Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

Maria Teresa Landi, D. Timothy Bishop, Stuart MacGregor, Mitchell J. Machiela, Alexander J. Stratigos, Paola Ghiorzo, Myriam Brossard, Donato Calista, Jiyeon Choi, Maria Concetta Fargnoli, Tongwu Zhang, Monica Rodolfo, Adam J. Trower, Chiara Menin, Jacobo Martinez, Andreas Hadjisavvas, Lei Song, Irene Stefanaki, Richard Scolyer, Rose YangAlisa M. Goldstein, Miriam Potrony, Katerina P. Kypreou, Lorenza Pastorino, Paola Queirolo, Cristina Pellegrini, Laura Cattaneo, Matthew Zawistowski, Pol Gimenez-Xavier, Arantxa Rodriguez, Lisa Elefanti, Siranoush Manoukian, Licia Rivoltini, Blair H. Smith, Maria A. Loizidou, Laura Del Regno, Daniela Massi, Mario Mandala, Kiarash Khosrotehrani, Lars A. Akslen, Christopher I. Amos, Per A. Andresen, Marie Françoise Avril, Esther Azizi, H. Peter Soyer, Veronique Bataille, Bruna Dalmasso, Lisa M. Bowdler, Kathryn P. Burdon, Wei V. Chen, Veryan Codd, Jamie E. Craig, Tadeusz Dębniak, Mario Falchi, Shenying Fang, Eitan Friedman, Sarah Simi, Pilar Galan, Zaida Garcia-Casado, Elizabeth M. Gillanders, Scott Gordon, Adele Green, Nelleke A. Gruis, Johan Hansson, Mark Harland, Jessica Harris, Per Helsing, Anjali Henders, Marko Hočevar, Veronica Höiom, David Hunter, Christian Ingvar, Rajiv Kumar, Julie Lang, G. Mark Lathrop, Jeffrey E. Lee, Xin Li, Jan Lubiński, Rona M. Mackie, Maryrose Malt, Josep Malvehy, Kerrie McAloney, Hamida Mohamdi, Anders Molven, Eric K. Moses, Rachel E. Neale, Srdjan Novaković, Dale R. Nyholt, Håkan Olsson, Nicholas Orr, Lars G. Fritsche, Joan Anton Puig-Butille, Abrar A. Qureshi, Graham L. Radford-Smith, Juliette Randerson-Moor, Celia Requena, Casey Rowe, Nilesh J. Samani, Marianna Sanna, Dirk Schadendorf, Hans Joachim Schulze, Lisa A. Simms, Mark Smithers, Fengju Song, Anthony J. Swerdlow, Nienke van der Stoep, Nicole A. Kukutsch, Alessia Visconti, Leanne Wallace, Sarah V. Ward, Lawrie Wheeler, Richard A. Sturm, Amy Hutchinson, Kristine Jones, Michael Malasky, Aurelie Vogt, Weiyin Zhou, Karen A. Pooley, David E. Elder, Jiali Han, Belynda Hicks, Nicholas K. Hayward, Peter A. Kanetsky, Chad Brummett, Grant W. Montgomery, Catherine M. Olsen, Caroline Hayward, Alison M. Dunning, Nicholas G. Martin, Evangelos Evangelou, Graham J. Mann, Georgina Long, Paul D.P. Pharoah, Douglas F. Easton, Jennifer H. Barrett, Anne E. Cust, Goncalo Abecasis, David L. Duffy, David C. Whiteman, Helen Gogas, Arcangela De Nicolo, Margaret A. Tucker, Julia A. Newton-Bishop, GenoMEL Consortium, Q-MEGA and QTWIN Investigators, ATHENS Melanoma Study Group, 23andMe, The SDH Study Group, IBD Investigators, Essen-Heidelberg Investigators, AMFS Investigators, MelaNostrum Consortium, Matthew H. Law

    Research output: Contribution to journalArticlepeer-review

    4 Citations (Scopus)

    Abstract

    Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10−8) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.

    Original languageEnglish
    Pages (from-to)494-504
    Number of pages11
    JournalNature Genetics
    Volume52
    Issue number5
    DOIs
    Publication statusPublished - May 2020

    Keywords

    • genome-wide association study
    • meta-analyses
    • phenotypes
    • cutaneous melanoma
    • melanoma risk
    • nucleotide polymorphisms

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