This longitudinal cohort study (PPMI, July 2010–January 2026; replication via SURE-PD2/3 and STEADY-PD III, June 2009–June 2019) examined whether MC1R loss-of-function (LoF) variants—carried by >60% of Europeans—are associated with faster motor decline in 809 PPMI participants with PD (505 carriers, 304 noncarriers) and 587 replication participants, plus 53 prodromal participants, over up to 12 years.
In sporadic PD (n=383), MC1R LoF carriers showed **30% faster motor decline** on MDS-UPDRS III OFF-state (β=0.57 points/year; 95% CI 0.16–0.98; P=.006); replication showed **50% faster decline** (β=1.37; 95% CI 0.28–2.46; P=.01). Prodromal MC1R LoF carriers had a **>4-fold higher risk** of phenoconversion to PD (SHR 4.75; 95% CI 1.48–15.27; P=.009). No significant differences were seen in non-motor outcomes, DAT-SPECT, or CSF biomarkers.
- The prodromal phenoconversion analysis was very small (n=53; 34 carriers, 19 noncarriers), limiting precision. - The study population is predominantly of European descent, so findings may not generalize to other ancestries. - Survivorship bias in the replication cohort (faster progressors initiated treatment earlier and dropped out sooner) may underestimate true progression rates.
MC1R LoF genotyping could help identify a large, common genetic subgroup of PD patients (>60% of Europeans) with faster motor progression, supporting its use in **prognostic counseling and clinical trial enrichment**. Clinicians should be aware that standard non-motor and biomarker measures may not differentiate these patients.
