Alcohol consumption, DNA methylation and colorectal cancer risk: Results from pooled cohort studies and Mendelian randomization analysis

Xuan Zhou, Lijuan Wang, Jiarui Xiao, Jing Sun, Lili Yu, Han Zhang, Xiangrui Meng, Shuai Yuan, Maria Timofeeva, Philip J Law, Richard S Houlston, Kefeng Ding, Malcolm G Dunlop, Evropi Theodoratou, Xue Li

Research output: Contribution to journalArticlepeer-review


Alcohol consumption is thought to be one of the modifiable risk factors for colorectal cancer (CRC). However, the causality and mechanisms by which alcohol exerts its carcinogenic effect are unclear. We evaluated the association between alcohol consumption and CRC risk by analyzing data from 32 cohort studies and conducted two-sample Mendelian randomization (MR) analysis to examine for casual relationship. To explore the effect of alcohol related DNA methylation on CRC risk, we performed an epigenetic MR analysis with data from an epigenome-wide association study (EWAS). We additionally performed gene-alcohol interaction analysis nested in the UK Biobank to assess effect modification between alcohol consumption and susceptibility genes. We discovered distinct effects of alcohol on CRC incidence and mortality from the meta-analyses, and genetic predisposition to alcohol drinking was causally associated with an increased CRC risk (OR = 1.79, 95% CI: 1.23-2.61) using two-sample MR approaches. In epigenetic MR analysis, two alcohol-related CpG sites (cg05593667 and cg10045354 mapped to COLCA1/COLCA2 gene) were identified causally associated with an increased CRC risk (P < 8.20 × 10-4 ). Gene-alcohol interaction analysis revealed that carriage of the risk allele of the eQTL (rs3087967) and mQTL (rs11213823) polymorphism of COLCA1/COLCA2 would interact with alcohol consumption to increase CRC risk (PInteraction = .027 and PInteraction = .016). Our study provides comprehensive evidence to elucidate the role of alcohol in CRC and highlights that the pathogenic effect of alcohol on CRC could be partly attributed to DNA methylation by regulating the expression of COLCA1/COLCA2 gene.

Original languageEnglish
Pages (from-to)83-94
JournalInternational Journal of Cancer
Issue number1
Early online date25 Jan 2022
Publication statusPublished - 1 Jul 2022


  • Alcohol Drinking/epidemiology
  • Cohort Studies
  • Colorectal Neoplasms/epidemiology
  • DNA Methylation
  • Genome-Wide Association Study
  • Humans
  • Mendelian Randomization Analysis/methods
  • Neoplasm Proteins/genetics
  • Polymorphism, Single Nucleotide


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