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Event Review: Genetics and the Prospect of Personalised Medicine for Obesity

10 March 2014
Appeared in BioNews 745

British culture seems to take umbrage at the notion that genes play a role in obesity. Just a few weeks ago, a years-old BBC Have Your Say article about the weight of Europeans resurfaced to the 'most popular' page, bringing with it pages of vitriol and condemnation levied at the overweight - and that was just in the highest-rated comments.

It often seems that the media pushes the idea that the obesity epidemic is fuelled almost entirely by our increasingly well-fed and sedentary lives, which makes the opportunity to hear solid evidence for the other side of the equation refreshing.

So it was last week, when the Physiological Society hosted a lecture by Alexandra Blakemore, professor of human molecular genetics at Imperial College London, on the genetics of obesity.

Kicking off the first in a series of lectures in the Society's new home, the talk started by going over what we think we know about fat. We were reminded that while losing fat from your body can be healthy if you have too much, it can also be unhealthy when you have too little. Your body needs fat, of the right types, in the right amounts and in the right places, to function properly.

But how do we know if genes are involved in controlling our weight, or our adiposity (that is, how much fat you have)? Well, there's a tried and tested way to do this: get a bunch of twins, and see if the identical twins (who share all their genes) share a trait more often than fraternal twins (who share only share half their genes).

If they do, then it's a good indication that genes influence that trait. You can guess where this is going. That's right, identical twins are more likely than fraternal twins to both be obese, and are likely to have similar levels of obesity.

Then we get on to Professor Blakemore's field of research - finding and investigating genetic differences that play a role in adiposity. This is where we start to see the complexity of the genetic contribution to obesity.

The simplest genetic change that can influence obesity (or indeed anything else) is when one letter of DNA differs between people, which we call a single nucleotide polymorphism (SNP). There are currently at least 32 SNPs associated with body mass index (BMI). A number of these, we were told, lie in or near the gene FTO, which when described in mice was originally called Fatso, due to the DNA coding sequence being so long. Needless to say, when people found out that it was linked to obesity in humans it underwent a hasty name change.

Despite so many SNPs being found, we're still only seeing part of the picture. Having particular obesity-associated versions of FTO was linked to an average weight increase of three kilograms; 'I'm sorry, but I could do that in a weekend!' Professor Blakemore joked.

These SNPs therefore appear just to influence on which side of average-weight people end up, despite the twin studies discussed earlier having shown strong evidence for a genetic involvement. This discrepancy gets called the 'missing heritability' of obesity.

There are of course more ways for genomes to differ than by single letters. Chromosomal deletions, where a chunk of DNA gets removed from the genome, are known to cause various syndromes which include obesity as a symptom. Professor Blakemore's own research group identified a case of Prader-Willi Syndrome that was not detected by the usual diagnostic methods, by looking for extremely short deletions.

Finally, mutations in individual genes can influence obesity, as is the case with deficiencies in the hormone leptin, or the melanocortin-4 receptor. All this work done by Professor Blakemore and others serves to demonstrate the complexity of the genes involved in regulation of our weight.

There is a theme running through these weight-associated genes; the vast majority are involved in the regulation of behaviour. If you consider how common some of the variants are, and how different combinations of them might interact, we begin to get a feel for just where that missing heritability might be coming from.

The lecture ended with a consideration of how we can use all this genetic information. First, we can use it to inform personalised medicine, or to guide research into new therapies. On a different scale, we could try to moderate or overcome media stigmatisation of obesity, by recognising that the neural circuitry which strongly influences eating behaviour can indeed differ between individuals.

We could also increase the use of genetic screening and counselling, to help people decide how best to play the genetic hand they were dealt. In a sad, timely example, just two days after this lecture a story broke of how 74 children in parts of the UK have been taken into care in the last three years for being overweight. Who knows what underlying genetic factors might have influenced these children's weights - shouldn't that have come into consideration?

This was one of the best evening lectures I have been to in a long time. I went into this talk not knowing much about the genetics of obesity and I learnt a lot. Professor Blakemore was an engaging, personable speaker, who not only dealt with the scientific but the social implications of genetic involvement in obesity. The Society filmed the event, so I suspect it will end up online; if it does, I highly recommend you watch it.

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