Genome-wide association study identifies three new melanoma susceptibility loci

Jennifer H Barrett, Mark M Iles, Mark Harland, John C Taylor, Joanne F Aitken, Per Arne Andresen, Lars A Akslen, Bruce K Armstrong, Marie-Francoise Avril, Esther Azizi, Bert Bakker, Wilma Bergman, Giovanna Bianchi-Scarrà, Brigitte Bressac-de Paillerets, Donato Calista, Lisa A Cannon-Albright, Eve Corda, Anne E Cust, Tadeusz Dębniak, David Duffy, Alison M Dunning, Douglas F Easton, Eitan Friedman, Pilar Galan, Paola Ghiorzo, Graham G Giles, Johan Hansson, Marko Hocevar, Veronica Höiom, John L Hopper, Christian Ingvar, Bart Janssen, Mark A Jenkins, Göran Jönsson, Richard F Kefford, Giorgio Landi, Maria Teresa Landi, Julie Lang, Jan Lubiński, Rona Mackie, Josep Malvehy, Nicholas G Martin, Anders Molven, Grant W Montgomery, Frans A van Nieuwpoort, Srdjan Novakovic, Håkan Olsson, Lorenza Pastorino, Susana Puig, Joan Anton Puig-Butille, Juliette Randerson-Moor, Helen Snowden, Rainer Tuominen, Patricia Van Belle, Nienke van der Stoep, David C Whiteman, Diana Zelenika, Jiali Han, Shenying Fang, Jeffrey E Lee, Qingyi Wei, G Mark Lathrop, Elizabeth M Gillanders, Kevin M Brown, Alisa M Goldstein, Peter A Kanetsky, Graham J Mann, Stuart MacGregor, David E Elder, Christopher I Amos, Nicholas K Hayward, Nelleke A Gruis, Florence Demenais, Julia A Newton Bishop, D Timothy Bishop

We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10(-5) and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10(-3): an SNP in ATM (rs1801516, overall P = 3.4 × 10(-9)), an SNP in MX2 (rs45430, P = 2.9 × 10(-9)) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 × 10(-10)). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 × 10(-7) under a fixed-effects model and P = 1.2 × 10(-3) under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.