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Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease
S J Lubbe1, V Escott-Price2, A Brice3
1Department of Clinical Neuroscience, UCL Institute of Neurology, London, United Kingdom.
Abstract:
A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis.
Insights
Genetic links between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) were explored. Researchers found no significant association with CMM risk genes, but identified a potential link with the TYR gene in Parkinson's disease susceptibility.
Area of Science:
- Genetics
- Neuroscience
- Oncology
Background:
- A potential shared genetic basis between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been hypothesized.
- Investigating rare variants in CMM-associated genes may elucidate PD pathogenesis.
Purpose of the Study:
- To assess the contribution of rare variants in 29 CMM risk genes to Parkinson's disease (PD) risk.
- To identify potential genetic overlaps between CMM and PD.
Main Methods:
- Analysis of rare variation in 29 CMM risk genes using genotype data from 6875 PD cases and 6065 controls.
- Replication analysis using whole-exome sequencing data from an independent cohort of 1255 PD cases and 473 controls.
Main Results:
- No statistically significant enrichment of rare variants in CMM genes was found in PD cases compared to controls.
- Non-significant trends for altered carrier frequencies were observed for BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53.
- The TYR p.V275F variant was more frequent in PD cases across three cohorts, suggesting a potential role in dopamine metabolism and PD susceptibility.
Conclusions:
- The study did not find evidence supporting a significant role of rare variants in CMM risk genes in PD pathogenesis.
- The TYR gene warrants further investigation for its potential role in the dopamine-biosynthetic pathway and susceptibility to Parkinson's disease.
- Larger cohort studies are necessary to confirm the association between TYR variants and PD risk.
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