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

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.

Metadata

Authors/Creators:	Landi, MT Bishop, DT https://orcid.org/0000-0002-8752-8785 MacGregor, S Machiela, MJ Stratigos, AJ Ghiorzo, P Brossard, M Calista, D Choi, J Fargnoli, MC Zhang, T Rodolfo, M Trower, AJ Menin, C Martinez, J Hadjisavvas, A Song, L Stefanaki, I Scolyer, R Yang, R Goldstein, AM Potrony, M Kypreou, KP Pastorino, L Queirolo, P Pellegrini, C Cattaneo, L Zawistowski, M Gimenez-Xavier, P Rodriguez, A Elefanti, L Manoukian, S Rivoltini, L Smith, BH Loizidou, MA Del Regno, L Massi, D Mandala, M Khosrotehrani, K Akslen, LA Amos, CI Andresen, PA Avril, M-F Azizi, E Soyer, HP Bataille, V Dalmasso, B Bowdler, LM Burdon, KP Chen, WV Codd, V Craig, JE Dębniak, T Falchi, M Fang, S Friedman, E Simi, S Galan, P Garcia-Casado, Z Gillanders, EM Gordon, S Green, A Gruis, NA Hansson, J Harland, M Harris, J Helsing, P Henders, A Hočevar, M Höiom, V Hunter, D Ingvar, C Kumar, R Lang, J Lathrop, GM Lee, JE Li, X Lubiński, J Mackie, RM Malt, M Malvehy, J McAloney, K Mohamdi, H Molven, A Moses, EK Neale, RE Novaković, S Nyholt, DR Olsson, H Orr, N Fritsche, LG Puig-Butille, JA Qureshi, AA Radford-Smith, GL Randerson-Moor, J https://orcid.org/0000-0003-0303-0072 Requena, C Rowe, C Samani, NJ Sanna, M Schadendorf, D Schulze, H-J Simms, LA Smithers, M Song, F Swerdlow, AJ van der Stoep, N Kukutsch, NA Visconti, A Wallace, L Ward, SV Wheeler, L Sturm, RA Hutchinson, A Jones, K Malasky, M Vogt, A Zhou, W Pooley, KA Elder, DE Han, J Hicks, B Hayward, NK Kanetsky, PA Brummett, C Montgomery, GW Olsen, CM Hayward, C Dunning, AM Martin, NG Evangelou, E Mann, GJ Long, G Pharoah, PDP Easton, DF Barrett, JH https://orcid.org/0000-0002-1720-7724 Cust, AE Abecasis, G Duffy, DL Whiteman, DC Gogas, H De Nicolo, A Tucker, MA Newton-Bishop, JA 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 Peris, K Chanock, SJ Demenais, F Brown, KM Puig, S Nagore, E Shi, J Iles, MM https://orcid.org/0000-0002-2603-6509 Law, MH
Copyright, Publisher and Additional Information:	© 2020, Springer Nature. This is an author produced version of an article published in Nature Genetics. Uploaded in accordance with the publisher's self-archiving policy.
Keywords:	Genome-wide association studies; Melanoma
Dates:	Accepted: 9 March 2020 Published (online): 27 April 2020 Published: May 2020
Institution:	The University of Leeds
Depositing User:	Symplectic Publications
Date Deposited:	30 Jul 2020 15:57
Last Modified:	27 Oct 2020 01:39
Status:	Published
Publisher:	Nature Research
Identification Number:	https://doi.org/10.1038/s41588-020-0611-8