{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:38:04Z","timestamp":1791859084461,"version":"4.3.4"},"reference-count":40,"publisher":"American Medical Association (AMA)","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Neurol"],"published-print":{"date-parts":[[2026,10,1]]},"abstract":"\n Importance<\/jats:title>\n \n Melanocortin 1 receptor (\n MC1R<\/jats:italic>\n ) is a key regulator of pigmentation and oxidative stress implicated in Parkinson disease (PD).\n MC1R<\/jats:italic>\n loss-of-function variants, defined by experimentally demonstrated reductions in\n MC1R<\/jats:italic>\n function, are carried by more than 60% of individuals of European descent.\n <\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n To determine whether\n MC1R<\/jats:italic>\n loss-of-function variants are associated with accelerated PD progression.\n <\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n \n 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\n MC1R<\/jats:italic>\n loss-of-function carrier status (505 carriers and 304 noncarriers) and classified as having sporadic PD (n\u2009=\u2009383) or monogenic PD (n\u2009=\u2009426) based on\n LRRK2<\/jats:italic>\n and\n GBA<\/jats:italic>\n 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.\n <\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n \n MC1R<\/jats:italic>\n loss-of-function carrier status.\n <\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n Rate of motor decline per Movement Disorder Society Unified Parkinson\u2019s 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.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n 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\n MC1R<\/jats:italic>\n loss-of-function carriers and 64.6 (10.5) for noncarriers.\n MC1R<\/jats:italic>\n loss-of-function carriers exhibited 30% faster motor decline (\u03b2, 0.57 points\/year; 95% CI, 0.16-0.98;\n P<\/jats:italic>\n \u2009=\u2009.006) than noncarriers. In the replication cohort,\n MC1R<\/jats:italic>\n loss-of-function carriers exhibited 50% faster motor decline than noncarriers (\u03b2, 1.37; 95% CI, 0.28-2.46;\n P<\/jats:italic>\n \u2009=\u2009.01). In a small prodromal cohort,\n MC1R<\/jats:italic>\n 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;\n P<\/jats:italic>\n \u2009=\u2009.009).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n \n The findings of this cohort study suggest that\n MC1R<\/jats:italic>\n 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.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamaneurol.2026.2998","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T15:00:35Z","timestamp":1788879635000},"page":"981","source":"Crossref","is-referenced-by-count":1,"title":["Common\n MC1R<\/i>\n Variants and Parkinson Disease Progression"],"prefix":"10.1001","volume":"83","author":[{"given":"Jackson G.","family":"Schumacher","sequence":"first","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston"},{"name":"Aligning Science Across Parkinson\u2019s Collaborative Research Network, Chevy Chase, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[{"name":"Aligning Science Across Parkinson\u2019s Collaborative Research Network, Chevy Chase, Maryland"},{"name":"Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes M.","family":"Dijkstra","sequence":"additional","affiliation":[{"name":"Department of Neurology, School of Medicine, Fujita Health University, Toyoake, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirohisa","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Neurology, School of Medicine, Fujita Health University, Toyoake, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, The Pennsylvania State University, University Park"},{"name":"Now with Department of Nutrition and Food Hygiene, School of Public Health, Institute of Nutrition, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Cortese","sequence":"additional","affiliation":[{"name":"Departments of Epidemiology and Nutrition, Harvard T. 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Chan School of Public Health, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric A.","family":"Macklin","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston"},{"name":"Aligning Science Across Parkinson\u2019s Collaborative Research Network, Chevy Chase, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Schwarzschild","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston"},{"name":"Aligning Science Across Parkinson\u2019s Collaborative Research Network, Chevy Chase, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiqun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston"},{"name":"Aligning Science Across 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