4.6×10-5 / 11 / 0.84 / 0.548 / 0 / 0.84 / 0.570 / 0 / 0.951
rs34853285 / chr6:144141545..144197005 (55kb) / G / 0.24 / 0.48 / 9.3×10-5 / 20 / 1.09 / 0.726 / 0 / 1.02 / 0.937 / 0 / 0.955
rs324480 / chr9:9069839..9138757 (68kb) / T / 0.39 / 2.18 / 6.3×10-5 / 69 / 1.00 / 0.994 / 0 / 1.00 / 0.989 / 0 / 0.986
chr9:113584517 / chr9:113584517..113637854 (53kb) / A / 0.20 / 0.38 / 7.7×10-5 / 47 / 1.17 / 0.551 / 0 / 1.18 / 0.548 / 0 / 0.951
rs10904688 / chr10:16211254..16286345 (75kb) / T / 0.19 / 0.46 / 6.0×10-5 / 24 / 0.87 / 0.565 / 0 / 0.85 / 0.546 / 0 / 0.951
rs11217586 / chr11:119794853..119848377 (53kb) / A / 0.15 / 2.97 / 1.7×10-5 / 24 / 2.23 / 0.007 / 24 / 2.40 / 0.004 / 24 / 0.055
rs7951479 / chr11:119834038..119845535 (11kb) / T / 0.39 / 0.46 / 1.3×10-5 / 7 / 0.96 / 0.835 / 0 / 0.97 / 0.879 / 0 / 0.951
rs633223 / chr11:119822879..119850725 (27kb) / A / 0.44 / 0.44 / 4.4×10-6 / 25 / 0.69 / 0.078 / 1 / 0.71 / 0.120 / 1 / 0.801
rs2155993 / chr11:119854514..119878269 (23kb) / T / 0.30 / 0.37 / 3.1×10-7 / 22 / 0.79 / 0.273 / 1 / 0.83 / 0.420 / 1 / 0.944
rs1944511 / chr11:119863584..119878901 (15kb) / A / 0.27 / 2.23 / 3.1×10-5 / 3 / 1.87 / 0.005 / 3 / 2.00 / 0.003 / 3 / 0.042
rs648374 / chr11:119875598..119879425 (3kb) / C / 0.43 / 2.23 / 1.9×10-5 / 3 / 1.30 / 0.202 / 2 / 1.26 / 0.293 / 2 / 0.930
rs10773983 / chr12:1831246..1928289 (97kb) / A / 0.34 / 0.45 / 8.6×10-5 / 5 / 0.97 / 0.902 / 0 / 1.02 / 0.912 / 0 / 0.955
rs10772646 / chr12:13409864..13465365 (55kb) / C / 0.38 / 0.50 / 8.7×10-5 / 21 / 0.98 / 0.927 / 0 / 0.91 / 0.651 / 0 / 0.951
rs11622270 / chr14:88969388..89134686 (165kb) / C / 0.19 / 2.77 / 1.1×10-5 / 29 / 0.68 / 0.141 / 0 / 0.75 / 0.282 / 0 / 0.904
rs410068 / chr20:15114240..15141014 (26kb) / T / 0.40 / 1.98 / 4.6×10-5 / 109 / 1.30 / 0.205 / 0 / 1.25 / 0.297 / 0 / 0.942
rs458032 / chr20:15193932..15221650 (27kb) / C / 0.34 / 2.13 / 4.6×10-5 / 9 / 1.23 / 0.339 / 0 / 1.19 / 0.450 / 0 / 0.944
rs2222208 / chr21:21059294..21084437 (25kb) / A / 0.37 / 2.08 / 6.0×10-5 / 7 / 1.19 / 0.415 / 0 / 1.17 / 0.470 / 0 / 0.944
rs5748383 / chr22:19640218..19643245 (3kb) / G / 0.25 / 2.37 / 8.6×10-5 / 5 / 1.13 / 0.626 / 0 / 1.11 / 0.682 / 0 / 0.951
Smoking
rs17011439 / chr2:31612781..31933896 (321kb) / T / 0.12 / 0.34 / 5.2×10-5 / 73 / 0.76 / 0.404 / 0 / 0.74 / 0.382 / 0 / 0.811
rs17197681 / chr2:137911275..138042567 (131kb) / G / 0.32 / 0.43 / 8.5×10-6 / 33 / 0.94 / 0.756 / 0 / 1.05 / 0.827 / 0 / 0.809
rs9877596 / chr3:20573619..20576566 (2kb) / A / 0.30 / 2.22 / 5.4×10-5 / 2 / 1.73 / 0.019 / 2 / 1.95 / 0.006 / 2 / 0.067
rs4864379 / chr4:137941164..137967448 (26kb) / G / 0.42 / 0.46 / 3.8×10-5 / 100 / 0.92 / 0.689 / 0 / 0.97 / 0.899 / 0 / 0.810
rs3857404 / chr5:78116794..78117584 (0kb) / T / 0.38 / 2.17 / 7.1×10-5 / 2 / 0.77 / 0.207 / 0 / 0.77 / 0.219 / 0 / 0.774
chr5:117939653 / chr5:117928253..117945961 (17kb) / C / 0.24 / 2.69 / 1.4×10-5 / 39 / 1.05 / 0.867 / 0 / 1.08 / 0.796 / 0 / 0.811
rs6925493 / chr6:15923026..16019115 (96kb) / G / 0.05 / 4.61 / 8.4×10-5 / 41 / 0.80 / 0.601 / 0 / 0.83 / 0.675 / 0 / 0.811
rs1860516 / chr7:38204054..38329610 (125kb) / A / 0.23 / 2.42 / 3.4×10-5 / 114 / 0.88 / 0.583 / 0 / 0.83 / 0.455 / 0 / 0.811
rs1002839 / chr7:38323398..38335954 (12kb) / A / 0.31 / 2.08 / 8.8×10-5 / 10 / 0.87 / 0.508 / 0 / 0.79 / 0.302 / 0 / 0.799
rs4286865 / chr7:153881161..153934210 (53kb) / T / 0.21 / 0.47 / 7.7×10-5 / 46 / 0.99 / 0.977 / 0 / 1.00 / 0.986 / 0 / 0.802
rs1604292 / chr8:132969825..133035899 (66kb) / T / 0.32 / 0.45 / 6.8×10-5 / 10 / 0.77 / 0.236 / 0 / 0.78 / 0.282 / 0 / 0.802
rs10815144 / chr9:5002011..5215064 (213kb) / A / 0.49 / 0.46 / 1.6×10-5 / 44 / 1.54 / 0.035 / 0 / 1.52 / 0.052 / 0 / 0.438
rs1980756 / chr10:26925722..27017022 (91kb) / C / 0.34 / 2.21 / 4.4×10-5 / 69 / 0.83 / 0.362 / 0 / 0.80 / 0.311 / 0 / 0.798
rs1361137 / chr13:109383641..109460881 (77kb) / C / 0.23 / 0.40 / 5.9×10-5 / 55 / 0.96 / 0.845 / 0 / 0.94 / 0.806 / 0 / 0.811
rs61020490 / chr14:49771228..49839034 (67kb) / A / 0.16 / 2.93 / 3.3×10-5 / 35 / 0.77 / 0.391 / 0 / 0.73 / 0.331 / 0 / 0.802
rs7172116 / chr15:95255177..95280319 (25kb) / A / 0.19 / 2.52 / 3.4×10-5 / 36 / 0.51 / 0.007 / 0 / 0.58 / 0.042 / 0 / 0.383
rs12162013 / chr16:62038196..62194176 (155kb) / T / 0.39 / 2.14 / 6.8×10-5 / 56 / 1.48 / 0.066 / 17 / 1.50 / 0.067 / 22 / 0.526
rs35643510 / chr16:86442236..86467111 (24kb) / T / 0.43 / 0.47 / 2.2×10-5 / 45 / 1.03 / 0.900 / 0 / 1.09 / 0.684 / 0 / 0.811
rs637005 / chr18:10054685..10066396 (11kb) / C / 0.13 / 0.29 / 9.9×10-5 / 12 / 2.15 / 0.013 / 0 / 2.08 / 0.023 / 0 / 0.250
rs9945428 / chr18:71788676..71788898 (2kb) / A / 0.28 / 0.40 / 4.4×10-5 / 2 / 1.53 / 0.068 / 0 / 1.70 / 0.029 / 0 / 0.312
rs1543703 / chr20:52696990..52711514 (14kb) / A / 0.48 / 2.07 / 4.6×10-5 / 9 / 1.12 / 0.569 / 0 / 1.25 / 0.277 / 0 / 0.804
rs6003396 / chr22:23288012..23355251 (67kb) / A / 0.16 / 2.36 / 8.7×10-5 / 52 / 1.09 / 0.733 / 0 / 1.17 / 0.568 / 0 / 0.811
Alcohol consumption
rs6741102 / chr2:43274822..43282963 (8kb) / C / 0.29 / 0.47 / 9.3×10-5 / 5 / 0.98 / 0.915 / 0 / 1.03 / 0.910 / 0 / 0.758
rs10210134 / chr2:153801307..153956908 (155kb) / A / 0.39 / 0.47 / 9.1×10-5 / 33 / 1.02 / 0.932 / 0 / 0.96 / 0.841 / 0 / 0.861
rs9311963 / chr3:6726173..6757331 (31kb) / C / 0.35 / 2.17 / 1.1×10-5 / 48 / 0.88 / 0.586 / 0 / 0.87 / 0.564 / 0 / 0.880
rs35882004 / chr4:58189742..58288262 (98kb) / T / 0.07 / 0.27 / 9.6×10-5 / 52 / 0.64 / 0.293 / 1 / 0.65 / 0.321 / 1 / 0.864
rs10484642 / chr6:54201114..54289275 (88kb) / C / 0.14 / 2.76 / 7.0×10-5 / 58 / 0.85 / 0.601 / 0 / 0.93 / 0.807 / 0 / 0.863
rs737539 / chr6:137816163..137843002 (26kb) / G / 0.27 / 0.42 / 4.5×10-5 / 23 / 1.21 / 0.424 / 0 / 1.23 / 0.397 / 0 / 0.877
rs1385941 / chr7:46076841..46170470 (93kb) / G / 0.45 / 0.50 / 4.5×10-5 / 23 / 1.24 / 0.335 / 0 / 1.25 / 0.325 / 0 / 0.864
rs11992036 / chr8:5661134..5696509 (35kb) / T / 0.18 / 0.39 / 3.4×10-5 / 12 / 1.39 / 0.274 / 0 / 1.45 / 0.228 / 0 / 0.745
rs7004307 / chr8:89951288..90167337 (216kb) / A / 0.06 / 4.85 / 5.3×10-6 / 112 / 1.27 / 0.577 / 0 / 1.29 / 0.565 / 0 / 0.880
rs11989778 / chr8:90008085..90164259 (156kb) / C / 0.33 / 2.02 / 5.4×10-5 / 93 / 0.70 / 0.126 / 0 / 0.75 / 0.243 / 0 / 0.804
rs35246532 / chr9:13921479..13959282 (37kb) / T / 0.20 / 0.36 / 2.2×10-5 / 31 / 1.10 / 0.732 / 0 / 1.34 / 0.309 / 0 / 0.849
rs3009687 / chr9:81248146..81316115 (67kb) / G / 0.41 / 2.08 / 7.0×10-5 / 20 / 0.64 / 0.040 / 0 / 0.64 / 0.045 / 0 / 0.416
chr9:139137626 / chr9:139101583..139141908 (40kb) / C / 0.30 / 2.17 / 9.6×10-5 / 22 / 0.93 / 0.772 / 0 / 0.97 / 0.903 / 0 / 0.829
rs10218849 / chr10:117984288..118106468 (122kb) / C / 0.44 / 2.08 / 4.1×10-5 / 34 / 0.98 / 0.928 / 0 / 0.92 / 0.702 / 0 / 0.863
rs11036902 / chr11:42461563..42507864 (46kb) / G / 0.25 / 2.50 / 6.3×10-5 / 55 / 0.62 / 0.085 / 0 / 0.64 / 0.112 / 0 / 0.620
rs4884965 / chr13:54863170..54920810 (57kb) / G / 0.21 / 2.65 / 2.6×10-5 / 28 / 1.06 / 0.836 / 0 / 1.12 / 0.711 / 0 / 0.863
rs12870649 / chr13:40371377..40419314 (4kb) / T / 0.26 / 2.58 / 9.6×10-5 / 19 / 2.21 / 0.003 / 19 / 2.16 / 0.005 / 19 / 0.051
rs4792171 / chr17:11615945..11669494 (53kb) / T / 0.35 / 2.09 / 9.8×10-5 / 17 / 0.80 / 0.345 / 0 / 0.76 / 0.256 / 0 / 0.821
rs2052778 / chr18:10375022..10375115 (0kb) / A / 0.34 / 2.01 / 7.1×10-5 / 2 / 1.46 / 0.089 / 0 / 1.49 / 0.081 / 0 / 0.555
rs9955850 / chr18:49294017..49364869 (70kb) / C / 0.08 / 0.16 / 4.8×10-5 / 19 / 1.12 / 0.775 / 0 / 1.21 / 0.626 / 0 / 0.880
rs34173341 / chr18:66826511..66877627 (51kb) / C / 0.12 / 0.27 / 8.4×10-5 / 3 / 0.95 / 0.893 / 0 / 0.86 / 0.674 / 0 / 0.863

P values and odds ratios (OR=exp(G) for stage I, OR=(I) for stage II) refer to a logistic regression analysis employing an allele-based genetic risk model. §Positions according to NCBI build 37 (see Methods section for the definition of clumping SNPs); MAF: minor allele frequency in controls (n=1,002);pc: multiplicity-corrected p value obtained by the Westfall and Young Step-Down MaxT procedure (Westfall et al. 1993) with 10,000 iterations

Figure S1-S3. Quantile-quantile plots(Q-QPlots)of G×E interaction p values

Figure S1. Q-QPlot ofG×E interactions with overweight (stage I).

Figure S2. Q-QPlot ofG×E interactions with smoking (stage I).

Figure S3. Q-QPlot ofG×E interactions with alcohol consumption (stage I).

Figure S4-S6. Power calculations for stage I. Depicted is the power of the stage I case-only data (assuming n=300) to detect a G×E interaction, at the 5% significance level, in the absence of a marginal genetic effect. The minor allele frequency was set equal to either 0.20 (solid line) or 0.05 (dashed line).exp(ßG): allelic exposure odds ratio as assumed for the SNP of interest.

Figure S4. Power to detect a G×E interaction with overweight (stage I). The environmental odds ratio was set equal to 1.24 for men (blue), 1.09 for women (red), and 1.15 for both sexes combined (black). The prevalence was set equal to 0.75 (men), 0.59 (women) and 0.65 (both), respectively.

Figure S5. Power to detect a G×E interaction with smoking (stage I). The environmental odds ratio was set equal to 1.18.The prevalence was set equal to 0.36 for men (blue), 0.27 for women (red), and 0.3 for both sexes combined (black).

Figure S6. Power to detect a G×E interaction with alcohol consumption (stage I). The environmental odds ratio was set equal to 1.21. The prevalence was set equal to 0.95 for men (blue), 0.85 for women (red), and 0.9 for both sexes combined (black).

Figure S7. LocusZoomplot of G×E for 11q23.3 and BMI (stageI)

The LocusZoom plot (Pruim et al. 2010) shows the results of a G×E interaction analysisof SNPs at 11q23.3 and BMI (stageI caseonly). The x-axis corresponds to the physical location (Mb) of a SNP according to NCBI build 19; the y-axis shows the p value of the interaction on the –log10 scale. Each dot represents one SNP colored according to its LD with rs1944511 (yellow diamond). This SNP showed the lowest interaction p value in validation stageII. The blue line corresponds to the recombination rate in cM per Mb. Known genes at 11q23.3 are depicted in the bottom panel.