Study Uncovers Genetic Variants Linked to Disease Progression

Scientists have identified genetic variations that are associated with different rates of disease progression in people with Parkinson’s disease.

The findings suggest that the genetic changes that affect disease progression are distinct from those that impact whether a person will get Parkinson’s at all, and that disease initiation and progression may be caused by distinct biological processes.

The study, “Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease,” was published in Nature Genetics.

In recent decades, genetic studies have made substantial strides in identifying genetic variations associated with Parkinson’s susceptibility (whether a person will develop the disease). However, little is understood about the genetic factors that influence disease progression.

“The patients who come to see me in the clinic are concerned about their future, rather than their past risk factors,” Clemens Scherzer, MD, co-author of the new study, said in a press release. “They want to know how they will be doing in the future and need medications designed to stop the disease from rapidly progressing.”

“This is the central question in our study: Which genes determine whether a patient will have an aggressive or benign course, and which variants influence who will develop dementia?” added Scherzer, director of the Center for Advanced Parkinson Research at Brigham and Women’s Hospital.

In the study, researchers analyzed data from 3,821 people with Parkinson’s in North America and Europe. Between 1986 and 2017, these patients collectively underwent 31,578 study visits, where their cognitive abilities were assessed. They were also tested to determine whether they had Parkinson’s disease dementia.

Using statistical models, the researchers looked for connections between variations in each person’s genetic code, and their risk of worsening cognition. In total, the team analyzed more than 11 million different genetic variations.

The team’s analysis revealed that a variation in the gene RIMS2, called rs182987047, was significantly associated with a worse prognosis — individuals with this genetic variation were nearly five times more likely to develop Parkinson’s dementia, and were also significantly more likely to have more extensive cognitive decline.

The analysis also revealed variations in two other genes — TMEM108 and WWOX — as potentially connected to cognitive decline, though the results were less clear-cut. These genes “can now be prioritized for further evaluation,” the researchers wrote.

The team also conducted analyses to test whether variations in genes that have previously been implicated in the prognosis of Parkinson’s, namely GBA and APOE, were similarly implicated in their analysis. Consistent with prior data, patients with high-risk variants in GBA were about two times more likely to have dementia, while those with high-risk variants in APOE were nearly 1.5 times more likely to have dementia.

Further analyses showed that statistical models using combinations of these different risk variants could effectively predict dementia.

In other analyses, the researchers compared the genetic variations associated with disease prognosis, to those associated with susceptibility. The comparison revealed little overlap.

“Progression variants were not associated with susceptibility,” the researchers wrote. “Susceptibility variants and scores did not appear to predict progression. This is consistent with the hypothesis that disease initiation and progression may, in part, be governed by diverging genetics and mechanism.”

The team added that the results “suggest a new paradigm for drug development. Disease-modifying drugs that target the genetic drivers of disease progression could potentially turn fast progressors into slow progressors and substantially improve quality of life.”

Being able to identify patients whose disease is more likely to progress faster could be useful in clinical trials, the researchers noted, since it is generally easier to see the effect of treatment in people who have more severe disease.