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Targeting ‘obesity genotype’ will require larger studies, effect sizes
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Obesity is a multifactorial disease that involves a complex interplay among genetics, environment and personal habits. The genetic component is 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. “Some people have a high genetic risk, and others, a very low one. We need to specify this because, otherwise, people in the general population will think that these numbers apply specifically to them.”
Many genes, small effects
In the largest genome-wide association study of obesity to date, based on data from nearly 350,000 people, Adam E. Locke, PhD, and colleagues at the Center for Statistical Genetics in the department of biostatistics at the University of Michigan in Ann Arbor identified approximately 100 genomic variants associated with obesity risk, almost all with extremely small effect sizes, “a fraction of 1%,” Bouchard said.
As large as that study was, Bouchard said, future studies of millions of people will likely reveal many more variants, or alleles, that together define genetic predisposition to obesity.
“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,” Bouchard said. “These alleles and their interactions are potentially influencing the food we eat, the exercise we do or the sedentary time we indulge in.”
Obesity risk is a continuum. Individuals with more or fewer alleles will have relatively more or less difficulty controlling their weight.
“Most people could probably succeed in reining in their biology in the presence of a moderate or, perhaps, even a high-risk profile for obesity, but they have to work hard at it,” Bouchard said. “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.”
An obesogenic environment has a greater influence than genetic makeup on the likelihood that someone will become obese — as seen in the much greater prevalence of obesity today than a century ago, Bouchard said. Fewer cheap palatable food options and more physical labor in the past allowed even those with a predisposition to obesity to remain lean. Many of those who would have maintained a normal weight in the past would have overweight or obesity today. And, even those without a particularly high genetic risk may have difficulty resisting an obesogenic environment.
“It is not clear yet what is the probability that someone who has a low or a moderate genetic risk for obesity will become obese,” Bouchard said. “One can only speculate that this probability is higher than it was decades or centuries ago.
“Today, the genes have not changed; it’s too short a period of time for meaningful changes in our genome and in our biology,” Bouchard said. “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.”
Treatment targets
Until researchers can identify further risk alleles and how these interact, general prevention and treatment of obesity based on one or more “obesity genotypes” is not possible, Bouchard said. Even with a fuller understanding of genotypes, it would be necessary to work out how to target the relevant biological pathways.
Conditions associated with few alleles that have large effect sizes are the place to start, Bouchard said. Congenital leptin deficiency, for example, is caused by mutations in a single gene. Those affected have increased weight from birth and develop more severe obesity over time. Leptin replacement therapy can help these patients lose weight and improve their metabolic health.
“This is an example of a situation where an adequate understanding of the genetic defect and its metabolic effects has allowed the development of an intervention with great efficacy,” Bouchard said. “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 and Jill Rollet
- Reference:
- Locke AE, et al. Nature. 2015;doi:10.1038/nature14177.
- 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.