A large-scale DNA study finds rare genetic variants that protect against obesity

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A large-scale DNA study finds rare genetic variants that protect against obesity. For some people, no amount of exercise and diet allows them to lose weight. For others, thinness comes naturally. Now, scientists may know a reason. In one of the most comprehensive studies of obesity genetics to date, a research team has identified rare genetic variants that protect lucky carriers from weight gain.

A large-scale DNA

The work is “a genetics tour de force,” says Sadaf Farooqui, an obesity researcher at the University of Cambridge who was not involved in the study. Geneticists often look for mutations that cause disease, but people can also carry different versions of genes that promote good health. Farooqui points out that it is very difficult to find rare variants that confer protection against a disease because sequencing studies are usually small. However, such variants could lead to new drug targets, he adds.

At least 2.8 million people die each year from being overweight or medically obese. Obesity increases your risk of developing type 2 diabetes, heart disease, some cancers, and even severe COVID-19. Diet and exercise can help obese people lose weight, but genetics also have a lot to do with whether a person develops the disease. Studies focusing on extremely obese people have identified common genetic variants, such as the “broken” copy of the MC4R gene, linked to appetite regulation, that make people more likely to be overweight. Thousands of genetic variants have been found in other work, each with little effect on body weight; Together, they can significantly increase the likelihood of obesity.

In the new study, the researchers sequenced the genomes of more than 640,000 people from Mexico, the United States and the United Kingdom, which are found only in the exome, the part of the genome that codes for proteins. It’s a “lot of work,” says Ruth Loos, a human geneticist at the University of Copenhagen who was not involved in the study. Just as an image with thousands of pixels reveals the tiny details in a scene, she says, a large number of studies participants provided “very high resolution to achieve the rarest of shapes.”

The researchers then looked at mutations within genes that were associated with a low or high body mass index (BMI), the most commonly accepted, albeit incomplete, measure of obesity. Of the 16 genes that bind to BMI, five encode cell surface proteins known as G protein-coupled receptors. In addition to the evidence that they affect weight, the scientists found that these five genes are expressed in the hypothalamus, a region of the brain that controls appetite and metabolism.

The GPR75 variant of one of these genes had the greatest effect on BMI. As researchers report today in Science, individuals with the mutation inactivated one copy of that gene weighed an average 5.3 kilograms less and were half as likely to be obese than those with functional versions.

To see how GPR75 affected weight gain, the researchers engineered mice that lacked a working copy of the gene. When fed a high-fat diet, the rodents gained 44% less weight than control mice. The modified mice also had better blood sugar control and were more sensitive to insulin. However, GPR75 variants that inactivate the gene are rare:

Only one person out of 3000 wears them. “It affects a very small group of the world,” says Giles Yeo, a Cambridge geneticist who was not involved in the study. The fact that GPR75 deficiency has such a clear and strong protective effect in mice is involved in metabolic pathways related to obesity, he says, and tells us a lot of new biology that could affect everyone in the world.

As such, GPR75 could be a potential drug target, scientists say; There are two molecules proven to activate the GPR75 receptor, but drugs that deactivate it could provide new drug options for patients struggling with obesity.

The work also suggests that “it is possible to generalize this approach to other symptoms and diseases,” such as type 2 diabetes and other metabolic disorders, said Luca Lotta, a genetic epidemiologist at the Regeneron Genetics Center who led the study. . However, for Loos, the real value of the research lies in the sequencing scale. “This confirms that to study complex diseases like obesity, we need large samples.”

Small genetic differences add up to large behavioral effects. Thousands of different genetic variants are responsible for complex behavior. Genome-wide association studies (GWAS) allow us to correlate genetic differences with behavioral traits. There is no single gene that explains behavior; Rather, behavior results from the complex interaction of many different genes, each of which plays only a minor role. Society must be vigilant as we learn more about behavioral genetics.

Life flourishes with diversity, because diversity gives nature something to choose from, providing flexibility to adapt to change. The variation between humans seems endless, both in appearance and behavior. Variation among humans is due in large part to our flexible nature that allows us to adapt to a wide variety of possible life trajectories, and in part to the determined dimensions of variation in our biological structure shaped by the hands of time.

Genome-wide association studies

Four billion years of natural selection created the sophisticated machinery we all share, encoded in most of our DNA, as well as a carefully selected space for variation, encoded in a minority of DNA differences. If the 3.2 billion nucleotides of our DNA can fit in a 300-page book, the difference between two random people is barely two pages. Several decades of research on twins and family members shows that a considerable part of the differences in human behavior stem from a few small differences within those two pages.

If the 3.2 billion nucleotides of our DNA can fit in a 300-page book, the difference between two random people is barely two pages. It is difficult to uncover the evolutionary stories behind these differences, but perhaps it helps to unravel how these genetic differences lead to diversity in our behavioral repertoire.

Recent advances in genetic research allow us to link specific DNA nucleotides on those two pages to complex behavioral results. Studies that link genetic variation to complex traits at the molecular level are called genome-wide association studies (GWAS). In a GWAS, millions of individual DNA nucleotides are tested one by one to determine their relationship to the most complex human traits, including behavior.

Professor Karin Verweis and I recently published an article in Nature Human Behavior, in which we review what we have learned so far from GWAS about human behavior and what steps we need to take to learn more. Here, I will summarize some of the highlights of my article and consider their social relevance.

Multiple genes with little effect

Over the past decade, we have been able to link thousands of genetic variants to human behavioral traits, including personality, education, cognition, and mental health. The effects of these genetic variants on behavior are very weak for an individual. Twin and family studies have estimated that, on average, about half of individual differences in behavioral outcomes are due to genetic differences, which would mean that thousands of genetic variants would be needed for these estimates of heritability.

It is difficult to estimate the small effects of individual genetic variants unless unusually large groups are studied. In a typical GWAS, we study millions of DNA types from hundreds of thousands of individuals. The sum of these small effects can be used to predict people’s genetic risk for all kinds of outcomes. The predictive power of DNA increases as our studies progress, but we still understand little about the nature of these predictions.

There are probably no genes that directly affect complex behavioral outcomes. Instead, many small genetic influences travel through multiple cascades of mostly unknown biological processes that react to and affect the physical and social environments in which people live. Before allowing DNA prediction to reach the clinic or other uses, such as embryo selection or mate selection, it is important that we first invest in a better understanding of the nature of the relationship between genetic differences and behavioral outcomes.

Everything is connected

The physical machinery that carries out our budding mind and behavior consists of many complex and interconnected systems. Modifying one part will affect many other results. This is visible at the gene level: genetic influences are often shared in an orderly fashion between different behavioral outcomes. Genes that increase the chance of becoming addicted to alcohol increase the risk of feeling lonely. Genes that increase the risk of autism increase the likelihood of a high IQ. Genes that increase the risk of anorexia increase the probability of obtaining a higher education.

These shared genetic effects are widespread among behavioral outcomes. The genetic effects that we estimate reflect a mosaic of multiple underlying behavioral consequences. While many are eager to use these genetic influences to dive into behavioral biology, we argue that we must first do more to dissect these genetic influences into their subcomponents.

For example, for educational attainment, we recently divided the portion of genetic influences associated with IQ, which accounts for 43 percent, from genetic influences on educational achievement, and the “no IQ” portion, 57 percent. remaining. We’re still not sure exactly what the remaining 57 percent are involved in, but we do see that those genes increase the risk of schizophrenia and bipolar disorder. This may be because people with a higher genetic risk for schizophrenia or bipolar disorder tend to be more creative and more open to new experiences.

These shared genetic influences teach us a lot about the genetic makeup of human behavior and also make us realize that it is difficult to select one trait without influencing many others. This is a strong argument against using DNA prediction to influence the DNA of your offspring through embryo selection, a service that some companies have unfortunately already begun to offer.

Behavioral genetics is controversial

The highest proportion of shared genetic effects was observed between educational level and income. These associations have been reported in different publications and the genetic effect in each one is almost identical. Both posts attracted a lot of attention in the media and on social media. While in terms of educational attainment, the responses were mostly positive, the publication on genetic effects on income was largely criticized.

These contrasting responses to the same genetic signal can occur in people’s brains, and income is more closely related to social inequalities. Trying to explain social inequalities as something that people are born with can lead to fear that science is being misused to justify the status of marginalized groups. Instead, these molecular genetic influences are helping to explain the injustice inherent in the way our societies are organized.

A closer look at these genetic influences reveals a substantial number of environmental influences. Our initial studies had trouble separating the two because they are highly correlated. When your genes predispose you to higher education, it means that your parents also carry those genes and are therefore more likely to pursue higher education, allowing them to nurture you with a better environment. Better resources (money) are available to you. If you are born with a gene that makes learning easier, it will also increase your chances of moving to a prosperous neighborhood with healthier living conditions. These “double advantages” and “double disadvantages” make us confuse the effects of systematic social disadvantage with genetic effects, increasing the estimates of inheritance.

These gene-environment correlations were recently found by studying the DNA of people who were exclusively of white European descent. Systematic differences in environmental influences are likely to be much worse between different ethnic groups, raising further questions about the claims of white supremacists, who use these inflated inheritance estimates to support their genetic explanation for socioeconomic group differences. that they like to wear.

Conclusion

Even after two decades of reading the human genome, we are still only scratching its surface. We are beginning to deduce only a fraction of the total heritability that we can currently capture with molecular genetic data. Much of humanity is still underrepresented in our measurements, making it difficult to make more general claims. We go into more detail in our Nature Human Behavior article on the steps we need to take in our data collection methods and strategies to better understand the differences in our DNA.

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