Obesity is highly heritable. Because of that, that means we can use tools of genetics to gain insight into both the pathology of obesity and come up with more precise treatments. In this video, we're going to describe both how family studies and genome-wide association studies have led to our understanding of both the heritability and pathology of obesity. We can discriminate between genes that might be involved in appetite versus genes that might be involved in energy expenditure to figure out which are the stronger genetic drivers of obesity risk. Finally, we're going to integrate this information with what we know about the food environment to try to understand what explains the recent rise in obesity rates in Western societies. First, let's talk about how different alleles can exist in our population. Some alleles are highly penetrant versus not highly penetrant. A highly penetrant allele is very likely to cause the particular condition. So if you have a highly penetrant obesity risk allele, that means that having that allele very likely means that you will become obese. On the other hand, a low penetrance allele means it may have some effect on your obesity risk, but it is not essentially determinative. Another axis by which you can think about any kind of gene is whether the allele is rare in the population or common in the population. A very rare allele might exist in only one in a million people, whereas a very common allele might exist in up to half of the population. Most of the things we know about obesity are either high penetrance rare alleles identified from pedigree studies or low penetrance common alleles, which have been identified by GWAS studies. In this video, we're going to go through some examples of each of these. First, let's go through the example of leptin. Leptin was identified from a pedigree family looking at a very rare, syndromic form of obesity. If you look on the graph on the right, individuals that had extreme early onset obesity shown in the shaded end squares and circles. Two individuals, OB1 and OB2's growth trajectories, are graphed on the left. The dashed lines indicate the second, fifth, and ninth, eighth, central of growth. Ninety-eight percent of people are at the upper dashed line. As you can see, OB1 and OB2 gained substantially more than even the ninth, eighth, central of weight gain. These individuals gained excessive weight about 90 kilograms by the time they were 10 years old. By comparing the genetics of these two individuals to their unaffected siblings, they were able to locate mutations in a particular gene called leptin, as causal of their syndromic form of early onset obesity. Leptin, as further studies have shown, is a hormone that is actually released from adipose tissue. In most individuals, as adipose tissue expands, leptin is released, which then signals to the brain to decrease food intake. This is part of a normal homeostatic loop by which excessive weight gain signals to the brain to prevent food intake and prevent further weight gain. However, in individuals who cannot make leptin, such as individual OB1 and OB2, as their adipose tissue expands, they cannot signal to their brain to suppress their appetite, and therefore they do not have the attendant decrease in food intake. They continue to eat as per normal, and therefore their body weight keeps increasing. Leptin is quite rare. There have only been a few cases of leptin deficiencies that have ever been discovered. On this table, I'm showing you a few other genes that have been described from these syndromic forms of obesity. Syndromic forms of obesity are generally identified as leptin was from pedigree analysis, looking at extremely strong effects of obesity risk within families. As you can see, these range from leptin to things like the melanocortin receptor, which is rare, but still exists in about 5% of early onset people, or about 0.2% of the total population. These are highly penetrant genes. Several of these genes that turns out leptin, leptin receptor, melanocortin, the melanocortin receptor, BDNF, and the BDNF receptor, and track 2, all function in a similar way, and they all associate with appetite control. Within the brain, there is a neural signaling pathway. It's normally generally active, and it is suppressed by several signals. One of those signals is leptin. In the adipose tissue, signals through the leptin receptor to suppress appetite. Further on in the brain, other signals, including melanocortin, and the melanocortin receptor, BDNF, and the BDNF receptor, all signal to reduce appetite. If the function of any of those genes are impaired, you're taking the breaks of appetite control, and therefore generally result in overeating. It's striking that almost every syndromic variant of obesity that we've ever identified is associated with these particular neural pathways. This tells us that the regulation of appetite is highly connected to the genetics of obesity risk. Another approach to identifying genes that are associated with obesity is something called genome-wide association studies. In this group, rather than connecting entire family trees, we take DNA from both cases and controls, in this case, patients with obesity versus patients with auto-bisity, we collect their DNA and we look for associations between specific variants in DNA and the risk for obesity. Using this approach, we have identified over 100 individual genetic locations that are associated with obesity. Several of these overlap with variants that we've identified through pedigree analyses. This includes the melanocortin receptor, the leptin receptor, and BDNF. These common variants are generally less deleterious than the syndromic variants. So it's interesting that these pathways overlap. More interestingly, the vast majority of genes identified by GWAS studies are expressed exclusively in the brain and not in the periphery. Again, this highlights that neurological function, for example, appetite, is critically important to the genetic risk of obesity. Most of these common alleles exist in over 5% of the population. However, they only modify our obesity risk by a small amount, generally much less than a kilogram per individual allele. However, we can use something called a polygenic risk score to sum the effects of these alleles. To do this, what you do is you look at each of these alleles and you assign an individual whether they have most of the obesity causing alleles or the fewest of the obesity causal alleles. Shown in the graph on the right is their score shown in desiles, with 10 indicating having most of the obesity alleles and 1 indicating having the fewest obesity causing alleles. As you can see here, individuals that have a higher polygenic risk score generally have a BMI of about 5 points higher than an individual with the lowest polygenic risk score. Therefore, even knowing nothing about the family history of an individual, you can use this polygenic risk score and it can have highly predictive value for assessing an individual's obesity risk at any point in their life, even as they're born. So does genetics explain the increased obesity? Shown in the graph on the right is changes in obesity over time. You can see that since the 1970s, the number of individuals with obesity has increased quite dramatically and the number of individuals with extreme obesity defined as a BMI over 40 has also increased from being quite rare to nearly 10% of the population. This is a major public health challenge. However, this cannot be explained exclusively by genetics. That's because in the time from 1970 to now, the population genetics have not changed. The number of alleles is similar in the population over this time. However, the two main changes are in our food environment and our physical activity. So how does obesity genetics relate to the obesity epidemic? The best explanation researchers have at this point is that individuals may have a certain set of susceptibility genes. For example, eating highly processed food in some individuals may be satiating and some individuals may be quite unsatiating and they may eat quite a bit more of it. Historically, in evolution, when the food environment did not contain ultra-palatable foods, those individuals may not have been exposed to that environment and therefore, even though they had those genes, were unlikely to become obese. However, in our modern food environment, those obesity susceptibility genes are interacting with our food environment to work together to increase our risk in obesity. In summary, studies of the genetics of obesity has not only just told us that obesity is highly heritable, but it has also told us that it is intimately connected to the negative regulation of appetite. Most obesity risk alleles are highly connected to appetite regulation. Understanding the family history of an individual is important for assessing obesity risk, but polygenic risk scores are a useful tool now for measuring obesity risk in the absence of a family history. The obesity epidemic is unlikely to be due to changes in obesity risk alleles. Instead, it is most likely due to how the obesity risk alleles intersect with our food environment, resulting in higher levels of obesity risk.