Genetic mutations are thought to cause blindness in almost everyone who carries them, but new research has found that less than 30% of people actually experience vision loss.
This study challenges the concept of Mendelian diseases, or diseases or disorders that are thought to be caused by a single genetic mutation. The idea is that Mendelian diseases, such as the neurological disorder Huntington’s disease and the bleeding disorder hemophilia, are passed down in families in a predictable manner, such that if one person has the disease-causing mutation, the other person will also have the mutation.
you may like
“What we are suggesting is that there is an overlap,” Dr. Eric Pierce, an ophthalmologist at Harvard Medical School and lead author of the new study, told Live Science. In other words, many diseases that were thought to have simple Mendelian causes may be much more complex than previously thought.
And this doesn’t just apply to hereditary blindness. Similar results have been found for other genes once thought to be strongly associated with health conditions. A 2023 study of ovarian dysfunction, which causes infertility and early menopause, found that 99.9% of disease-causing variants are actually present in healthy women. And a 2022 study found that certain types of genetic diabetes also have more complex genetics than previously thought.
Anna Murray, a geneticist at the University of Exeter who led the research into ovarian dysfunction, said: “We are entering an era in which we are discovering much more about the complexity of the genome.”
Is it simple or complex?
Pierce and his colleagues focused on inherited retinal diseases (IRDs), said study co-author Dr. Elizabeth Rossin, an ophthalmologist at Harvard University. This disease is a group of diseases that cause significant vision loss as early as the age of 10 and in some cases by the age of 40. Researchers have uncovered the genetic causes of these diseases by conducting genetic tests on affected patients and their families.
But that method can lead to a problem called confirmation bias, Pearce said. Indeed, it turns out that some genetic mutations are associated with this disease. However, because we only study people with the disease and their relatives, we do not have a clear idea of how many people have the same genetic mutation and do not go blind.
To broaden their perspective, the researchers used data from two large biobanks containing people’s genetic sequence data, medical diagnoses, and demographic information. One, the All of Us Biobank, is a program run by the National Institutes of Health that included approximately 318,000 individuals with both genetic and electronic health record data at the time of the study. Another, the UK Biobank, is less diverse, but contains data from 500,000 people, including around 100,000 who have submitted images of their retinas to the database.
The researchers selected 167 genetic variants that were thought to have the strongest causal relationship with IRD and searched them in the All of Us database. Next, they used health record data to see if people with the mutation had vision loss. Surprisingly, only 9.4% to 28.1% of people with the mutation showed signs of retinal or visual impairment, depending on the diagnosis code used.
you may like
“Given what we know about these diseases, you would expect that almost 100% of people would go blind,” Rossin told Live Science. “But it was a lot less than that.”
To verify their findings, the researchers turned to the UK Biobank, this time using the retinal images it contained to look for evidence of IRD itself. They found that only between 16.1% and 27.9% of carriers of the genetic mutation showed potential for retinal disease.
Older people with these retinal disease genes are less likely to become blind. And there was no other evidence that their results were because they were catching people who might later lose their eyesight. Rather, Pierce says, the complexity of these putative Mendelian diseases appears to have been underestimated.
“The mutations that we thought were disease-causing don’t exist 100% in isolation,” he says. Instead, people carry tens or hundreds of thousands of other genes, some of which may protect against retinal diseases, he added.
new treatment options
In theory, these protective gene variants could lead to ways to treat these retinal diseases.
“We’re going to need a lot of data to find these less effective variants,” Pearce said. “There are probably many of them, each contributing a little bit to protection from disease.”
Murray said there are good reasons to study the genes of patients with certain disorders. For example, finding genes associated with a disease can help researchers pinpoint the biology underlying the disease, even if it doesn’t necessarily cause the disease. In ovarian dysfunction, such patient-centered studies have shown that genes related to DNA repair are important for this disorder. However, such studies should still be viewed with a grain of salt.
“For the first time ever, we’re able to look at the detailed genetic sequences of hundreds of thousands of people,” she says. To learn more, these databases need to become more diverse, she added. At the same time, she added, biomedical researchers need better laboratory models of disease to test for specific genetic mutations and their effects.
“There are probably some [diseases] It’s really a one-to-one correspondence,” Pierce said. [that] Most of these obstacles will share this new complexity. ”
The new findings were published January 8 in the American Journal of Human Genetics.
Source link
