Investigating shared genetic architecture between pigmentation genetics and Parkinson's Disease

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 Parkinsons patients, suggesting a potential genetic interplay between pigmentation pathways and Parkinsons 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.