Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease

Neurobiol Aging. 2016 Dec;48:222.e1-222.e7. doi: 10.1016/j.neurobiolaging.2016.07.013. Epub 2016 Jul 28.


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.

Keywords: Cutaneous malignant melanoma; Parkinson's; Pigmentation; Shared genetic background; Tyrosinase.

MeSH terms

  • Cohort Studies
  • DCC Receptor
  • Dopamine / biosynthesis
  • Genetic Association Studies*
  • Genetic Predisposition to Disease / genetics*
  • Genetic Variation / genetics*
  • Genotype
  • Humans
  • Melanins / biosynthesis
  • Melanoma / genetics*
  • Membrane Glycoproteins / genetics
  • Monophenol Monooxygenase
  • Oxidoreductases / genetics
  • Parkinson Disease / genetics*
  • Pigmentation / genetics
  • Receptor, ErbB-4 / genetics
  • Receptors, Cell Surface / genetics
  • Risk
  • Skin Neoplasms / genetics*
  • Tumor Suppressor Proteins / genetics
  • Ubiquitin Thiolesterase / genetics


  • BAP1 protein, human
  • DCC Receptor
  • DCC protein, human
  • Melanins
  • Membrane Glycoproteins
  • Receptors, Cell Surface
  • Tumor Suppressor Proteins
  • neuromelanin
  • Oxidoreductases
  • TYRP1 protein, human
  • Monophenol Monooxygenase
  • ERBB4 protein, human
  • Receptor, ErbB-4
  • Ubiquitin Thiolesterase
  • Dopamine