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September 25, 2020

All Obesity is Not the Same: Recognizing Genetic Causes of Obesity

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There have been significant advances in research focused on understanding how genetics influence body weight in recent years. Severe obesity is caused by a wide range of environmental and genetic factors that affect the balance between energy intake and energy expenditure. Some naturally arising variants in specific genes are associated with obesity, but the impact of these variants on body weight can vary considerably. In rare cases, variants in just one gene may cause early-onset, severe forms of obesity associated with an insatiable hunger.

The key to improving the care for many patients and their families is recognizing that not all obesity is the same and understanding that lifestyle changes may not be effective for everyone. For example, genetic disorders of obesity can be polygenic, syndromic, and non-syndromic.

Generally, most cases of general obesity are polygenic. Prevalence estimates are as high as one in three people living with polygenic obesity in some parts of the world. People living with polygenic obesity often carry multiple common gene variants – more than 200 genes have been implicated. Each of these variants contributes additively to an individual’s obesity, and the environment plays a significant role, too.

In syndromic obesity the environment may play a smaller role. These rare disorders affect about one in 20,000-1,000,000 people. For most of them, obesity is just one of multiple symptoms. More than 50 genes have been implicated in these syndromes. Examples include Bardet-Biedl syndrome, Alström syndrome, and Prader-Willi syndrome.

Genetic disorders of obesity that are non-syndromic obesity, commonly known as monogenic obesity, include ultra-rare disorders that each affect about one in 1,000,000 people. More than 20 genes have been implicated in these disorders. For people living with genetic disorders of obesity that are non-syndromic, environment may also play a smaller role. Examples include pro-opiomelanocortin (POMC) deficiency obesity, leptin receptor (LEPR) deficiency obesity, and melanocortin-4 receptor (MC4R) deficiency obesity.

Today, we have unprecedented insight into how genes define us and how variants in genes can cause specific disorders. In obesity, a deeper understanding of the genetics that underly each individual’s clinical presentation can lead to more successful management and treatment programs. It is important to continue to advance the understanding and awareness of rare genetic disorders of obesity and use this knowledge to positively impact the care of people living with these disorders.

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