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Overlapping genetic architecture between Parkinson disease and melanoma

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A Correction to this article was published on 14 March 2020

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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.

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  • 14 March 2020

    The original version of this article unfortunately contained a mistake. Supplementary Tables��3 and 4 are not available with the rest of the supplementary material available online.

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Acknowledgements

We thank Dr. Susan Searles Nielsen for helpful comments on a previous version of this manuscript. This work was supported by grants from the National Institutes of Health (R01AG044546, P01AG003991, RF1AG053303, R01AG058501, U01AG058922, K01AG046374, K08NS101118 and R01HL119813), the Alzheimer Association (NIRG-11-200110, BAND-14-338165, AARG-16-441560 and BFG-15-362540). This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders and the Departments of Neurology and Psychiatry at Washington University School of Medicine. We acknowledge the support of all participants, investigators, and researchers from the Melanoma-Meta-analysis Consortium; complete acknowledgements for this meta-analysis can be found in the supplemental data of Law et al., 2015 [45]. We thank the International Genomics of Alzheimer Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i-Select chips was funded by the French National Foundation on Alzheimer disease and related disorders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Université de Lille 2 and the Lille University Hospital. GERAD/PERADES was supported by the Medical Research Council (Grant no. 503480), Alzheimer Research UK (Grant no. 503176), the Wellcome Trust (Grant no. 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) Grant no. 01GI0102, 01GI0711, 01GI0420. CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01–AG–12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer Association grant ADGC–10–196728. We acknowledge the PDGENE investigators of the original study [64] and Drs Lill and Bertram from PDGene [50] for sharing vbnthe genetics data used for this study. We would like to thank the research participants and employees of 23andMe for making this work possible. Consortium Investigators: List of members of the Melanoma Meta-analysis Consortium: Law MH, Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Bishop DT, Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK; Lee JE, Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Brossard M, INSERM, UMR 946, Genetic Variation and Human Diseases Unit, Paris, France, Institut Universitaire d’Hématologie, Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Martin NG, Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Moses EK, Centre for Genetic Origins of Health and Disease, Faculty of Medicine, Dentistry and Health Sciences, University of Western Australia, Perth, Western Australia, Australia; Song F, Department of Epidemiology and Biostatistics, Key Laboratory of Cancer Prevention and Therapy, Tianjin, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Barrett JH, Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK; Kumar R, Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany; Easton DF, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Pharoah PD, Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK; Swerdlow AJ, Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK, Division of Breast Cancer Research, The Institute of Cancer Research, London, UK; Kypreou KP, Department of Dermatology, University of Athens School of Medicine, Andreas Sygros Hospital, Athens, Greece; Taylor JC, Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK; Harland M, Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK; Randerson-Moor J, Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK; Akslen LA, Centre for Cancer Biomarkers (CCBIO), Department of Clinical Medicine, University of Bergen, Bergen, Norway, Department of Pathology, Haukeland University Hospital, Bergen, Norway; Andresen PA, Department of Pathology, Molecular Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Avril MF, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Service de Dermatologie, Université Paris Descartes, Paris, France; Azizi E, Department of Dermatology, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv, Israel, Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Scarrà GB, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy, Laboratory of Genetics of Rare Cancers, Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria (IRCCS AOU) San Martino l’Istituto Scientifico Tumori Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; Brown KM, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA; Dȩbniak T, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland; Duffy DL, Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Elder DE, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA; Fang S, Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Friedman E, Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Galan P, Université Paris 13, Equipe de Recherche en Epidémiologie Nutritionnelle (EREN), Centre de Recherche en Epidémiologie et Statistiques, INSERM U1153, Institut National de la Recherche Agronomique (INRA) U1125, Conservatoire National des Arts et Métiers, Communauté d’Université Sorbonne Paris Cité, Bobigny, France; Ghiorzo P, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy, Laboratory of Genetics of Rare Cancers, Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria (IRCCS AOU) San Martino l’Istituto Scientifico Tumori Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; Gillanders EM, Inherited Disease Research Branch, National Human Genome Research Institute, US National Institutes of Health, Baltimore, Maryland, USA; Goldstein AM, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA; Gruis NA, Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands; Hansson J, Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Helsing P, Department of Dermatology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Hočevar M, Department of Surgical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia; Höiom V, Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Ingvar C, Department of Surgery, Clinical Sciences, Lund University, Lund, Sweden; Kanetsky PA, Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA; Chen WV, Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA; GenoMEL Consortium; Essen-Heidelberg Investigators; SDH Study Group; Q-MEGA and QTWIN Investigators; AMFS Investigators; ATHENS Melanoma Study Group, Landi MT, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA; Lang J, Department of Medical Genetics, University of Glasgow, Glasgow, UK; Lathrop GM, McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada; Lubiński J, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland; Mackie RM, Department of Medical Genetics, University of Glasgow, Glasgow, UK, Department of Public Health, University of Glasgow, Glasgow, UK; Mann GJ, Centre for Cancer Research, University of Sydney at Westmead, Millennium Institute for Medical Research and Melanoma Institute Australia, Sydney, New South Wales, Australia; Molven A, Department of Pathology, Haukeland University Hospital, Bergen, Norway, Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway; Montgomery GW, Molecular Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Novaković S, Department of Molecular Diagnostics, Institute of Oncology Ljubljana, Ljubljana, Slovenia; Olsson H, Department of Oncology/Pathology, Clinical Sciences, Lund University, Lund, Sweden, Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden; Puig S, Melanoma Unit, Departments of Dermatology, Biochemistry and Molecular Genetics, Hospital Clinic, Institut d’Investigacions Biomèdica August Pi Suñe, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain; Puig-Butille JA, Melanoma Unit, Departments of Dermatology, Biochemistry and Molecular Genetics, Hospital Clinic, Institut d’Investigacions Biomèdica August Pi Suñe, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain; Wu W, Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana, USA, Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana, USA; Qureshi AA, Department of Dermatology, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA; Radford-Smith GL, Inflammatory Bowel Diseases, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia, Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia, University of Queensland School of Medicine, Herston Campus, Brisbane, Queensland, Australia; van der Stoep N, Department of Clinical Genetics, Center of Human and Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands; van Doorn R, Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands; Whiteman DC, Cancer Control Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Craig JE, Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia; Schadendorf D, Department of Dermatology, University Hospital Essen, Essen, Germany, German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany; Simms LA, Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana, USA; Burdon KP, Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia; Nyholt DR, Molecular Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia; Pooley KA, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Orr N, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK; Stratigos AJ, Department of Dermatology, University of Athens School of Medicine, Andreas Sygros Hospital, Athens, Greece; Cust AE, Cancer Epidemiology and Services Research, Sydney School of Public Health, University of Sydney, Sydney, New South Wales, Australia; Ward SV, Centre for Genetic Origins of Health and Disease, Faculty of Medicine, Dentistry and Health Sciences, University of Western Australia, Perth, Western Australia, Australia; Hayward NK, Oncogenomics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Han J, Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana, USA, Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana, USA; Schulze HJ, Department of Dermatology, Fachklinik Hornheide, Institute for Tumors of the Skin at the University of Münster, Münster, Germany; Dunning AM, Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK; Bishop JA, Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK; Demenais F, INSERM, UMR 946, Genetic Variation and Human Diseases Unit, Paris, France, Institut Universitaire d’Hématologie, Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Amos CI, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA; MacGregor S, Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Iles MM, Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK. Law MH, Bishop DT, MacGregor S, Iles MM supervised equally. Lee JE, Brossard M, Demenais F, Amos CI contributed equally. List of members of the 23andMe Research Team: The following members of the 23andMe Research Team contributed to this study: Michelle Agee, Babak Alipanahi, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson, Pierre Fontanillas, Nicholas A. Furlotte, David A. Hinds, Karen E. Huber, Aaron Kleinman, Nadia K. Litterman, Jennifer C. McCreight, Matthew H. McIntyre, Joanna L. Mountain, Elizabeth S. Noblin, Carrie A.M. Northover, Steven J. Pitts, J. Fah Sathirapongsasuti, Olga V. Sazonova, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Joyce Y. Tung, Vladimir Vacic, and Catherine H. Wilson

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UD conceived the project, designed the study, collected the data, performed the analyses, interpreted the results, and wrote the manuscript. BAB performed the microarray gene expression analyses. LI, JPB, BAB, AAD, OH, MMI, MHL, and KB contributed to data collection and result interpretation. CC designed the study, collected the data, supervised the analyses, interpreted the results, and wrote the manuscript. All authors read and contributed to the final manuscript.

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Correspondence to Carlos Cruchaga.

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CC receives research support from: Biogen, EISAI, Alector and Parabon. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. CC is a member of the advisory board of ADx Healthcare, Halia Therapeutics and Vivid Genomics.

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The members of 23andMe Research Team and Melanoma-Meta-analysis Consortium are mentioned in Acknowledgements.

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Dube, U., Ibanez, L., Budde, J.P. et al. Overlapping genetic architecture between Parkinson disease and melanoma. Acta Neuropathol 139, 347–364 (2020). https://doi.org/10.1007/s00401-019-02110-z

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