Genome-wide methylation data improves dissection of the effect of smoking on body mass index

Variation in obesity-related traits has a genetic basis with heritabilities between 40 and 70%. While the global obesity pandemic is usually associated with environmental changes related to lifestyle and socioeconomic changes, most genetic studies do not include all relevant environmental covariates, so the genetic contribution to variation in obesity-related traits cannot be accurately assessed. Some studies have described interactions between a few individual genes linked to obesity and environmental variables but there is no agreement on their total contribution to differences between individuals. Here we compared self-reported smoking data and a methylation-based proxy to explore the effect of smoking and genome-by-smoking interactions on obesity related traits from a genome-wide perspective to estimate the amount of variance they explain. Our results indicate that exploiting omic measures can improve models for complex traits such as obesity and can be used as a substitute for, or jointly with, environmental records to better understand causes of disease.Author summary: Most diseases and health-related outcomes are influenced by genetic and environmental variation. Hundreds of genetic variants associated with obesity-related traits, like body mass index (BMI), have been previously identified, as well as lifestyles contributing to obesity risk. Furthermore, certain combinations of genetic variants and lifestyles may change the risk of obesity more than expected from their individual effects. One obstacle to further research is the difficulty in measuring relevant environmental impacts on individuals. Here, we studied how genetics (genome-wide markers) and tobacco smoking (self-reported) affect BMI. We also used DNA methylation, a blood-based biomarker, as a proxy for to self-reported information to assess tobacco usage. We incorporated the effect of interactions between genetics and self-reported smoking or methylation. We estimated that genetics accounted for 50% of the variation in BMI. Self-reported smoking status contributed only 2% of BMI variation, increasing to 22% when estimated using DNA methylation. Interactions between genes and smoking contributed an extra 10%. This work highlights the potential of using biomarkers to proxy lifestyle measures and expand our knowledge on disease and suggests that the environment may have long-term effects on our health through its impact on the methylation of disease-associated loci.