Overlapping genetic architecture between Parkinson disease and melanoma.

Umber Dube,Carlos Cruchaga,Oscar Harari,Albert A Davis,Laura Ibanez,Mark M Iles,Matthew H Law,Bruno A Benitez,John P Budde,Kevin M Brown

doi:10.1007/s00401-019-02110-z

Abstract

Epidemiologic studies have reported inconsistent results regarding an association between Parkinson disease (PD) and cutaneous melanoma (melanoma). Identifying shared genetic architecture between these diseases can support epidemiologic findings and identify common risk genes and biological pathways. Here, we apply polygenic, linkage disequilibrium-informed methods to the largest available case-control, genome-wide association study summary statistic data for melanoma and PD. We identify positive and significant genetic correlation (correlation: 0.17, 95% CI 0.10-0.24; P = 4.09 × 10-06) between melanoma and PD. We further demonstrate melanoma and PD-inferred gene expression to overlap across tissues (correlation: 0.14, 95% CI 0.06 to 0.22; P = 7.87 × 10-04) and highlight seven genes including PIEZO1, TRAPPC2L, and SOX6 as potential mediators of the genetic correlation between melanoma and PD. These findings demonstrate specific, shared genetic architecture between PD and melanoma that manifests at the level of gene expression.

Highlights

An association between idiopathic Parkinson disease (PD), neuropathologically characterized by the degeneration of pigmented dopaminergic neurons, and cutaneous melanoma, a cancer of pigment-producing melanocytes, was first reported in 1972[80]
To investigate whether the eGenes we identified as being independently associated with both melanoma and PD demonstrated differential expression in PD, we downloaded publicly available, normalized microarray gene expression data derived from substantia nigra brain tissues donated by individuals with and without PD
We further investigated the genetic correlation between melanoma and the meta-analyzed PD dataset by stratifying it to the level of minor allele frequency and chromosome annotations

Summary

Introduction

An association between idiopathic Parkinson disease (PD), neuropathologically characterized by the degeneration of pigmented dopaminergic neurons, and cutaneous melanoma (melanoma), a cancer of pigment-producing melanocytes, was first reported in 1972[80]. The majority of studies have found that individuals with PD appear to have a lower incidence of most cancers, with the exception of melanoma [21, 27, 36, 67, 68, 81, 91]. Both prospective and retrospective studies have found an increased risk of melanoma in PD that appears to be independent of L-DOPA treatment [5, 29, 42, 67, 91].

Methods

Results

Conclusion