Abstract
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 Statement
Financial Disclosure/Conflict of Interest: FRW is an employee and stockholder of Regeneron Pharmaceuticals.
Funding Statement
EJP received funding from the Natural Sciences and Engineering Research Council of Canada (NSERC Discovery Grant).
Author Declarations
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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/).
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Data Availability
Scripts 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
