The weirder side of obesity: genetic forms of obesity are rare yet numerous

While scientists have been aware of about two dozen genetic conditions that can cause obesity, a new study published Monday in the journal Obesity Reviews finds there are many more.

The Canadian researchers have identified and cataloged 79 rare genetic syndromes where obesity is a key symptom. A body mass index of 30 or higher is considered obese, where weight is higher than what is considered healthy for a given height.

Despite their focus on rare genetic syndromes, the researchers say their work will be helpful to the millions worldwide who have lost control of their weight for reasons other than genetics.

“If you know the gene and the function of the gene, then you know which biological mechanism is defective,” said David Meyre, senior author of the study and an associate professor at McMaster University’s School of Medicine in Ontario, Canada. This knowledge of obesity genetics, then, can be applied to more common forms of the condition, he said.

A case in point would be leptin, which is a hormone produced by the body’s fat cells and is found to be deficient in some people due to genetic mutations. The gene responsible for producing the “satiety hormone,” as leptin is known, was first identified in 1990. Since then, knowledge of this gene has shifted our understanding of fat cells and how weight gain occurs.

One in a million

“The reason we studied this is very simple,” said Meyre. “Every time I was writing a research paper and I was describing what we knew about the genetics of obesity, I didn’t have a reference.” One day, he decided to write the necessary reference himself, since he suspected the 20 to 30 commonly known genetic syndromes might be, in fact, an underestimation.

“For the study, we focused on monogenic forms of obesity,” said Meyre. He explained that monogenic or “Mendelian” forms mean that if you have one mutation, you develop the disease. “It’s not that it increases your risk, it’s 100% sure you develop the disease,” he said. For example, Huntington’s disease, a progressive brain disorder that causes uncontrolled movements and loss of thinking ability, is caused by a single inherited gene mutation.

The monogenic obesity syndromes are very rare, Meyre noted, so rare they may collectively represent only 0.5% of the obese population in Canada, while individually some of these syndromes represent one in a million births.

About 20% of adult Canadians are classified as obese, according to Statistics Canada, while in the United States, the Centers for Disease Control and Prevention categorizes more than a third of adults as obese. Obesity-related conditions include heart disease, stroke, type 2 diabetes and certain types of cancer, some of the leading causes of preventable death.

Meyre and his colleagues from McMaster University and University of British Columbia searched seven databases for papers on the topic. The team adopted a systematic strategy for reviewing the scientific literature, which included two independent reviews of each paper.

All told, the researchers analyzed 161 papers and found 79 obesity syndromes reported in the scientific literature.

“My intuition was correct,” said Meyre.

In the monogenic obesity syndromes, not only does the genetic defect result in obesity but it also causes additional abnormal features, including mental disability, characteristic facial features, kidney disease and heart malformation.

Of the 79 syndromes identified, 19 had the genetics worked out completely so that a simple lab test would be able to confirm the condition. Another 11 had been partially clarified, while 27 had been mapped to a chromosomal region. For the remaining 22 syndromes, researchers had not yet identified the genes or location along the chromosomes.

“Identifying genes is very important for the families,” said Meyre. He explained that some of the more common syndromes have been treated with a hormone that works very well to improve symptoms. If the genetics are worked out for each of these syndromes, that should enable scientists to find or develop appropriate treatments.

“We also hope that our study will help clinicians to recognize these syndromes,” said Meyre. Since in the entire course of their careers, doctors may encounter just one, maybe two patients with these syndromes, most of the time, due to a lack of familiarity and information, the conditions go unrecognized and patients do not get help.

Additionally, the results will help scientists better understand the genes and molecules important to obesity among members of the general population.

Understanding what’s common by examining what’s rare

Mary Freivogel, president of the National Society of Genetic Counselors, found the comprehensive nature of the new study to be a strength.

“One weakness of the study is that some of these obesity syndromes are so rare that it was not possible for the authors to determine how often the syndrome occurs in the general population nor how reliable the information reported about the syndrome was,” said Freivogel, who played no part in the new study.

“Most of the obesity in the United States is NOT syndromic, said Freivogel. She explained that the overwhelming majority of cases are “polygenic and multifactorial,” meaning it has resulted from a combination of multiple genetic factors, as well as environmental and lifestyle factors. Freivogel added that anyone wishing to undergo a genetic test might want to talk with a counselor to ensure the test is the right choice and any results are interpreted correctly.

Phil Beales, a professor and head of genetics and genomic medicine at University College London, also appreciated the comprehensiveness of the study and said “the author’s methodology appears to be reasonably sound.”

Beales, who was not involved in the new study, also felt pleased that someone had updated this “specialised category of obesity.” However, he disagrees with the recommendation proposed by Meyre and his co-authors to name each disease after the scientists who discovered them.

“This is an antiquated notion and unhelpful,” said Beales, who observed the preferred name for DiGeorge syndrome – a common genetic disorder resulting in cognitive impairment and other medical complications – is now called Deletion22 syndrome, which is a more useful way to look at the disease.

Still, the work has its virtues, said Beales.

“I think where a catalogue of this nature is valuable is that it provides a good resource for researchers who are interested in extrapolating from rare to common,” said Beales. “The Mendelian disorders have an untapped potential to reveal mechanistic insights (and possibly new treatments) to common (non-syndromic) obesity.”

Dr. Liam R. Brunham, an assistant professor of medicine at University of British Columbia, said the most remarkable finding of the review may be that of the 79 obesity syndromes, the genetic basis of only one-quarter of them is known. Very likely, then, there is “a huge amount regarding the genetics of obesity that remains to be discovered,” said Brunham. He was not involved in the study.

Using leptin as an example, Brunham said there’s much that can be learned regarding the biology of obesity from even a single gene.

“This suggests that discovering the genetic basis of the remaining obesity syndromes will yield huge advances in our understanding of obesity, which could lead to new opportunities for its treatment and prevention,” said Brunham.