Table 1.

Description of the extension of the Human Genome Epidemiology Network's Venice criteria that were used to assess cumulative evidence on joint effects of genes and environments on cancer risk

Steps	Description
Step 1 Score for the strength of the observed evidence for the G×E interactions	First, we scored the strength of the observed evidence for the interaction between environmental exposures and genetic variants. Each G×E association was graded based on (i) the amount of evidence, (ii) the extent of replication and (iii) the protection from bias.
	(i) For the amount of evidence, the grade A, B or C was assigned when the total number of individuals in the smallest comparison group (assuming 1:1 ratio of cases and controls) in the meta‐analysis was greater than 1,000, 100–1,000, or less than 100, respectively.
	(ii) The replication consistency was assessed by the reported heterogeneity: grade A, I 2 < 25%; grade B, 25% ≤ I 2 ≤ 50%; grade C, I 2 > 50% or p value for heterogeneity <0.10.
	(iii) For protection from bias 3 aspects of G×E association were taken into account as suggested by Boffetta P et al.8: protection from bias for the environmental exposure, for the genetic analysis and for the overall interaction. Grade A means that bias, if present, may change the magnitude but not the presence of an association; grade B means that there is no evidence of bias that would invalidate an association, but important information is missing; and grade C means that there is a strong possibility of bias that would render the finding of an association invalid.
	On the basis of the combination of these 3 criteria (amount of evidence, degree of replication and protection from bias, each of which can be scored A, B and C), the epidemiological evidence for the association between G×E interaction and CRC risk was classified as strong, moderate or weak8 (Supporting Information Fig. S1).
Step 2 Prior score (expected) for G×E interactions	Second, we established a prior score category (expected) for the G×E interactions using a framework presented in Boffetta P et al.8, which is based on prior scores for (i) the evidence of the main environmental and (ii) the evidence of the main genetic effects (Supporting Information Table 2).
	(i) Environmental main effect score: We scored the main environmental effects based on the meta‐analyses of the associations between environmental factors and CRC risk that were presented in the World Cancer Research Fund International (WCRF)/American Institute for Cancer Research (AICR) Third Expert Report,10 the subsequent Continuous Update Project (CUP) CRC reports11 and the CUP CRC Systematic Literature Review 2016.12 For the information of environmental risk factors that was not available in the above mentioned sections, we performed an additional literature search in MEDLINE and abstracted the relevant data as summarized and presented in Supporting Information methods. We then categorized the environmental factors in terms of strength of evidence by applying previously described set of criteria.13 The evidence was classified as convincing (Class I), highly suggestive (Class II), suggestive (Class III) or weak evidence (Class IV) based on sample size, highly significant summary associations, the 95% prediction intervals, presence of the small‐study effect and the excess significance bias.
	(ii) Genetic main effect score: For the genetic main effects, a search in the National Human Genome Research Institute‐European Bioinformatics Institute catalog of GWAS,14 the GWAS central database15 and MEDLINE was conducted as described in Supporting Information methods. Subsequently, we scored the genetic associations using the Human Genome Epidemiology Network Venice criteria.9, 16, 17 Only genetic effects with p <10−5 were considered for evaluation, and the evidence was classified as strong, moderate or weak based on a combination of the 3 criteria (amount of evidence, degree of replication and protection from bias), each of which was scored A, B or C (Supporting Information Fig. S1). For the genetic variants that reached genome‐wide significance threshold, the evidence class of the genetic variant was only based on the amount of evidence.16 The search strategies, the Medical Subject Headings terms and the numbers of hits are presented in Supporting Information Tables 3 and 4, respectively.
Step 3 Combined score	Lastly, we examined the overall plausibility of each interaction by combining the prior score and the strength of the observed evidence. Higher weight was given to the observed evidence in case of conflicting results between the observed evidence and the prior scores.