Hirohisa Watanabe

IMPORTANCE: Melanocortin 1 receptor (MC1R) is a key regulator of pigmentation and oxidative stress implicated in Parkinson disease (PD). MC1R loss-of-function variants, defined by experimentally demonstrated reductions in MC1R function, are carried by more than 60% of individuals of European descent. OBJECTIVE: To determine whether MC1R loss-of-function variants are associated with accelerated PD progression. DESIGN, SETTING, AND PARTICIPANTS: This longitudinal cohort study used data from July 2010 to January 2026 in the Parkinson Progression Markers Initiative (PPMI) cohort and June 2009 to June 2019 in a replication cohort using 3 US-based multicenter randomized clinical trials (SURE-PD phase 2, SURE-PD3, and STEADY-PD III), with up to 12 years of follow-up. Analysis was performed in May 2026. Of 926 PPMI participants with PD and available genomewide sequencing data, 66 without dopamine deficiency and 51 with pathogenic variants in known PD-associated genes were excluded. The remaining 809 participants were stratified by MC1R loss-of-function carrier status (505 carriers and 304 noncarriers) and classified as having sporadic PD (n = 383) or monogenic PD (n = 426) based on LRRK2 and GBA carrier status. The replication cohort included 587 participants with PD (410 carriers and 177 noncarriers). An additional 53 PPMI participants with prodromal PD (34 carriers and 19 noncarriers) were assessed. EXPOSURES: MC1R loss-of-function carrier status. MAIN OUTCOMES AND MEASURES: Rate of motor decline per Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III score, assessed via linear mixed-effects models adjusted for age at onset, sex, race, baseline score, and levodopa equivalent daily dose. Phenoconversion risk, assessed via Fine-Gray subdistribution hazards model. RESULTS: Among 383 participants with sporadic PD, 130 were female, 253 were male, and the mean (SD) age at onset was 61.3 (9.9) years for MC1R loss-of-function carriers and 64.6 (10.5) for noncarriers. MC1R loss-of-function carriers exhibited 30% faster motor decline (β, 0.57 points/year; 95% CI, 0.16-0.98; P = .006) than noncarriers. In the replication cohort, MC1R loss-of-function carriers exhibited 50% faster motor decline than noncarriers (β, 1.37; 95% CI, 0.28-2.46; P = .01). In a small prodromal cohort, MC1R loss-of-function carriers showed a more than 4-fold increased risk of phenoconversion to PD (subdistribution hazard ratio, 4.75; 95% CI, 1.48-15.27; P = .009). CONCLUSIONS AND RELEVANCE: The findings of this cohort study suggest that MC1R loss-of-function variants may define a large, readily identifiable genetic subgroup with accelerated progression, highlighting their utility for potential prognostic stratification and clinical trial enrichment in patients of European descent with PD.