By Jessica Kent, Health IT Analytics | August 22, 2019
Using machine learning and EHR data, researchers found that certain clinical diseases are far more prevalent in people with the FMR1 premutation.
By applying machine learning tools to EHR data, researchers at the University of Wisconsin-Madison (UW-Madison) and the Marshfield Clinic have discovered that carriers of the FMR1 premutation, a well-known genetic variant, are more likely to experience conditions such as depression, anxiety, mood disorders, sleep apnea, and a host of other conditions.
Scientists long believed that the FMR1 premutation, which occurs when there is an excessive number of trinucleotide repeats in the FMR1 gene, had no direct impact on those who carry it. Until recently, the only recognized effect on carriers of the gene was the risk of having offspring with fragile X syndrome, a rare form of developmental disability.
In the last several years, at least two conditions have been well documented in FMR1 carriers themselves: an age-dependent neurodegenerative disorder, and early menopause in female carriers.
To see if any other conditions are linked to this genetic variant, researchers mined the EHRs of nearly 20,000 people using machine learning techniques.
Researchers found that carriers of the gene experienced a much higher prevalence and severity of a wide range of disorders, such as mood disorders, stomach problems, and bone fractures.
“Our extensive phenotyping shows that premutation carriers experience a clinical profile that is significantly different from controls, and that is evident throughout adulthood,” researchers said.
These findings have important implications for the estimated one million people who carry premutations of the FMR1 gene. Generally, people are unaware they carry the altered gene unless a family member is found to have fragile X syndrome, which is very rare.
In addition to submitting their EHRs, study participants contributed their DNA through the Marshfield Clinic’s Personalized Medicine Research Project, which allowed researchers to identify 98 patients who carry the FMR1 premutation.
A primary goal of the study was to use EHRs to set up a double-blind methodology, where both clinicians and patients were blind to the genotype. By doing this, researchers were able to assess whether premutation carriers differed in their patterns of clinical diagnoses from those who don’t have the premutation.
“The research was especially challenging as not all carriers are affected and the specific conditions each may experience varies,” explained Marsha Mailick, researcher and professor at UW–Madison’s Waisman Center. “Yet the overall pattern revealed in the electronic health record was striking.”
Some clinical reports have suggested that premutation carriers were at greater risk for a wide range of health conditions, including autoimmune diseases, migraines, neuropathy, and infertility, all with varying frequencies and emerging at different stages of life.
These correlations are the stuff of biomedical controversy, as nearly all of the studies associating these conditions with the premutation were the result of a family member being diagnosed with fragile X. After diagnosis of fragile X, family members are offered genetic testing, which identifies individuals with the altered gene.
Awareness of that genetic premutation by clinicians and patients can confuse prevalence estimates of symptoms, researchers said. Often, clinicians and carriers blame carriers’ medical conditions on the stress of caring for a family member with fragile X syndrome.
“This is a controversy,” says Mailick. “There wasn’t unbiased data available before this study to inform the controversy. This study does so in a powerful way. The data validate the clinical experience.”
For men, clinical diagnoses frequently found in the EHRs of FMR1 carriers include depression, respiratory diseases, urinary incontinence, and half a dozen other conditions. The research team was surprised at the range and number of health effects they found in carriers.
“We see conditions nobody ever associated with the premutation,” said Arezoo Movaghar, a UW–Madison graduate student and lead author of the study.
The team expects that the approach used in this study could be applied to other genetic variants that are also believed to be innocuous but that may potentially have significant effects on health and wellness.