Multiple lifestyle factors modify the effect of the common genetic variants with the largest effect on obesity 

There has been considerable interest about the extent to which genetic factors interact with environmental and lifestyle factors in human traits.  Alex Young and colleagues in Peter Donnelly’s group at the Wellcome Trust Centre for Human Genetics have used the latest UK Biobank data to discover novel interactions between genetic variants at the FTO locus and lifestyle factors, including sleep duration and alcohol consumption. 

Body mass index (BMI), weight divided by height squared, is the most commonly used measure of adiposity, with individuals exceeding a certain threshold classed as obese. Obesity is associated with many diseases and mortality, and with a growing proportion of adults being classed as overweight or obese, obesity is a growing public health concern. Studies of twins indicate a substantial contribution from genetic variation to variation in BMI. However, a genetic predisposition to gain weight may only be realised given a certain lifestyle. Understanding how lifestyle modifies genetic risk for obesity could help understand the biological mechanisms leading to obesity as well as pave the way for personalised health advice and prediction.

In work in which Centre researchers (McCarthy Group) played leading roles, common genetic variants in the FTO gene have been shown to have the largest effect on BMI out of all common variants.  (Although the variants reside in the FTO gene, this does not mean that their effect on BMI is mediated through the FTO gene, with recent studies implicating regulation of other genes involved in thermogenesis.)

Previous studies have indicated that physical activity may reduce the effect of FTO variants on BMI while intake of fried and fatty foods may increase their effect, examples of gene-by-environment interactions. These previous studies have been limited by only examining one lifestyle factor at a time. The problem with this is that many lifestyle factors known to be associated with BMI are highly correlated with each other, so the interactions reported in the literature may not be independent of each other or other lifestyle factors. The joint measurement of many lifestyle factors on a large (~150,000) sample of individuals in the UK Biobank offers an opportunity to assess evidence for interactions between FTO variants and lifestyle factors in a way that accounts for the correlations between different lifestyle factors.

Alex Young and colleagues discovered that more frequent consumption of alcohol is associated with a reduced effect of FTO variants on BMI. This is consistent with observations that frequency of consumption of alcohol is associated with reduced BMI whereas total alcohol consumption is associated with increased BMI.

Sleep duration has a complicated relationship with BMI: more sleep is associated with lower BMI around the average sleep duration, but both too much and too little sleep is associated with higher BMI. The study discovered that those sleeping too much or too little also experience an increased effect of FTO variants on BMI.

The study found that dietary variation was the strongest modifier of the effect of FTO variants on BMI, discovering evidence that individuals who add salt to their food more frequently experience an increased effect of FTO variants on BMI.

The study demonstrates the power of the UK Biobank for discovery of lifestyle factors that modify the effect of genetic variants on traits related to health and disease. It shows that even a single genetic variant’s effect may be dependent on multiple lifestyle factors, which could be modified to reduce the public health impact of genetic risk variants.  


The paper can be accessed via the Nature Communications page.