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

S. J. Lubbe, V. Escott-Price, A. Brice, T. Gasser, A. M. Pittman, J. Bras, J. Hardy, P. Heutink, N. M. Wood, A. B. Singleton, D. G. Grosset, C. B. Carroll, M. H. Law, F. Demenais, M. M. Iles, D. T. Bishop, J. Newton-Bishop, N. M. Williams, H. R. Morris

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)222.e1-222.e7
JournalNeurobiology of Aging
Volume48
DOIs
Publication statusPublished - 1 Dec 2016

Cite this

Lubbe, S. J., Escott-Price, V., Brice, A., Gasser, T., Pittman, A. M., Bras, J., ... Morris, H. R. (2016). Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease. Neurobiology of Aging, 48, 222.e1-222.e7. https://doi.org/10.1016/j.neurobiolaging.2016.07.013
Lubbe, S. J. ; Escott-Price, V. ; Brice, A. ; Gasser, T. ; Pittman, A. M. ; Bras, J. ; Hardy, J. ; Heutink, P. ; Wood, N. M. ; Singleton, A. B. ; Grosset, D. G. ; Carroll, C. B. ; Law, M. H. ; Demenais, F. ; Iles, M. M. ; Bishop, D. T. ; Newton-Bishop, J. ; Williams, N. M. ; Morris, H. R. / Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease. In: Neurobiology of Aging. 2016 ; Vol. 48. pp. 222.e1-222.e7.
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title = "Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease",
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.",
keywords = "Cutaneous malignant melanoma, Parkinson's, Pigmentation, Shared genetic background, Tyrosinase",
author = "Lubbe, {S. J.} and V. Escott-Price and A. Brice and T. Gasser and Pittman, {A. M.} and J. Bras and J. Hardy and P. Heutink and Wood, {N. M.} and Singleton, {A. B.} and Grosset, {D. G.} and Carroll, {C. B.} and Law, {M. H.} and F. Demenais and Iles, {M. M.} and Bishop, {D. T.} and J. Newton-Bishop and Williams, {N. M.} and Morris, {H. R.}",
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Lubbe, SJ, Escott-Price, V, Brice, A, Gasser, T, Pittman, AM, Bras, J, Hardy, J, Heutink, P, Wood, NM, Singleton, AB, Grosset, DG, Carroll, CB, Law, MH, Demenais, F, Iles, MM, Bishop, DT, Newton-Bishop, J, Williams, NM & Morris, HR 2016, 'Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease' Neurobiology of Aging, vol. 48, pp. 222.e1-222.e7. https://doi.org/10.1016/j.neurobiolaging.2016.07.013

Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease. / Lubbe, S. J.; Escott-Price, V.; Brice, A.; Gasser, T.; Pittman, A. M.; Bras, J.; Hardy, J.; Heutink, P.; Wood, N. M.; Singleton, A. B.; Grosset, D. G.; Carroll, C. B.; Law, M. H.; Demenais, F.; Iles, M. M.; Bishop, D. T.; Newton-Bishop, J.; Williams, N. M.; Morris, H. R.

In: Neurobiology of Aging, Vol. 48, 01.12.2016, p. 222.e1-222.e7.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease

AU - Lubbe, S. J.

AU - Escott-Price, V.

AU - Brice, A.

AU - Gasser, T.

AU - Pittman, A. M.

AU - Bras, J.

AU - Hardy, J.

AU - Heutink, P.

AU - Wood, N. M.

AU - Singleton, A. B.

AU - Grosset, D. G.

AU - Carroll, C. B.

AU - Law, M. H.

AU - Demenais, F.

AU - Iles, M. M.

AU - Bishop, D. T.

AU - Newton-Bishop, J.

AU - Williams, N. M.

AU - Morris, H. R.

PY - 2016/12/1

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N2 - 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.

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KW - Cutaneous malignant melanoma

KW - Parkinson's

KW - Pigmentation

KW - Shared genetic background

KW - Tyrosinase

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Lubbe SJ, Escott-Price V, Brice A, Gasser T, Pittman AM, Bras J et al. Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease. Neurobiology of Aging. 2016 Dec 1;48:222.e1-222.e7. https://doi.org/10.1016/j.neurobiolaging.2016.07.013