Common Genetic Marker Predicts Faster Motor Decline in Parkinson’s Disease

Clinicians have few scalable tools to stratify patients by progression risk early in the disease course. Genetic markers that help identify individuals more likely to worsen quickly could improve trial enrollment and follow-up strategies. A new study shows that common genetic variants are associated with faster motor decline in Parkinson’s disease.

Researchers at the Mass General Brigham Neuroscience Institute (Boston, MA, USA) identified variants in the melanocortin 1 receptor (MC1R) gene as markers of faster motor decline in Parkinson’s disease (PD). MC1R regulates hair and skin pigmentation and also influences cellular responses to oxidative stress in the dopamine-producing neurons affected by PD. Variants that partially reduce MC1R function are common, occurring in more than 60% of patients with PD of European descent.

Using longitudinal data from the international Parkinson’s Progression Markers Initiative (PPMI), with up to 12 years of follow-up, the primary analysis included 383 participants with sporadic PD and compared carriers of MC1R loss-of-function variants with noncarriers. Among patients without a known PD-related mutation, carriers experienced approximately 30% faster motor decline. The association showed an allele dose-response pattern, with two copies of a loss-of-function variant linked to 63% faster decline compared with 27% for one copy.

Findings were replicated in a pooled clinical trial–based cohort of 587 patients, in which carriers had approximately 50% faster motor decline. In a smaller prodromal group not yet clinically diagnosed, carriers were more than four times as likely to develop PD. Together, these data suggest MC1R status may help identify a large subgroup of patients at risk for rapid progression.

The study was published in JAMA Neurology on September 8, 2026. The authors note that these clinical observations, alongside prior preclinical evidence that MC1R agonists can be neuroprotective, support investigating MC1R-based therapeutic strategies in Parkinson’s disease. The work also builds on prior links between MC1R biology, pigmentation, and Parkinson’s disease.

"MC1R variants were common among individuals in our study and associated with substantially faster disease progression," said Xiqun Chen, M.D., Ph.D., senior author and investigator with the Mass General Brigham Neuroscience Institute. "This finding suggests that a simple genetic test could help improve prognostic assessment and clinical trial design for a large proportion of patients. Importantly, MC1R is a druggable target, and drugs that activate this pathway have shown protective effects in preclinical models of PD."

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Mass General Brigham Neuroscience Institute