MC1R loss-of-function is associated with accelerated Parkinson's disease motor decline

Sep 29, 2026

Melanocortin 1 receptor (MC1R) loss-of-function variants increase Parkinson’s disease (PD) risk, but their role in PD progression remained unclear. Using 802 participants from the Parkinson's Progression Markers Initiative (PPMI), the study tested associations between MC1R variants and motor decline as well as phenoconversion, incorporating 13 years of clinical assessments and 5 years of dopamine transporter imaging. In 45 prodromal participants, time-to-event survival analysis evaluated phenoconversion risk.

LanguageEnglish

CategoryHealthcare

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Pages22

Reading Time55 min

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Abstract

Methods

Results

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Introduction

medRxiv preprint doi: [https://doi.org/10.64898/2025.12.26.25343003](https://doi.org/10.64898/2025.12.26.25343003); this version posted December 29, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . MC1R loss-of-function is associated with accelerated Parkinson’s disease motor decline Jackson G. Schumacher1,2,*, Xinyuan Zhang3,*, Jian Wang2,4, Michael A. Schwarzschild1,2, Marianna Cortese5,6, Xiqun Chen1,2,\# 1 Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA 2 Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA 3 Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA 4 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. 5 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA 6 Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA * Denotes equal contribution \# Denotes corresponding author Correspondence to: Xiqun Chen, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA Email: [xchen17@mgh.harvard.edu](xchen17@mgh.harvard.edu) Author ORCIDs: Jackson G. Schumacher 0009-0000-4227-4710, Xinyuan Zhang 0000-0002-2974- 8392, Jian Wang 0000-0001-7104-0673, Michael A. Schwarzschild 0000-0001-6019-8280, Marianna Cortese 0000-0002-3665-2006, Xiqun Chen 0000-0001-8582-8891 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 mixedeffects 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. NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: [https://doi.org/10.64898/2025.12.26.25343003](https://doi.org/10.64898/2025.12.26.25343003); this version posted December 29, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . 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 anon-statistically significant 24% faster rate of non-motor declin

FAQs

What was the primary aim of the study involving MC1R loss-of-function variants?

To determine whether MC1R loss-of-function variants are associated with PD progression and phenoconversion, using PPMI cohort data.

How was PD progression evaluated in the 802 PPMI participants?

Motor, non-motor, and cognitive changes were assessed over 13 years, alongside 5 years of dopamine transporter imaging, analyzed with linear mixed-effects models adjusted for confounders.

What did the results show about motor decline in MC1R PD participants?

Participants with MC1R PD had a 23% faster motor decline than sporadic PD participants, with the R160W variant showing the strongest association.

Sep 29, 2026

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