The Complex Genetics of Obesity

Ben Roberts
June 2, 2019

1 Introduction
Obesity and type 2 diabetes have become a serious epidemic in recent decades, both in
the United States (Ogden et al., 2016) and parts of Europe (Berghöfer et al., 2008). The
exploration of the human genome over the same time period has also led to many advances
in understanding the causes of the disease, and in some cases how treat it more effectively.

Elks et al. (2012) reviewed papers estimating the heritability of obesity from twin and
family studies, finding that estimates varied widely but ranged between 0.24 and 0.90. Study
design factors accounting for half the variability. Twin and children studies each showed
higher heritability, decreasing with age through adulthood. This implies that environmental
factors exert greater influence with age.

Early studies (Farooqi & O’Rahilly, 2006) had some success understanding obesity as
mutations in the leptin-melanocortin pathway. Leptin is a protein produced in adipose
tissue that binds to receptors in the hypothalamus (thereby signalling the body has sufficient
energy stores), while melanocortins are signalling molecules within the brain which appear
to interact with the leptin pathway downstream (Campfield, Smith, & Jeanrenaud, 2007).
As our models and understanding of the human genome have grown, so has our ability
to discover new genetic markers, polymorphisms, environmental factors, mechanisms, and
treatments for this condition.

2 Major Obesity Genes

Choquet and Meyre (2011) sum up the understanding of the genes determining obesity as
producing a “continuum” between monogenic and polygenic forms. That is, significant genes
can contain mutations that singlehandedly cause obesity, but other mutations in the same
genes may require polygenic interactions to produce the same phenotype. As of 2011, nine
loci had been found that could be involved in monogenic obesity and 58 loci could contribute
to polygenic obesity. Four of these are involved in both. Below is a discussion of some of the
most significant genes and how their mutations work.

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 Farooqi and O’Rahilly (2006) describe phenotypes of subjects with leptin deficiency due
to mutations in the LEP gene that codes for the protein. These individuals quickly gain
weight within months of birth to become obese. As infants, they are described as intensely
food-seeking and aggressive if food is not provided. Since leptin is a necessary signalling
hormone for the brain to know that it has had enough to eat, it is understandable that
such individuals would have no good way to regulate their food intake. Such mutations in
LEP must be homozygous and nonsense in order to produce such a significant influence on
phenotype, and are thus rare, but it is an important case study in dispelling social myths
that obesity is about lack of willpower or discipline.

There are several important mutations in other genes that have been subject to much
research. Two of the most significant are a single-nucleotide polymorphism (SNP) near
MC4R, which codes for the melanocortin-4 receptor, and another SNP in an intron of the
gene FTO (rs9939609). Each are associated with increased food intake and increased feelings
of hunger among children and adults. FTO presents an interesting study in the discovery of
new and unexpected gene functions through exploring the genetics of obesity, as its function
had been unknown before an obesity link was discovered in 2007. It now appears to have
many (in humans, its complete deficiency is a recessive lethal), and its influence on obesity
is still poorly understood. (Choquet & Meyre, 2011) Recent speculation has suggested
FTO may play a role in epigenetic regulation of adipose tissue (Choquet & Meyre, 2011)
or it may mediate the effects of nearby genes (Speakman, 2015). The gene responsible for
producing melanocortins, POMC, is unsurprisingly also important for influencing obesity.
POMC produces proopiomelanocortin, which is post-translationally processed into all of
the melanocortin signalling molecules, so polymorphisms in different parts of the gene alter
different molecules and can have different altered functions. (Choquet & Meyre, 2011)

The sheer number of mutations and markers that appear to be involved in obesity is
daunting. Recently, Khera et al. (2019) have produced a polygenic risk scoring model that
purports to identify those susceptible to polygenic forms of obesity. Such models, however,
should be interpreted with caution in light of the many environmental factors at play (below),
as well as criticism from other researchers (Wald & Old, 2019) who point out that they are
being built only using odds ratios or hazard ratios. These ignore statistical aspects critical
to making the models’ predictions useful. Still, such epidemiological approaches are helping
to identify many new polymorphisms that may contribute to the phenotype.

3 Environmental Factors
Researchers have explored a variety of environmental factors related to obesity and how
their influence changes based on genotype. Choquet and Meyre (2011) cite many examples.
For instance, increased physical activity has been shown to reduce the risk of developing
obesity for those posessing the above FTO allele, and separately for some obesity-related
SNPs. A high-fat diet can amplify the risk associated with FTO and the APOA2 265T>C
SNP. Strangely, individuals with a MC4R loss-of-function mutation have not been found to
follow a more general established correlation between a low level of eduation and likelihood

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of developing obesity. Age, gender, and ethnicity demonstrate similarly peculiar exceptions
that may be indicative of the mechanisms behind various genotypes.

4 Epigenetic Factors
Recent investigations into possible epigenetic mechanisms of inheritance for obesity have
resulted in some curious findings. Huypens et al. (2016) report that mice made obese through
a high fat diet produce offspring with greater risk for developing obesity and type 2 diabetes,
even when using in vitro fertilization on the gametes to control for differences in gestation
characteristics. Huypens et al. believe this may be due to small RNAs present in the oocytes
and sperm.

5 Gene-Related Treatment
The most common treatments for obesity are lifestyle modifications and bariatric surgery.
There are indications that genotype plays a role in the success of each available treatment.
For instance, the weight lost after gastric banding surgery was found to be less for individ-
uals with the above-mentioned FTO allele than others, but this pattern was not present
with gastric bypass surgery (Choquet & Meyre, 2011). A Swiss study of over 1200 obese
patients who were followed for 6 years after receiving bariatric surgery showed that some
rare mutations in MC4R were associated with higher rates of complications and reoperation
(Bonnefond et al., 2016). These and similar results suggest the promise of tailoring obesity
treatments to an individual’s genotype.

Montagne et al. (2018) have developed a new method, called CoDE-seq, to make this easier.
This method relies on whole exome sequencing with targeted probe sites that improve the
reliability of detecting copy number variants, while keeping cost below that of traditional
Sanger sequencing.

One of the earliest and most notable successes at treating obesity pharmacologically was
in the leptin-deficient children mentioned earlier. Farooqi and O’Rahilly (2006) reports that
administering daily leptin injections to affected children allowed them to return to a normal
weight. Unfortunately, many obese individuals develop leptin resistance in the hypothalamus
as part of their condition, so this treatment has not been successful in those with partial
leptin deficiency or other genotypes.

While no other pharmacotherapies have been so effective to date, Tsai et al. (2017) reports
success in treating obese mice using macrophage inhibitory cytokine (MIC-1/GDF15), a
stress response cytokine that has been found to cause anorexia in humans and animals.
When administered, recombinant MIC-1/GDF15 reduced weight and rate of food intake in
obese mice raised on a high-fat diet compared with mice fed normal chow. Further research
into the therapeutic characteristics of MIC-1/GDF15, combined with insights from genetics,
may lead to new treatments in humans.

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References
Berghöfer, A., Pischon, T., Reinhold, T., Apovian, C. M., Sharma, A. M., & Willich, S. N.
(2008). Obesity prevalence from a European perspective: A systematic review. BMC
Public Health, 8 (1). doi:10.1186/1471-2458-8-200
Bonnefond, A., Keller, R., Meyre, D., Stutzmann, F., Thuillier, D., Stefanov, D. G., . . . Kral,
J. G. (2016). Eating behavior, low-frequency functional mutations in the melanocortin-
4 receptor (MC4R) gene, and outcomes of bariatric operations: A 6-year prospective
study. Diabetes Care, 39 (8), 1384–1392. doi:10.2337/dc16-0115
Campfield, L. A., Smith, F. J., & Jeanrenaud, B. (2007). Central integration of peripheral
signals in the regulation of food intake and energy balance: Role of leptin and insulin.
In G. A. Bray & C. Bouchard (Eds.), Handbook of obesity (2nd ed., Chap. 16, pp. 461–
479). 270 Madison Avenue, New York, New York 10016: Marcel Dekker, Inc.
Choquet, H. & Meyre, D. (2011). Genetics of obesity: What have we learned? Current Ge-
nomics, 12 (3), 169–179. doi:10.2174/138920211795677895
Elks, C. E., den Hoed, M., Zhao, J. H., Sharp, S. J., Wareham, N. J., Loos, R. J. F., & Ong,
K. K. (2012). Variability in the heritability of body mass index: A systematic review
and meta-regression. Frontiers in Endocrinology, 3. doi:10.3389/fendo.2012.00029
Farooqi, I. S. & O’Rahilly, S. (2006). Genetics of obesity in humans. Endocrine Reviews,
27 (7), 710–718. doi:10.1210/er.2006-0040
Huypens, P., Sass, S., Wu, M., Dyckhoff, D., Tschöp, M., Theis, F., . . . Beckers, J. (2016).
Epigenetic germline inheritance of diet-induced obesity and insulin resistance. Nature
Genetics, 48 (5), 497–499. doi:10.1038/ng.3527
Khera, A. V., Chaffin, M., Wade, K. H., Zahid, S., Brancale, J., Xia, R., . . . Kathiresan, S.
(2019). Polygenic prediction of weight and obesity trajectories from birth to adulthood.
Cell, 177 (3), 587–596.e9. doi:10.1016/j.cell.2019.03.028
Montagne, L., Derhourhi, M., Piton, A., Toussaint, B., Durand, E., Vaillant, E., . . . Bonne-
fond, A. (2018). CoDE-seq, an augmented whole-exome sequencing, enables the accu-
rate detection of CNVs and mutations in mendelian obesity and intellectual disability.
Molecular Metabolism, 13, 1–9. doi:10.1016/j.molmet.2018.05.005
Ogden, C. L., Carroll, M. D., Lawman, H. G., Fryar, C. D., Kruszon-Moran, D., Kit, B. K., &
Flegal, K. M. (2016). Trends in obesity prevalence among children and adolescents in
the United States, 1988-1994 through 2013-2014. JAMA, 315 (21), 2292. doi:10.1001/
jama.2016.6361
Speakman, J. R. (2015). The ‘fat mass and obesity related’ (FTO) gene: Mechanisms of
impact on obesity and energy balance. Current Obesity Reports, 4 (1), 73–91. doi:10.
1007/s13679-015-0143-1
Tsai, V. W., Zhang, H. P., Manandhar, R., Lee-Ng, K. K. M., Lebhar, H., Marquis, C. P., . . .
Breit, S. N. (2017). Treatment with the TGF-b superfamily cytokine MIC-1/GDF15
reduces the adiposity and corrects the metabolic dysfunction of mice with diet-induced
obesity. International Journal of Obesity, 42 (3), 561–571. doi:10.1038/ijo.2017.258
Wald, N. J. & Old, R. (2019). The illusion of polygenic disease risk prediction. Genetics in
Medicine. doi:10.1038/s41436-018-0418-5