11 october 2010

Apple and pear shapes: partly down to genes

Health

obesity in women
Gene variations have a stronger influence on women's body shapes

A whole set of new genes associated with body fat distribution and obesity have been identified in two major studies by an international team of researchers, including the largest study yet of DNA variation across our genomes involving almost ¼ million people.

The group has identified 13 new gene regions where variations in DNA sequence can be linked to whether we are apple-shaped or pear-shaped. The majority of these variations have a markedly stronger effect in women than in men.

The scientists, led by researchers at Oxford University and the Medical Research Council (MRC) Epidemiology Unit in Cambridge, have also found 18 new genetic variations associated with increased susceptibility to obesity.

The results, published in Nature Genetics, give greater insight into the biological processes that can lead to obesity and that are involved in determining body fat distribution. The work immediately opens up new avenues of research into the biological basis of obesity, but it is possible that such understanding could in time guide the development of new ways of preventing or treating obesity.

Where we store fat in our bodies can influence our health. More fat around our waists (being apple-shaped) is associated with increased risk of type 2 diabetes and heart disease, even after correction for obesity. In comparison, storing fat in thighs and bums (being pear-shaped) has been suggested in some research to offer some protection against diabetes and high blood pressure.

Our waist-to-hip ratio is a good measure of this difference in body fat distribution, and is known – like predisposition to obesity – to be determined to some extent by the genes we inherit.

There are also clear differences in body shape between men and women, but the body processes that determine these differences are not well understood.

the potential to alter patterns of fat distribution may offer an alternative for future drug discovery

Dr Cecilia Lindgren

The researchers completed a large genome-wide search for DNA variations that could be connected to waist-to-hip ratios. They identified 13 new gene regions linked to body fat distribution, and confirmed the one previously known genetic link. They show that these genetic variations affect waist-to-hip ratio distinct from any effect on overall obesity.

Seven of the identified genetic variations have much stronger effects in women than in men, suggesting they may underlie some of the difference in fat distribution between the sexes.

Although the gene regions identified explain only around 1% of the variation in waist-to-hip ratios in the population, they do point towards specific biological mechanisms that are involved in regulating where the body stores fat. The regions implicate genes involved in regulating cholesterol, triglyceride levels, insulin and insulin resistance.

‘By finding genes that have an important role in influencing whether we are apple shaped or pear shaped, and the ways in which that differs between men and women, we hope to home in on the crucial underlying biological processes,’ says Dr Cecilia Lindgren of the Wellcome Trust Centre for Human Genetics at Oxford University, senior researcher on the waist-to-hip ratio study and who was involved in both papers.

‘Understanding biology through finding genes is just a first step in a long journey towards treatment, but it is a vital one. As efforts to tackle obesity through changes in lifestyle or by different treatment options have proved extremely challenging, the potential to alter patterns of fat distribution may offer an alternative for future drug discovery.'

The second study looked for genes connected to body mass index (BMI). BMI is a measure commonly used to classify adults as being overweight (BMI of 25–29.9) or obese (BMI of 30 or greater). The discovery of 18 new genetic regions has more than doubled the DNA variations reliably linked to BMI to 32.

Some of the new findings indicate the involvement of genes active in the brain that influence our appetite and also genes involved in the control of insulin levels and metabolism.

The study also showed that people who inherit many of the BMI-increasing DNA variants from their parents weigh 7–9 kg more than those who inherit few of these variants; this difference in weight is solely due to the fact that they differ genetically. Despite the large difference between the most susceptible and least susceptible, together the 32 confirmed genetic associations still only explain 1.45% of the variation seen in people’s BMIs, suggesting there are many more genetic associations still to be found.

‘We have conducted the largest ever genome-wide association study so far, and by including almost 250,000 individuals we have been able to identify 18 new genetic regions associated with obesity,’ says Dr Ruth Loos of the MRC Epidemiology Unit in Cambridge, senior researcher on the BMI study and who was involved in both studies.

‘These two studies are the beginning of new insights into to biology of obesity and body shape, which in turn may lead to more targeted approaches to obesity prevention and potentially to the development of new drugs. But we should not forget that, while the genetic contribution to obesity is substantial, a large part of obesity susceptibility remains down to our lifestyle.’

The studies were carried out by the GIANT (Genetic Investigation of Anthropometric Traits) consortium, an international collaboration of more than 400 scientists from 280 research institutions with support from many funding agencies worldwide.