Uveal melanoma (UM) is a rare but frequently metastasizing cancer. Genome-wide association studies have identified three common genome-wide significant germline risk loci. Here, we perform a genome-wide association study on 401 new cases and conduct a meta-analysis with three independent previously published cohorts for a total sample size of 2,426 cases. We confirm the three previously identified risk loci and identify four additional genome-wide significant loci. We find that eye pigmentation-decreasing variants are systematically associated with increased UM risk and that selection for lighter pigmentation in the past 5,000 years explains about 73% of the difference in UM incidence between Northern and Southern Europe. We find evidence of effect size heterogeneity at significant loci across cohorts, in particular, a weaker association between eye pigmentation and UM in a Finnish cohort. Finally, we confirm differential effect sizes between uveal melanoma cases with and without loss of chromosome 3, the major determinant of metastatic risk. Our study identifies novel germline risk factors for UM and highlights genetic and environmental heterogeneity in its etiology.

Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic; Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Department of Genetics University of Pennsylvania Perelman School of Medicine Philadelphia PA USA

Department of Genetics University of Pennsylvania Perelman School of Medicine Philadelphia PA USA; Department of Surgery University of Pennsylvania Perelman School of Medicine Philadelphia PA USA; Department of Surgery Corporal Michael Crescenz VA Medical Center Philadelphia PA USA

Department of Surgery University of Pennsylvania Perelman School of Medicine Philadelphia PA USA

Hopp Children's Cancer Center Heidelberg Germany

INSERM U1339 CNRS UMR3666 DNA Repair and Uveal Melanoma Team Institut Curie PSL Research University Paris France

Liverpool Clinical Laboratories Liverpool University Hospitals Foundation Trust Liverpool UK

Liverpool Ocular Oncology Research Group Department of Eye and Vision Sciences University of Liverpool Liverpool UK

MSB Medical School Berlin Berlin Germany

Ocular Oncology Service Wills Eye Hospital Thomas Jefferson University Philadelphia PA USA

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