Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region

Abstract

Background: Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer. Methods: Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers (>28 g/day) with light-to-moderate drinkers (1–28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models. Results: For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 > 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose–response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06–1.17; OR for AA genotype = 1.22; 95% CI, 1.14–1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif. Conclusions: Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region. Impact: The study identifies multifaceted evidence of a possible functional effect for rs1318920.

Alcohol-associated bowel disease: new insights into pathogenesis

“…DNA mismatch repair gene mutation carriers are more susceptible to alcohol-induced CRC. 94 A genome-wide study indicated a possible interaction between alcohol intake and genetic variants in the 10q24.2/COX15 region, 95 and the A allele of single nucleotide polymorphisms rs2300985 has an increased risk for CRC in light-to-moderate drinkers. For heavy alcohol consumption, however, higher risk and worse prognosis of CRC might be associated with hypomethylation of insulin-like growth factor 2.…”

Improved two‐step testing of genome‐wide gene–environment interactions

“…All models included the following set of adjustment covariates—age, study, and ancestry as defined by the first three principal components. Analyses using similar adjustment covariates were used in a recent investigation of $$G\times $$ Alcohol interaction in these data Jordahl et al (2022).…”

Improved two-step testing of genome-wide gene-environment interactions

“…All models included the following set of adjustment covariates - age, study/genotyping batch, and ancestry as defined by the first three principal components. Analyses using similar adjustment covariates were used in a recent investigation of G× Alcohol interaction in these data Jordahl et al (2022).…”

“…Bonferroni: Standard Bonferroni correction within bin; simpleM : The simpleM procedure proposed by Gao et al (2008) as defined by the first three principal components. Analyses using similar adjustment covariates were used in a recent investigation of G×Alcohol interaction in these data Jordahl et al (2022). Similar to the simulation study, bin significance threshold cutoffs for SB-weighted testing were based on cutoffs τ = (0, 5/M, 15/M, 35/M, .…”