Abstract
Previous genome-wide association studies (GWAS) have identified hundreds of genetic loci to be associated with body mass index (BMI) and risk of obesity. Genetic effects can differ between individuals depending on lifestyle or environmental factors due to gene-environment interactions. In this study, we examine gene-environment interactions in 362,496 unrelated participants with Caucasian ancestry from the UK Biobank resource. A total of 94 BMI-associated SNPs, selected from a previous GWAS on BMI, were used to construct weighted genetic scores for BMI (GSBMI). Linear regression modeling was used to estimate the effect of gene-environment interactions on BMI for 131 lifestyle factors related to: dietary habits, smoking and alcohol consumption, physical activity, socioeconomic status, mental health, sleeping patterns, as well as female-specific factors such as menopause and childbirth. In total, 15 lifestyle factors were observed to interact with GSBMI, of which alcohol intake frequency, usual walking pace, and Townsend deprivation index, a measure of socioeconomic status, were all highly significant (p = 1.45*10−29, p = 3.83*10−26, p = 4.66*10−11, respectively). Interestingly, the frequency of alcohol consumption, rather than the total weekly amount resulted in a significant interaction. The FTO locus was the strongest single locus interacting with any of the lifestyle factors. However, 13 significant interactions were also observed after omitting the FTO locus from the genetic score. Our analyses indicate that many lifestyle factors modify the genetic effects on BMI with some groups of individuals having more than double the effect of the genetic score. However, the underlying causal mechanisms of gene-environmental interactions are difficult to deduce from cross-sectional data alone and controlled experiments are required to fully characterise the causal factors.
Highlights
Gene-environment interactions result from individuals responding differently to environmental stimuli depending on their genotype, or from genetic effects that vary between groups of individuals depending on their lifestyles
Genome-wide association studies (GWAS) have identified hundreds of genes as being associated with body mass index (BMI). How these genetic effects are modulated by lifestyle factors has not been extensively investigated previously
Our results show that many lifestyle factors influence the genetic effects, which suggests that changing our lifestyle may be a way to influence our genetic risk for obesity and other common human disorders
Summary
Gene-environment interactions result from individuals responding differently to environmental stimuli depending on their genotype, or from genetic effects that vary between groups of individuals depending on their lifestyles. Obesity and being overweight are serious public health issues due to their strong associations with diseases such as cardiovascular disease, type 2 diabetes and cancer. Their global prevalence has increased dramatically over the latter part of the 20th century and up to the present day [2]. Previous studies have reported physical activity to attenuate the effect of genetic factors on BMI, including the effects of genetic variants within the FTO locus [6,7,8,9]. The effects of genetic variants identified through GWAS are generally small [4], and differences in the effects of genetic variants between groups exposed to different lifestyle factors may be difficult to detect in smaller cohorts due to lack of statistical power
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