PT - JOURNAL ARTICLE AU - Abbatangelo, Cristina L AU - Newton, Brendan AU - Wendt, Frank R AU - Parra, Esteban J TI - Investigating shared genetic architecture between pigmentation genetics and Parkinson’s Disease AID - 10.1101/2025.04.30.25326753 DP - 2025 Jan 01 TA - medRxiv PG - 2025.04.30.25326753 4099 - http://medrxiv.org/content/early/2025/05/03/2025.04.30.25326753.short 4100 - http://medrxiv.org/content/early/2025/05/03/2025.04.30.25326753.full AB - Peripheral melanin and neuromelanin share a common biosynthetic initiation. Peripheral melanin (eumelanin and pheomelanin) is cyclically produced and degraded, while neuromelanin accumulates in dopaminergic neurons over time. Neurons containing excess neuromelanin (e.g., substantia nigra) exhibit increased degeneration in Parkinson’s patients, suggesting a potential genetic interplay between pigmentation pathways and Parkinson’s Disease (PD). We used linkage disequilibrium score regression (LDSC), polygenic risk score (PRS) analysis, Mendelian Randomization (MR), and multi-trait association analysis to examine shared genetic architecture between PD and nine pigmentation-related traits (basal cell carcinoma, brown hair, melanoma, nevi, red hair, skin colour, tanning response, vitiligo, vitamin D levels). PRS analyses identified limited shared genetic variation (max 0.15% for nevi), and MR analyses did not provide evidence of a causal relationship. Together, the ten-trait and pairwise multi-trait analyses identified 48 SNPs with suggestive pleiotropy, 31 of which were protein-coding and could be mapped to 22 different genes. Overall, while some genetic overlap exists, no definitive correlative or causal relationships were established. These results contribute to the broader understanding of the differing roles of melanin and neuromelanin, as well as potential implications in neurodegenerative diseases.Competing Interest StatementFinancial Disclosure/Conflict of Interest: FRW is an employee and stockholder of Regeneron Pharmaceuticals.Funding StatementEJP received funding from the Natural Sciences and Engineering Research Council of Canada (NSERC Discovery Grant).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:All summary statistics used are publicly available, and were accessed from GWAS Atlas (https://atlas.ctglab.nl/) and GWAS Catalog (https://www.ebi.ac.uk/gwas/).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesScripts for each step of the analysis can be found on CLA's GitHub (https://github.com/cl-abba/Shared-Genetic-Architecture). All data produced in the present study are available upon reasonable request to the authors. https://github.com/cl-abba/Shared-Genetic-Architecture