Abstract
BACKGROUND: Melanocortin 1 receptor (MC1R) is a key regulator of pigmentation. Previous studies have linked MC1R loss-of-function variants to increased risk for Parkinson's disease (PD); however, whether they are associated with PD progression remains unknown. Using data from the Parkinson's Progression Markers Initiative (PPMI) cohort, we aimed to test whether MC1R loss-of-function variants, especially those previously associated with an increased risk of PD, are associated with PD progression and phenoconversion. METHODS: We analyzed PD progression in 802 PPMI participants (n=185 sporadic PD, 220 MC1R PD (139 heterozygotes, 64 compound heterozygotes, 17 homozygotes), 84 LRRK2 PD, 43 GBA PD, 187 MC1R + LRRK2 PD, and 83 MC1R + GBA PD) with 13 years of motor, non-motor, and cognitive assessments alongside 5 years of dopamine transporter imaging using linear mixed-effects models adjusted for potential confounders. Additionally, we explored risk of phenoconversion in 45 prodromal participants (n=16 sporadic, 29 MC1R) using time-to-event survival analysis. RESULTS: Participants with MC1R PD exhibited a 23% faster rate of motor decline (p=0.035) than participants with sporadic PD. The R160W variant (n=43 carriers), previously associated with an increased risk of PD, exhibited the strongest association with motor decline (p=0.023). High penetrance variants exhibited a stronger association with motor decline than low penetrance variants. Further, stratifying by genotype revealed that homozygotes exhibited a stronger association with motor decline than heterozygotes. Participants with MC1R PD also exhibited a non-statistically significant 24% faster rate of non-motor decline (p=0.070) than participants with sporadic PD. The rate of change in MoCA and DAT-SPECT SBR was minimal in all groups. Although not statistically significant, prodromal participants with MC1R loss-of-function variants exhibited a 3.81-fold increased risk of phenoconversion compared to noncarriers (p=0.059). INTERPRETATION: MC1R loss-of-function variants are associated with accelerated PD motor decline in the PPMI cohort. Together with previous biological findings from our group and others, these results highlight the potential role of MC1R in PD prognosis, warranting further validation and investigation into whether MC1R-targeted interventions may modify PD progression.