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.
authors.affiliation: Department of Clinical Neuroscience, UCL Institute of Neurology, London, United Kingdom.
authors.forename: S J
authors.initials: SJ
authors.lastname: Lubbe
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: V
authors.initials: V
authors.lastname: Escott-Price
authors.affiliation: INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Epinière, ICM, France.
authors.forename: A
authors.initials: A
authors.lastname: Brice
authors.affiliation: Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, and DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Gasser
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
authors.forename: A M
authors.initials: AM
authors.lastname: Pittman
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
authors.forename: J
authors.initials: J
authors.lastname: Bras
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
authors.forename: J
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Department of Clinical Genetics, Section of Medical Genomics, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Heutink
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom; UCL Genetics Institute, London, United Kingdom.
authors.forename: N M
authors.initials: NM
authors.lastname: Wood
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Singleton
authors.affiliation: Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, United Kingdom.
authors.forename: D G
authors.initials: DG
authors.lastname: Grosset
authors.affiliation: Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, United Kingdom.
authors.forename: C B
authors.initials: CB
authors.lastname: Carroll
authors.affiliation: Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: M H
authors.initials: MH
authors.lastname: Law
authors.affiliation: INSERM, UMR 946, Genetic Variation and Human Diseases Unit, Paris, France; Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Demenais
authors.affiliation: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, Leeds, United Kingdom.
authors.forename: M M
authors.initials: MM
authors.lastname: Iles
authors.affiliation: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, Leeds, United Kingdom.
authors.forename: D T
authors.initials: DT
authors.lastname: Bishop
authors.affiliation: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, Leeds, United Kingdom.
authors.forename: J
authors.initials: J
authors.lastname: Newton-Bishop
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: N M
authors.initials: NM
authors.lastname: Williams
authors.affiliation: Department of Clinical Neuroscience, UCL Institute of Neurology, London, United Kingdom. Electronic address: h.morris@ucl.ac.uk.
authors.forename: H R
authors.initials: HR
authors.lastname: Morris
mesh_terms: D015331:Cohort Studies; D000075389:DCC Receptor; D004298:Dopamine / Q000096:biosynthesis; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008543:Melanins / Q000096:biosynthesis; D008545:Melanoma / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics; D014442:Monophenol Monooxygenase; D010088:Oxidoreductases / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics*; D010858:Pigmentation / Q000235:genetics; D066247:Receptor, ErbB-4 / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D012306:Risk; D012878:Skin Neoplasms / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics
chemical_list: C400134:BAP1 protein, human; D000075389:DCC Receptor; C501909:DCC protein, human; D008543:Melanins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C014121:neuromelanin; D010088:Oxidoreductases; C489799:TYRP1 protein, human; D014442:Monophenol Monooxygenase; C587689:ERBB4 protein, human; D066247:Receptor, ErbB-4; D043222:Ubiquitin Thiolesterase; D004298:Dopamine
keywords: Cutaneous malignant melanoma; Parkinson's; Pigmentation; Shared genetic background; Tyrosinase