Postgraduate Essay Prize winner 2010
Shwetha Ramachandrappa, University of Cambridge
The genetics of obesity: We can’t see the wood for the trees!
Explaining what I do to anybody who is not in my field of research is fraught with difficulty. Nobody
can see the point of studying the genetics of obesity, the reason we are all getting fatter is apparent
to everyone - we are lazier than we have ever been, and we eat a lot more unhealthily than ever
before. “Can’t you do something more useful with your time”, my mother has remarked to me on
several occasions, “being fat isn’t a disease, and you’re no Jamie Oliver”.
Of course, all of these couch geneticists are right, the acute global rise in obesity which has now
been termed “globesity” by the World Health Organisation is largely down to environmental factors.
Body Mass Index (BMI), which is defined as an individual’s weight divided by the square of their
height, is used as an indirect measure of fat accumulation. The overall distribution of BMI within the
population has shifted sharply upwards over the past forty years due to environmental factors[1].
However, the variation in BMI within the population is genetically determined and this has remained
roughly constant. Identifying the genetic factors which contribute to obesity will help us to
understand the biological processes which control body weight. We all know people that lead
healthy lifestyles but struggle to control their weight, and others who remain slim, despite eating to
excess. If we can understand the biological basis of these differences between individuals, we can try
and use it to help people control their weight more effectively.
Successes in this regard have arisen chiefly from the study of extremely obese individuals. These
studies were based on the premise that the body weight of this select group of people is so much
greater than the general population that it is likely to be driven by genetic defects causing a
fundamental difference in their ability to maintain their weight. By studying the DNA of these
patients, an individual whose obesity was a direct result of a single genetic defect was discovered. A
handful of further patients whose obesity was due to different genetic defects followed. These
patients were said to have monogenic obesity. Each harboured only one genetic defect, but this was
sufficient to cause obesity. Their symptoms gave us the first clues as to the functions of the proteins
encoded by their defective genes.
Eight monogenic causes of obesity have been identified to date[2]. Their discovery, at a time when
obesity was barely considered a disease but rather a failure of willpower, revolutionised the way
that obesity was regarded by the medical profession. Most of the proteins encoded by these genes
reside in the brain where they interact with each other to form a biological pathway which is
involved in the control of appetite and feeding. The emergence of these syndromes has therefore
firmly ascribed the control of body weight to the brain.
The first monogenic obesity syndrome to be discovered was the lack of a hormone called leptin
which is produced by fat cells and serves as a signal to the brain that there are adequate nutrients
around[3]. People who do not produce leptin due to a genetic defect lack this signal. Their brains are
unable to sense that they are adequately nourished and they have a constant drive to eat as a result.
In effect patients who lack leptin feel like they are in a permanent state of starvation. These patients
can be cured by daily injections of leptin which mimics the biological signal they are lacking[4].
Although the discovery of monogenic causes of obesity has been very informative in uncovering
some of the main biological pathways which control our weight, these diseases only affect a tiny
group of people, and as yet the only therapy which has emerged from them is the treatment of
leptin deficient patients with recombinant leptin. Initial excitement at its discovery, that leptin could
be used to treat obesity in the general population, proved to be premature when it was discovered
that most obese individuals have excessive levels of leptin in their bloodstream and are resistant to
its action[5]. As a result the research community has shifted its focus to looking at obesity within the
general population and trying to identify genetic factors which contribute to this.
The main tool which has been used in this endeavour is a technique called Genome-Wide
Association Scanning or GWAS. The heritable component of obesity within the population may
consist of a small number of genetic variants each with a large effect size, or a large number of
variants each with a small effect size. The GWAS approach is contingent upon two things. The first is
that in the general population an individual is obese because of the combined effects of several
weak genetic variants. The second is that there is a relatively small pool of variants in the population,
so that even though each individual may have a different combination of variants, at a population
level there is a large degree of overlap between the variants people carry. By looking at very large
groups of people and studying the correlation between their BMI and the variants they carry, we can
identify variants which are associated with a high BMI.
The first GWAS to look at obesity was published in 2007 and has been followed by several further
studies in larger and larger populations, involving collaborative efforts between numerous
institutions, from around the world[6]. In many ways this approach has been very informative but in
general it has not proved to be the panacea it was once proposed as. At last count 32 regions of the
genome had been identified which are associated with obesity[7]. However this has been the limit of
the information gained - new biological pathways or therapeutic targets have yet to emerge from
these studies. In part this is because we know very little about the regions of the genome where
variants have been found. There is undoubtedly a biological basis for each of these associations and
studying them is bound to prove fruitful, but it will take some time. Of more concern however, is the
fact that the associations which have been found only account for a small percentage of the
heritability of body weight within the population. The strongest association found to date accounts
for less than 1% of the heritability of body weight, indicating that the majority variants have flown
under the radar[8].
Recent evidence has suggested that part of the reason GWAS have failed to identify important
variants is because some of the assumptions that were inherent in this approach do not hold true.
This has huge implications for the entire field of obesity genetics. GWAS are only capable of picking
up variants which are shared by more than 5% of the population. This is not a problem if we assume
that obesity is caused by combinations of common variants which each have a small effect, but a
recent study has indicated that this might not be the case. In this study the genomes of 300 patients
with severe, early onset obesity were studied in detail and a large chromosomal deletion was
identified as the cause of obesity in 5 of these patients[9]. 19 similar deletions were then identified
from GWAS data in over 16,000 individuals from eight European cohorts[10]. Contrary to our
assumptions it seems that rare variants with large effects may constitute a significant proportion of
heritability within the general population. These variants are too rare to be picked up by GWAS.
Gene hunters need not despair however, there is a ready solution to this quandary which is to go
back to the study of extremely obese individuals and use them as a starting point. Monogenic
syndromes account for a tiny proportion of cases of extreme obesity. The remaining cases are likely
to be due to combinations of genetic variants with large effect sizes. Variants which have a large
effect but are extremely rare in the general population are likely to be much more common in this
population and may surpass the frequency threshold that enables detection by GWAS approaches.
In any event, the return to the study of extremely obese individuals is a welcome refocusing on the
overarching aim of these endeavours, which is to identify useful therapeutic targets. The study of
individuals who are extremely obese, but otherwise healthy, is the surest way towards identifying
molecules and pathways which can be manipulated safely, and in isolation from other biological
processes, to help us all get a bit more comfortable with the scales. We don’t need to know about
every tree in the forest, just the ones worth cutting down.
WORDS: 1451
References
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