Roughly 1 million Americans carry a gene mutation that increases the risk of having children with a particular developmental disability, and now a UW-Madison study says people with the flawed gene also face a higher risk of mental health disorders, infertility, incontinence, sleep apnea, bone fractures and other conditions.
In a study that illustrates the growing potential of computers and genetic testing to reveal new disease risks, UW researchers teamed up with the Marshfield Clinic to probe electronic medical records and DNA samples anonymously from 20,000 patients.
Using “machine learning,” a form of artificial intelligence, the researchers discovered that people who carry a gene mutation associated with having children with fragile X syndrome, a rare but serious developmental disability, have a higher prevalence and severity of a variety of medical conditions.
“This is, in the future, much more likely to be the kind of research that can be carried out,” said Marsha Mailick, a researcher at UW-Madison’s Waisman Center and senior author of the study, published Wednesday in the journal Science Advances. “Eventually we’re all going to know about our vulnerabilities.”
For years, an abnormality known as a “premutation” in a gene called FMR1 was known only to increase the chances of having a child with fragile X, not to affect the people who carry it.
But in recent years, other researchers showed that carriers have higher risks of a neurodegenerative disorder similar to Parkinson’s disease, mostly in men, and, in women, early menopause.
Additional studies suggested higher risks of other conditions. But critics said most of the studies involved people who learned they carried the flawed gene after a family member was diagnosed with fragile X. Knowing they had the gene may have made it more likely they were diagnosed with medical conditions, something known as ascertainment bias.
To avoid such bias, Mailick, graduate student Arezoo Movaghar and their colleagues at UW-Madison turned to Marshfield Clinic’s Personalized Medicine Research Project, launched in 2002.
The project has DNA samples and electronic medical records dating back 40 years from 20,000 participants.
By mining the data, the researchers found 98 people with FMR1 premutations who didn’t know they had the flawed gene; neither did their doctors. Comparing those people to 1,000 similar people without the gene mutation, the researchers identified higher risks for several conditions among the carriers.
For women, the conditions include agoraphobia, social phobia, panic disorders, infertility, menstrual disorders, and falls and fractures. For men, the conditions include depression, respiratory diseases and urinary incontinence.
“Carriers of the premutation have a higher burden of disease than individuals who are normal,” Mailick said. “And it’s for specific characteristics, many of which have been observed in the clinical literature but have been the subject of controversy or skepticism because of all the ascertainment biases.”
The researchers identified new risks among the carriers, too, including adverse reactions to drugs such as antibiotics, opioid painkillers and blood pressure pills.
With companies such as Ancestry and 23andMe making DNA tests directly available to consumers, people might want to get tested for the FMR1 abnormality.
But it’s a complex situation, Mailick said. The mutation involves repeats of a sequence of DNA molecules. The more repeats, the more likely the person will have a child with fragile X or some of the medical conditions — but not always.
Knowing about the abnormality could help people prevent bone fractures, treat anxiety or avoid drug reactions, Mailick said. But some of the other conditions are less preventable, so the knowledge can have downsides.
“I would understand why they would want to get tested,” she said. “But this is a complicated clinical, ethical, genetic path to go down.”
Mailick is studying whether people with an usually low number of the repeats might also face increased medical risks.