Rare genes could be used to prevent weight gain, study finds

Consider two friends who both decide to make lifestyle changes together to lower their high blood pressure and cholesterol. Part of their common goal is to lose some body fat and to hold one another accountable, they eat almost identical meals and exercise together for a year. One loses 30 pounds, but the other only manages to shed 10.

Aside from feeling bitter, Friend Two is left confused and frustrated — he did all the “right” things, after all. But it could be that an invisible force is at play: his genes.

What’s new — A large new genetics study published Thursday in the journal Science makes that force a little less invisible, however. In the paper, researchers identify 16 genes that have rare variants implicated in weight gain — some of which have never been linked to obesity before. One of these, in particular, holds promise as a target for future drugs to treat obesity.

The study’s findings are based on the genetic analysis on 645,626 people living in the U.S., U.K., and Mexico.

“We’re really excited to... understand these new biological pathways that had not been linked to obesity before, and try to see how it may be modified to help people who struggle to maintain a healthy weight do that better,” geneticist Luca Lotta tells Inverse. Lotta is the senior author of the study and executive director of research into cardiovascular, metabolic, and skeletal human genetics at the Regeneron Genetics Center, which is funded by pharmaceutical company Regeneron.

Here’s the background — “Obesity” as a concept is complex, both in terms of medicine and culture. As a condition, obesity is influenced by societal and environmental factors — the availability of super-processed, high-calorie foods as opposed to a relative lack, the large-scale decline in physical activity. But it is also to do with factors out of individuals’ control, like the genes they have inherited, and the gene mutations they are born with.

In the past, researchers studied the genetics of obesity largely by looking at families where multiple generations appeared to inherit “early-onset” obesity to try and more recently, via larger genome-wide association studies, which use large genetic datasets of the general population to try identify the commonly occurring genetic variants that both make us who we are and play a role in our weight.

“These genetic variations have to be common, they’re not mutations, you and I are going to be packed full of them,” Giles Yeo tells Inverse. Yeo co-wrote a perspective article, also published in Science, on the new study and is a principal research associate in the Department of Clinical Biochemistry at Cambridge University.

Humans have about 3 billion base pairs — which are the building blocks of genes — and only a few million gene variants account for the differences from person to person, Yeo says. These “common variants,” Yeo explains, are often “non-coding,” which means that they don’t provide the blueprints for the proteins that essentially instruct cells in the body what to do. But they can influence a person’s characteristics, including their weight.

Digging into the details — In this study the researchers took a different approach. They use a technique that essentially lets them zoom in only on the part of the genome associated with making proteins, which scientists call the exome.

By doing this kind of targeted analysis, they were able to pick out “rare variants” — differences or mutations in genes that are not common to the general population — within the exome.

Because the study involved analysis of hundreds of thousands of participants, the sheer size allows for a higher degree of accuracy in picking out which of these rare variants that, when statistically analyzed alongside BMI, may be variants with “large phenotypic impact” — that is, a real influence on weight and weight gain.

They identified 16 such variants using the technique.

To try and confirm the findings, the scientists tested one of the variants in mice. This variant encodes for a protein receptor called GPR75 — by tweaking the mice’s genes, they then compared mice with and without the variant as they followed a high-fat diet designed to make them gain weight.

Mice that either did not carry the gene variant or that had only one copy of the gene, appeared to resist gaining weight to varying degrees of success. Mice that didn’t carry the variant at all were the most successful at keeping the weight off, gaining 44 percent less weight on average over the course of the diet. They also had improved insulin sensitivity and blood sugar levels, the researchers report.

In contrast, mice that had two copies of the gene gained the most weight on the diet.

Why it matters — Part of the study’s significance is to do with the culture surrounding obesity. Being diagnosed as “obese” has been historically framed as a personal failing or matter of choice, rather than the result of a much more complicated mix of factors stemming from both a person’s environment and their genetics.

The stigma faced by overweight people tends to further damage health, not help it.

It can also be exceedingly difficult to lose weight and keep it off — and popular diets are notoriously ineffective in this.

But if there was a drug that could help people whose metabolic health was affected by their genetics and weight, and for whom making changes to diet and exercise haven’t worked by themselves, it could fundamentally improve their health.

And importantly, discoveries like this one also help to validate what can be a frustrating experience — like the case of two friends who try the same things to lose weight but see vastly different results.

Jody Dushay is an assistant professor of medicine at Harvard Medical School and an endocrinologist at Beth Israel Deaconess Medical Center. Dushay tells Inverse that she sees this kind of situation play out all the time.

“You see that obesity runs in families. You see these patterns,” she says. “So it’s super exciting to know that there are people who are really working so hard to tease them apart because it just validates what people are telling you.”

While obesity does mean the risk of other metabolic problems, like high blood pressure, high cholesterol, and diabetes is higher, the weight isn’t necessarily a problem in itself.

“Obesity is seldom a problem because of the obesity per se, but actually, it’s because of all the diseases that it’s associated with it,” says Yeo. “That is what kills you.”

What’s next — Regeneron is using the findings to develop pharmaceuticals that could target GPR75. The receptor, the authors write in the study, may be involved in the regulation of “energy balance” in the body, via the brain.

“Using this large-scale sequencing approach in large ethnically diverse studies, one can really identify these rare variants that have a large impact on risk, and particularly these golden nuggets, if you will, there are hidden in the human genome,” Lotta says.

These variants, “one can hope, at some point, to be able to leverage therapeutically to help fight these diseases,” he adds.

Whatever drug may come out of this effort likely wouldn’t be for just anyone over a certain BMI — but potentially used as one of a number of approaches on an individual level, like another drug that was recently approved for weight loss called semaglutide.

People who do not fall into the “obese” category can also have metabolic problems, just as those who do fall into it can have no metabolic issues. Different ethnicities, Yeo says, have vastly different “capacities” for storing fat before they encounter health problems.

Weight, in a way, is an imperfect proxy for health problems that occur for various reasons. And though BMI as it was used in this study can be useful on a population level — it’s not necessarily a useful tool on an individual one.

Abstract: Large-scale human exome sequencing can identify rare protein-coding variants with a large impact on complex traits such as body adiposity. We sequenced the exomes of 645,626 individuals from the United Kingdom, the United States, and Mexico and estimated associations of rare coding variants with body mass index (BMI). We identified 16 genes with an exome-wide significant association with BMI, including those encoding five brain-expressed G protein–coupled receptors (CALCR, MC4R, GIPR, GPR151, and GPR75). Protein-truncating variants in GPR75 were observed in ~4/10,000 sequenced individuals and were associated with 1.8 kilograms per square meter lower BMI and 54% lower odds of obesity in the heterozygous state. Knock out of Gpr75 in mice resulted in resistance to weight gain and improved glycemic control in a high-fat diet model. Inhibition of GPR75 may provide a therapeutic strategy for obesity.