Non-linear interaction between physical activity and polygenic risk score of body mass index in Danish and Russian populations

PLoS One. 2021 Oct 18;16(10):e0258748. doi: 10.1371/journal.pone.0258748. eCollection 2021.


Body mass index (BMI) is a highly heritable polygenic trait. It is also affected by various environmental and behavioral risk factors. We used a BMI polygenic risk score (PRS) to study the interplay between the genetic and environmental factors defining BMI. First, we generated a BMI PRS that explained more variance than a BMI genetic risk score (GRS), which was using only genome-wide significant BMI-associated variants (R2 = 13.1% compared to 6.1%). Second, we analyzed interactions between BMI PRS and seven environmental factors. We found a significant interaction between physical activity and BMI PRS, even when the well-known effect of the FTO region was excluded from the PRS, using a small dataset of 6,179 samples. Third, we stratified the study population into two risk groups using BMI PRS. The top 22% of the studied populations were included in a high PRS risk group. Engagement in self-reported physical activity was associated with a 1.66 kg/m2 decrease in BMI in this group, compared to a 0.84 kg/m2 decrease in BMI in the rest of the population. Our results (i) confirm that genetic background strongly affects adult BMI in the general population, (ii) show a non-linear interaction between BMI genetics and physical activity, and (iii) provide a standardized framework for future gene-environment interaction analyses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics*
  • Body Mass Index
  • Denmark
  • Exercise*
  • Gene-Environment Interaction
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Multifactorial Inheritance*
  • Russia
  • Self Report


  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • FTO protein, human

Grant support

Data collection in the Inter99 study was supported economically by The Danish Medical Research Council (grant nr. 2028-00-0019 and 09-059174), The Danish Centre for Evaluation and Health Technology Assessment (grant nr. 3126-138-1998 and 263-12-1999 and 0-204-03-74), Novo Nordisk, Copenhagen County (grant nr. 9870006), The Danish Heart Foundation (grant nr. 98-2-5-71-22659 and 00-2-9-F4-22872 and 04-10-B201-A309-22171), The Danish Pharmaceutical Association (grant nr. 53-99 and 58-2003), Augustinus foundation (grant nr. 99-1663), Ib Henriksen foundation, and Becket foundation. Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center, based at the University of Copenhagen, Denmark, and partially funded by an unconditional donation from the Novo Nordisk Foundation ( (NNF18CC0034900). Dmitrii Borisevich is receiving funding from NNF Copenhagen Bioscience PhD Programme (NNF17CC0026760). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Genotek Ltd provided only financial support in the form of AR and VI salaries and the data for the analysis, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.