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Parkinson's Disease Progression Linked to Five Variants in Genome-Wide Survival Study

NEW YORK — Researchers have uncovered five genetic variants that influence the course of Parkinson's disease and developed a polygenic score to predict which patients will likely develop dementia related to the disease.

Nearly 1 million people in the US are estimated to have Parkinson's disease, which is marked by tremors, muscle stiffness, and balance issues. The course of the disease can be variable, and some patients also develop dementia, which greatly affects quality of life.

While genetic loci like GBA and APOE have been tied to cognitive decline in Parkinson's disease, researchers led by Harvard Medical School's Clemens Scherzer sought to find additional genetic variants that may influence disease progression. As they reported Thursday in Nature Genetics, they used a cohort of nearly 4,000 Parkinson's disease patients to conduct a genome-wide survival study, in which they uncovered a link between a locus in RIMS2 and disease progression as well as other loci with suggestive ties to disease course.

A polygenic hazard score encompassing these loci, meanwhile, could identify individuals with more aggressive Parkinson's disease, which could enable better clinical trials of treatments. "I hope that polygenic hazard scores will be useful for precision medicine trials," Scherzer said in an email. "Polygenic scores could help enrich clinical trials with a homogeneous target population. Ascertaining therapeutic efficacy using traditional trial designs for Parkinson's has not been successful, in part because these trials enrolled heterogeneous, noisy 'all comers.'"

The researchers analyzed the effects of 11.2 million variants on cognitive decline — as measured by a standard test of cognitive function — using 4,872 individuals with Parkinson's disease from 15 study cohorts. Following quality control steps, the researchers split the group into a discovery population of 2,650 individuals and a validation population of 1,171 individuals.

Through their genome-wide survival study, they identified and validated a signal in the RIMS2 locus that was associated with cognitive decline. RIMS2 encodes the regulating synaptic membrane exocytosis 2 protein, and knocking out its ortholog in mice leads to memory problems in the animals.

In their combined analysis, individuals with the lead variant in RIMS2 were more than four times as likely to develop dementia than those without the variant. The researchers likewise noted that cognitive function scores of carriers of the RIMS2 variant declined more quickly compared to noncarriers.

The analysis also uncovered loci in TMEM108 and WWOX that had suggestive ties to Parkinson's disease progression and confirmed established links between GBA and APOE and disease progression.

These disease progression-linked loci differ from those that have been associated with susceptibility to Parkinson's disease, suggesting the genetic drivers of disease development differ from those that influence progression, the researchers noted. "The baseline assumption equating susceptibility genetics and progression genetics may be overly simplistic," Scherzer said. "I believe over the next [few] years we will develop a much more granular and dynamic view of genetic architecture across the dimensions of time, cells, and traditional phenotypes."

Based on their findings, the researchers developed a polygenic risk score to predict which individuals with Parkinson's disease will develop dementia. They found that nearly 90 percent of patients with low scores survived for 10 years after disease onset without developing dementia.

The study's results highlight possible new therapeutic targets to transform fast-progressing disease into a slower-moving version and boost patients' quality of life, the researchers noted. At the same time, the polygenic scores could be used to identify people for clinical trials who may benefit the most from therapeutic intervention.

Scherzer added that his lab's ultimate goal is to be able to determine what drives disease in each patient and use personalized therapies to then prevent its progression.

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