Morbid Obesity May Be Due to Rare Genetic Deletion

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Philippe Froguel, MD, PhD, of Imperial College London, and colleagues reported in the journal Nature that missing sections of DNA may have a powerful impact on weight for a small segment of the population.

The deletion of genetic material could not be found in people of normal weight, but was found in several people – all of whom were morbidly obese (body mass index at least 40 kg/m2).

It is important to remember that the rise in obesity (BMI greater than 30 kg/m2) in the general population is due to high-calorie foods and more sedentary lifestyles. In America, the CDC reports that 20-30% of the adult population is obese.

These findings could offer clues to whether obesity can be "inherited" in some cases.

Scientists have found evidence that genes may play a significant role in influencing weight gain in some people. Their first clue came when it was noticed that a group of teenagers and adults with learning difficulties were at higher risk of obesity, although the reasons for this remains unclear.

When the researchers found 31 teens and adults who had the nearly identical deletions of at least 593 kilobases at chromosome 16p11.2 in one copy of their DNA and also had a BMI of over 30 kg/m2, the researchers decided to dig a little deeper.

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So to see whether the deletion was independent of neurodevelopmental problems, Froguel's group examined genome-wide association study data from general population cohorts totaling 11,856 individuals along with 2,772 from childhood obesity and adult morbid obesity case-control studies, 931 in an extreme early-onset obesity study, and 141 who had bariatric weight-loss surgery.

All adult carriers of the deletion were obese with the exception of one who was apparently diabetic. Each of the seven children and adolescents who carried the variant had a BMI in the top 0.1% for their age and gender.

None had any reported developmental or cognitive problems. Four had reported hyperphagia with excessive hunger and food intake.

Altogether, the 16p11.2 deletions predicted 29.8-fold elevated risk of obesity and 43.0-fold elevated risk of morbid obesity compared with lean or normal weight.

By extrapolation, the researchers extrapolated that about 0.4% of all morbidly obese cases are attributable to an inherited 16p11.2 deletion, with 0.3% arising from a de novo deletion in the same genetic region.

Professor Froguel said, "It is becoming increasingly clear that for some morbidly obese people, their weight gain has an underlying genetic cause. If we can identify these individuals through genetic testing, we can then offer them appropriate support and medical interventions, such as the option of weight loss surgery, to improve their long-term health."

Source reference:
Walters RG, et al "A new highly penetrant form of obesity due to
microdeletions on chromosome 16p11.2
" Nature 2010; DOI:10.1038/nature08727.

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