Alcohol consumption, blood DNA methylation and breast cancer: a Mendelian randomisation study

Xuan Zhou, Lili Yu, Lijuan Wang, Jiarui Xiao, Jing Sun, Yajing Zhou, Xiaolin Xu, Wanghong Xu, Athina Spiliopoulou, Maria Timofeeva, Xiaomeng Zhang, Yazhou He, Haomin Yang, Harry Campbell, Ben Zhang, Yimin Zhu, Evropi Theodoratou, Xue Li*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Alcohol intake is thought to be a risk factor for breast cancer, but the causal relationship and carcinogenic mechanisms are not clear. We performed an up-to-date meta-analysis of prospective studies to assess observational association, and then conducted MR analysis to make causal inference based on the genetic predisposition to alcohol consumption ("drinks per week") and pathological drinking behaviours ("alcohol use disorder" and "problematic alcohol use"), as well as genetically predicted DNA methylation at by alcohol-related CpG sites in blood. We found an observational dose-response association between alcohol intake and breast cancer incidence with an additional risk of 4% for per 10 g/day increase in alcohol consumption. Genetic predisposition to alcohol consumption ("drinks per week") was not causally associated with breast cancer incidence at the OR of 1.01 (95% CI 0.84, 1.23), but problematic alcohol use (PAU) was linked to a higher breast cancer risk at the OR of 1.76 (95% CI 1.04, 2.99) when conditioning on alcohol consumption. Epigenetic MR analysis identified four CpG sites, cg03260624 near CDC7 gene, cg10816169 near ZNF318 gene, cg03345232 near RIN3 gene, and cg26312998 near RP11-867G23.13 gene, where genetically predicted epigenetic modifications were associated with an increased breast cancer incidence risk. Our findings re-affirmed that alcohol consumption is of high risk for breast cancer incidence even at a very low dose, and the pathogenic effect of alcohol on breast cancer could be due to pathological drinking behaviour and epigenetic modification at several CpG sites, which could be potential intervention targets for breast cancer prevention.

Original languageEnglish
Pages (from-to)701-712
JournalEuropean Journal of Epidemiology
Issue number7
Early online date16 Jun 2022
Publication statusPublished - 1 Jul 2022


  • Alcohol Drinking/epidemiology
  • Breast Neoplasms/epidemiology
  • Cell Cycle Proteins/genetics
  • DNA Methylation
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Mendelian Randomization Analysis
  • Prospective Studies
  • Protein Serine-Threonine Kinases
  • Risk Factors


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