A polygenic-score-based approach for identification of gene-drug interactions stratifying breast cancer risk

Am J Hum Genet. 2021 Sep 2;108(9):1752-1764. doi: 10.1016/j.ajhg.2021.07.008. Epub 2021 Aug 6.


An individual's genetics can dramatically influence breast cancer (BC) risk. Although clinical measures for prevention do exist, non-invasive personalized measures for reducing BC risk are limited. Commonly used medications are a promising set of modifiable factors, but no previous study has explored whether a range of widely taken approved drugs modulate BC genetics. In this study, we describe a quantitative framework for exploring the interaction between the genetic susceptibility of BC and medication usage among UK Biobank women. We computed BC polygenic scores (PGSs) that summarize BC genetic risk and find that the PGS explains nearly three-times greater variation in disease risk within corticosteroid users compared to non-users. We map 35 genes significantly interacting with corticosteroid use (FDR < 0.1), highlighting the transcription factor NRF2 as a common regulator of gene-corticosteroid interactions in BC. Finally, we discover a regulatory variant strongly stratifying BC risk according to corticosteroid use. Within risk allele carriers, 18.2% of women taking corticosteroids developed BC, compared to 5.1% of the non-users (with an HR = 3.41 per-allele within corticosteroid users). In comparison, there are no differences in BC risk within the reference allele homozygotes. Overall, this work highlights the clinical relevance of gene-drug interactions in disease risk and provides a roadmap for repurposing biobanks in drug repositioning and precision medicine.

Keywords: GxE; UK Biobank; breast cancer; corticosteroids; drugs; gene-environment interactions; pharmacogenomics; polygenic score.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenal Cortex Hormones / adverse effects*
  • Alleles
  • Biological Specimen Banks
  • Breast Neoplasms / chemically induced
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / epidemiology
  • Breast Neoplasms / genetics*
  • Female
  • Gene Expression
  • Gene-Environment Interaction*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Incidence
  • Multifactorial Inheritance*
  • NF-E2-Related Factor 2 / genetics*
  • NF-E2-Related Factor 2 / metabolism
  • Polymorphism, Single Nucleotide
  • Precision Medicine / methods
  • Prescription Drugs / adverse effects*
  • Risk Assessment
  • United Kingdom / epidemiology


  • Adrenal Cortex Hormones
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Prescription Drugs