Identifying specific genes adds to growing evidence that biology, in part, drives obesity. Researchers hope the findings will lead to effective treatments, and in the meantime add to the understanding that there are many types of obesity that come from a mix of genes and environmental factors.
Although the study is not the first to point to specific genes, “we were quite surprised by the proposed function of some of the genes we identified,” Lena R. Kaisinger, lead study investigator and a PhD student in the MRC Epidemiology Unit at the University of Cambridge (England), wrote in an email. For example, the genes also manage cell death and influence how cells respond to DNA damage.
The investigators are not sure why genes involved in body size perform this kind of double duty, which opens avenues for future research.
Differences between women and men
The researchers found five new genes in females and two new genes in males linked to greater body mass index (BMI): DIDO1, KIAA1109, MC4R, PTPRG and SLC12A5 in women and MC4R and SLTM in men. People who recall having obesity as a child were more likely to have rare genetic changes in two other genes, OBSCN and MADD.
“The key thing is that when you see real genes with real gene names, it really makes real the notion that genetics underlie obesity,” said Lee Kaplan, MD, PhD, director of the Obesity and Metabolism Institute in Boston, who was not affiliated with the research.
Ms. Kaisinger and colleagues found these significant genetic differences by studying genomes of about 420,000 people stored in the UK Biobank, a huge biomedical database. The researchers decided to look at genes by sex and age because these are “two areas that we still know very little about,” Ms. Kaisinger said.
“We know that different types of obesity connect to different ages,” said Dr. Kaplan, who is also past president of the Obesity Society. “But what they’ve done now is find genes that are associated with particular subtypes of obesity ... some more common in one sex and some more common in different phases of life, including early onset obesity.”
The future is already here
Treatment for obesity based on a person’s genes already exists. For example, in June 2022, the Food and Drug Administration approved(Imcivree) for weight management in adults and children aged over 6 years with specific genetic markers.
Even as encouraging as setmelanotide is to Ms. Kaisinger and colleagues, these are still early days for translating the current research findings into clinical obesity tests and potential treatment, she said.
The “holy grail,” Dr. Kaplan said, is a future where people get screened for a particular genetic profile and their provider can say something like, “You’re probably most susceptible to this type, so we’ll treat you with this particular drug that’s been developed for people with this phenotype.”
Dr. Kaplan added: “That’s exactly what we are trying to do.”
Moving forward, Ms. Kaisinger and colleagues plan to repeat the study in larger and more diverse populations. They also plan to reverse the usual road map for studies, which typically start in animals and then progress to humans.
“We plan to take the most promising gene candidates forward into mouse models to learn more about their function and how exactly their dysfunction results in obesity,” Ms. Kaisinger said.
Three study coauthors are employees and shareholders of Adrestia Therapeutics. No other conflicts of interest were reported.
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