Physical Activity Attenuates the Genetic Predisposition to Obesity in 20,000 Men and Women from EPIC-Norfolk Prospective Population Study

Background

We have previously shown that multiple genetic loci identified by genome-wide association studies (GWAS) increase the susceptibility to obesity in a cumulative manner. It is, however, not known whether and to what extent this genetic susceptibility may be attenuated by a physically active lifestyle. We aimed to assess the influence of a physically active lifestyle on the genetic predisposition to obesity in a large population-based study.

Methods and Findings

We genotyped 12 SNPs in obesity-susceptibility loci in a population-based sample of 20,430 individuals (aged 39–79 y) from the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort with an average follow-up period of 3.6 y. A genetic predisposition score was calculated for each individual by adding the body mass index (BMI)-increasing alleles across the 12 SNPs. Physical activity was assessed using a self-administered questionnaire. Linear and logistic regression models were used to examine main effects of the genetic predisposition score and its interaction with physical activity on BMI/obesity risk and BMI change over time, assuming an additive effect for each additional BMI-increasing allele carried. Each additional BMI-increasing allele was associated with 0.154 (standard error SE] 0.012) kg/m² (p = 6.73×10⁻³⁷) increase in BMI (equivalent to 445 g in body weight for a person 1.70 m tall). This association was significantly (p _interaction = 0.005) more pronounced in inactive people (0.205 SE 0.024] kg/m² p = 3.62×10⁻¹⁸; 592 g in weight]) than in active people (0.131 SE 0.014] kg/m² p = 7.97×10⁻²¹; 379 g in weight]). Similarly, each additional BMI-increasing allele increased the risk of obesity 1.116-fold (95% confidence interval CI] 1.093–1.139, p = 3.37×10⁻²⁶) in the whole population, but significantly (p _interaction = 0.015) more in inactive individuals (odds ratio OR] = 1.158 95% CI 1.118–1.199; p = 1.93×10⁻¹⁶]) than in active individuals (OR = 1.095 (95% CI 1.068–1.123; p = 1.15×10⁻¹²]). Consistent with the cross-sectional observations, physical activity modified the association between the genetic predisposition score and change in BMI during follow-up (p _interaction = 0.028).

Conclusions

Our study shows that living a physically active lifestyle is associated with a 40% reduction in the genetic predisposition to common obesity, as estimated by the number of risk alleles carried for any of the 12 recently GWAS-identified loci. Please see later in the article for the Editors'' Summary