Beyond GWAS of colorectal cancer: Evidence of interaction with alcohol consumption and putative causal variant for the 10q24.2 region
Menée à partir de données d'études d'association sur le génome entier, cette étude analyse l'association entre 13 polymorphimes à simple nucléotide situés sur la région chromosomique 10q24.2 du gène COX15 et le risque de cancer colorectal, en fonction de la consommation d'alcool
Background:Currently known associations between common genetic variants and colorectal cancer (CRC) explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with CRC risk, non-drinking and heavy drinking are both risk factors for CRC. Methods:Individual-level data was pooled from Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare non-drinkers (<=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 non-drinking as compared to light-to-moderate drinking, the hybrid 2-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 CRC as compared to the G allele in light-to-moderate drinkers (odds ratio (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 non-drinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt a HNF4 transcription factor binding motif. Conclusions:Our study suggests that the association with CRC in 10q24.2/COX15 observed in GWAS is strongest in non-drinkers. 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.