Understanding genetics of obesity will require larger studies, effect sizes

Obesity is a multifactorial condition that involves a complex interplay among genetics, environment and personal habits. The genetic component is currently estimated to be about 40% to 50%. However, these percentages do not represent an individual’s personal risk for obesity.

“When we ask to what extent genes are contributing to anything, whether it’s obesity, heart disease, diabetes, anything, we have to realize that this is an estimate for a population. It has no concrete value for a given individual,” Claude Bouchard, PhD, John W. Barton Sr. Endowed Chair in Genetics and Nutrition at Pennington Biomedical Research Center in Baton Rouge, Louisiana, told Endocrine Today. “It doesn’t pertain to a given person. Some people have a high genetic risk, and others, a very low one. I have been asked this question a lot over the past 35 years. We need to specify this, because otherwise, people in the general population will think that these numbers apply specifically to them.”

Bouchard spoke with Endocrine Today about the latest research into the genetics of obesity, the DNA sequences involved, and the environmental factors that may have led to current increases in the prevalence of obesity.

What is known about the genes involved in obesity?

Bouchard: We can now explore the whole genome; we can perform global screens of the genome and test it for obesity with growing accuracy. Every time we have a new study, a larger study, we identify a few more obesity loci in the genome. The largest study published to date has been based on 350,000 people. That’s a large study, but not large enough to identify all the genes and loci that contribute to the risk for obesity mainly because the effect size of each of these genomic variants is small, when considered individually. A study based on 350,000 individuals was sufficient to identify about 100 genomic variants, but almost all of them had a very small effect size, a fraction of 1%. We know that there are many more obesity-predisposing variants, but one can predict that the new obesity variants will each make extremely small contribution to the obesity risk. So, in the end, when an appropriately large study is reported in the future, based maybe on 1 million or 2 million people, the complete obesity genomic profile could end up being determined by very large numbers of genomic variants, perhaps more than 1,000 variants that together will define the architecture of the genetic predisposition to obesity. If a person carries a very large number of these obesity genomic variants, he or she would be at a much higher risk of gaining weight and becoming obese than someone who has fewer of them.

But there is more to it than only the number of obesity risk alleles. Indeed, the biology of obesity is extremely complex as these hundreds of alleles are likely interacting with one another and affecting the functional levels of multiple pathways and systems. These alleles and their interactions are potentially influencing the food we eat, the exercise we do or the sedentary time we indulge in. In summary, the finer details of the obesity genotype are going to be hard to fully dissect, but it is entirely doable given the right resources.

If a person has a genome that predisposes to obesity, how likely is that person to have obesity?

Bouchard: Predisposition is a continuum. You may have few risk alleles or a large number of them. If you have a large number, say hundreds, it’s going to be more challenging for you to control your weight because your biology, in a sense, is stacked against you as this biology impacts the brain and endocrine systems — the regulation of appetite, the fate of nutrients in the body, metabolic rates, etc. So, if you have a lot of risk alleles, it’s a challenge. We see that it happens in nature. Some people have a hard time maintaining weight, while for others, it’s simpler. There are people who remain lean their entire lives, and they seem to be doing nothing special to control their weight. These people probably have few of the risk alleles; their biology is such that it favors leanness. Most people could probably succeed in reining in their biology in the presence of a moderate or a perhaps even a high-risk profile for obesity, but they have to work hard at it. If you are not as rigorous for a while in controlling your behavior, you can easily gain weight, and that’s what is being seen in practice.

How does one rein in their biology? Is it through diet and exercise, or something else?

Bouchard: Despite all the noise surrounding this issue, it still comes down to changing your behavior. It’s diet and exercise. You alter your intake and expenditure, and by doing this, you attempt to instill a sustained state of negative energy balance until you have reached your body-weight target. This is no small task. Caloric restriction is essential, and, if successful, it will entrain more lipid mobilization from adipose tissue depots and favor lipid oxidation. Increasing energy expenditure with regular physical activity is also an essential component of a serious weight-control plan. If done in sufficiently large amount and at a relatively high intensity, after a period of adaptation it could potentially increase metabolic rate, which would help in sustaining the targeted negative energy balance state.

Now, it is important to realize that when one experiences negative energy balance for a period of time, our biology begins to favor increased resistance to weight loss. This is particularly so in people who have been obese for a period of time. Adipose tissue cells have become resistant to lipid mobilization, and the hormonal profile favors protection of energy stored and conservation of energy, thus providing a resistance to weight-loss milieu.

So, in addition to the genetic predisposition to obesity, there is also our innate species biology favoring the conservation of our stored energy, plus an acquired component that nudges our biology to protect even more fiercely our fat depots and resist weight loss.

What is the likelihood of becoming obese for a person who does not have a genetic predisposition to obesity?

Bouchard: Up until about a century ago, the prevalence of obesity was much lower than it is today, and this was a consequence of lifestyle. Palatable cheap food was not as readily available as it is today, and we were then performing a lot more muscular work than we are doing today. So, a larger fraction of the population was normal weight and lean back then. Today, the genes have not changed; it’s too short a period of time for meaningful changes in our genome and in our biology, although one cannot rule out the fact that agents in our environment, such as pesticides or hormone-like substances, etc., could be related to events influencing our biology, such as DNA methylation, gut microbiome composition, etc. So, some people who would normally be normal weight are overweight or obese today. The environment — the built environment, the social environment — favors obesogenic behavior and thus puts more people at risk of living under sustained positive energy balance, even if they are not particularly prone to obesity. It is not clear yet what is the probability that someone has a low or a moderate genetic risk for obesity will become obese. One can only speculate that this probability is higher than it was decades or centuries ago.

Is there a particular gene or genes that predispose a person to leanness?

Bouchard: That’s an interesting issue. We have genomic screens for DNA variants associated with obesity; we don’t yet have them for leanness. Such a study should be high on our agenda. From genetic epidemiology studies we know that there is a genetic component to leanness, and it’s strong. We know that there are family lines where all members of the nuclear families are lean and stay lean all their lives. At the opposite end of the spectrum, we have family lines where parents are obese and offspring are obese or overweight, and everyone tends to remain that way throughout their lives. Therefore, it would be valuable and informative to begin looking for DNA variants associated with leanness. So, at both ends of the body-weight and adiposity spectrum, we have strong genetic components, and in both cases, we are likely dealing with a lot of alleles and small effect sizes.

What can genetics tell us about preventing and treating obesity?

Bouchard: A genetically informed response to that question will only be possible when we have a thorough understanding of the architecture of the genetic component of the predisposition to obesity: What are the genes? What are the biological pathways? What are the effects of these genes? Can we find ways to modulate the biology impacted by these alleles via medication or indirectly via behavior modification or the physical environment? We don’t know the responses to these questions yet, so it is hard to see how we can anchor a prevention or treatment strategy on our genes. We will also be limited in our ability to intervene successfully by the very nature of the complex obesity genotype — many alleles with small effect sizes. On the other hand, there are also cases where obesity is caused by one gene, for example, babies who are born with a deficiency in the leptin gene. When this happens, the person is heavy almost from birth, and obesity becomes severe with age. In these cases, we have a clear target, ie, a deficient gene that produces the hormone leptin. This constitutes a clear proof of concept situation: leptin replacement treatment by injection and obesity is essentially cured.
an adequate understanding of the genetic defect and its metabolic effects has allowed the development of an intervention with great efficacy. However, when the genetic disposition for obesity is defined by alleles at hundreds of genomic sites, it is a challenge to predict how a genomic-based prevention or treatment program would work. – by Jennifer Byrne

For more information:

Claude Bouchard, PhD, can be reached at 6400 Perkins Road, Baton Rouge, LA 70808; email: claude.bouchard@pbrc.edu.

Disclosure: Bouchard reports no relevant financial disclosures.

Obesity is a multifactorial condition that involves a complex interplay among genetics, environment and personal habits. The genetic component is currently estimated to be about 40% to 50%. However, these percentages do not represent an individual’s personal risk for obesity.

“When we ask to what extent genes are contributing to anything, whether it’s obesity, heart disease, diabetes, anything, we have to realize that this is an estimate for a population. It has no concrete value for a given individual,” Claude Bouchard, PhD, John W. Barton Sr. Endowed Chair in Genetics and Nutrition at Pennington Biomedical Research Center in Baton Rouge, Louisiana, told Endocrine Today. “It doesn’t pertain to a given person. Some people have a high genetic risk, and others, a very low one. I have been asked this question a lot over the past 35 years. We need to specify this, because otherwise, people in the general population will think that these numbers apply specifically to them.”

Bouchard spoke with Endocrine Today about the latest research into the genetics of obesity, the DNA sequences involved, and the environmental factors that may have led to current increases in the prevalence of obesity.

What is known about the genes involved in obesity?

Bouchard: We can now explore the whole genome; we can perform global screens of the genome and test it for obesity with growing accuracy. Every time we have a new study, a larger study, we identify a few more obesity loci in the genome. The largest study published to date has been based on 350,000 people. That’s a large study, but not large enough to identify all the genes and loci that contribute to the risk for obesity mainly because the effect size of each of these genomic variants is small, when considered individually. A study based on 350,000 individuals was sufficient to identify about 100 genomic variants, but almost all of them had a very small effect size, a fraction of 1%. We know that there are many more obesity-predisposing variants, but one can predict that the new obesity variants will each make extremely small contribution to the obesity risk. So, in the end, when an appropriately large study is reported in the future, based maybe on 1 million or 2 million people, the complete obesity genomic profile could end up being determined by very large numbers of genomic variants, perhaps more than 1,000 variants that together will define the architecture of the genetic predisposition to obesity. If a person carries a very large number of these obesity genomic variants, he or she would be at a much higher risk of gaining weight and becoming obese than someone who has fewer of them.

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But there is more to it than only the number of obesity risk alleles. Indeed, the biology of obesity is extremely complex as these hundreds of alleles are likely interacting with one another and affecting the functional levels of multiple pathways and systems. These alleles and their interactions are potentially influencing the food we eat, the exercise we do or the sedentary time we indulge in. In summary, the finer details of the obesity genotype are going to be hard to fully dissect, but it is entirely doable given the right resources.

If a person has a genome that predisposes to obesity, how likely is that person to have obesity?

Bouchard: Predisposition is a continuum. You may have few risk alleles or a large number of them. If you have a large number, say hundreds, it’s going to be more challenging for you to control your weight because your biology, in a sense, is stacked against you as this biology impacts the brain and endocrine systems — the regulation of appetite, the fate of nutrients in the body, metabolic rates, etc. So, if you have a lot of risk alleles, it’s a challenge. We see that it happens in nature. Some people have a hard time maintaining weight, while for others, it’s simpler. There are people who remain lean their entire lives, and they seem to be doing nothing special to control their weight. These people probably have few of the risk alleles; their biology is such that it favors leanness. Most people could probably succeed in reining in their biology in the presence of a moderate or a perhaps even a high-risk profile for obesity, but they have to work hard at it. If you are not as rigorous for a while in controlling your behavior, you can easily gain weight, and that’s what is being seen in practice.

How does one rein in their biology? Is it through diet and exercise, or something else?

Bouchard: Despite all the noise surrounding this issue, it still comes down to changing your behavior. It’s diet and exercise. You alter your intake and expenditure, and by doing this, you attempt to instill a sustained state of negative energy balance until you have reached your body-weight target. This is no small task. Caloric restriction is essential, and, if successful, it will entrain more lipid mobilization from adipose tissue depots and favor lipid oxidation. Increasing energy expenditure with regular physical activity is also an essential component of a serious weight-control plan. If done in sufficiently large amount and at a relatively high intensity, after a period of adaptation it could potentially increase metabolic rate, which would help in sustaining the targeted negative energy balance state.

PAGE BREAK

Now, it is important to realize that when one experiences negative energy balance for a period of time, our biology begins to favor increased resistance to weight loss. This is particularly so in people who have been obese for a period of time. Adipose tissue cells have become resistant to lipid mobilization, and the hormonal profile favors protection of energy stored and conservation of energy, thus providing a resistance to weight-loss milieu.

So, in addition to the genetic predisposition to obesity, there is also our innate species biology favoring the conservation of our stored energy, plus an acquired component that nudges our biology to protect even more fiercely our fat depots and resist weight loss.

What is the likelihood of becoming obese for a person who does not have a genetic predisposition to obesity?

Bouchard: Up until about a century ago, the prevalence of obesity was much lower than it is today, and this was a consequence of lifestyle. Palatable cheap food was not as readily available as it is today, and we were then performing a lot more muscular work than we are doing today. So, a larger fraction of the population was normal weight and lean back then. Today, the genes have not changed; it’s too short a period of time for meaningful changes in our genome and in our biology, although one cannot rule out the fact that agents in our environment, such as pesticides or hormone-like substances, etc., could be related to events influencing our biology, such as DNA methylation, gut microbiome composition, etc. So, some people who would normally be normal weight are overweight or obese today. The environment — the built environment, the social environment — favors obesogenic behavior and thus puts more people at risk of living under sustained positive energy balance, even if they are not particularly prone to obesity. It is not clear yet what is the probability that someone has a low or a moderate genetic risk for obesity will become obese. One can only speculate that this probability is higher than it was decades or centuries ago.

Is there a particular gene or genes that predispose a person to leanness?

Bouchard: That’s an interesting issue. We have genomic screens for DNA variants associated with obesity; we don’t yet have them for leanness. Such a study should be high on our agenda. From genetic epidemiology studies we know that there is a genetic component to leanness, and it’s strong. We know that there are family lines where all members of the nuclear families are lean and stay lean all their lives. At the opposite end of the spectrum, we have family lines where parents are obese and offspring are obese or overweight, and everyone tends to remain that way throughout their lives. Therefore, it would be valuable and informative to begin looking for DNA variants associated with leanness. So, at both ends of the body-weight and adiposity spectrum, we have strong genetic components, and in both cases, we are likely dealing with a lot of alleles and small effect sizes.

PAGE BREAK

What can genetics tell us about preventing and treating obesity?

Bouchard: A genetically informed response to that question will only be possible when we have a thorough understanding of the architecture of the genetic component of the predisposition to obesity: What are the genes? What are the biological pathways? What are the effects of these genes? Can we find ways to modulate the biology impacted by these alleles via medication or indirectly via behavior modification or the physical environment? We don’t know the responses to these questions yet, so it is hard to see how we can anchor a prevention or treatment strategy on our genes. We will also be limited in our ability to intervene successfully by the very nature of the complex obesity genotype — many alleles with small effect sizes. On the other hand, there are also cases where obesity is caused by one gene, for example, babies who are born with a deficiency in the leptin gene. When this happens, the person is heavy almost from birth, and obesity becomes severe with age. In these cases, we have a clear target, ie, a deficient gene that produces the hormone leptin. This constitutes a clear proof of concept situation: leptin replacement treatment by injection and obesity is essentially cured.
an adequate understanding of the genetic defect and its metabolic effects has allowed the development of an intervention with great efficacy. However, when the genetic disposition for obesity is defined by alleles at hundreds of genomic sites, it is a challenge to predict how a genomic-based prevention or treatment program would work. – by Jennifer Byrne

For more information:

Claude Bouchard, PhD, can be reached at 6400 Perkins Road, Baton Rouge, LA 70808; email: claude.bouchard@pbrc.edu.

Disclosure: Bouchard reports no relevant financial disclosures.