Author Identifier (ORCID)
Abstract
Objective: The aim of this research is to identify germline genetic variants that predispose to uveal melanoma (UM) using data from nine studies involving 5839 individuals with UM (3853 novel) and 349,863 healthy controls. Methods: Five novel UM genome-wide association studies (GWAS) were performed and included for meta-analysis with four previously published UM GWAS. A fixed-effects inverse-variance weighted (IVW) meta-analysis was performed by combining data from these nine UM case-control cohorts. A follow-up transcriptome-wide association study (TWAS) was conducted to identify candidate target genes at UM risk loci. Genetic correlations with melanoma-related phenotypes were measured to elucidate UM’s genetic architecture. Results: We identify nine linkage disequilibrium (LD)-independent loci (three novel) with an IVW P value of less than 5 × 10−8. TWAS analysis indicates five potential target genes, including MOB3B, RBAK, and MTSS1, which have established links to multiple cancer types. We note a significant genetic correlation (rg = 0.31, P = 0.01) between UM and cutaneous melanoma (CM), and a non-significant but consistent correlation with naevus count (rg = 0.25, P = 0.08). Conclusions: This meta-analysis offers new insights into the genetic architecture of UM, highlights potential therapeutic targets, and explores the genetic relationship with CM and skin pigmentation.
Keywords
uveal melanoma, genome-wide association study, genetic susceptibility, transcriptome-wide association study, melanoma genetics, risk loci
Document Type
Journal Article
Date of Publication
1-1-2026
ISSN
00070920
Publication Title
British Journal of Cancer
Publisher
Nature
School
Centre for Precision Health
RAS ID
99691
Funding Information
This project was supported by the National Health and Medical Research Council.
Funding received from the National Health and Medical Research Council (NHMRC)
1093017
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Recommended Citation
D’Mellow, M., Wang, H., Palmer, J. M., Hemminki, K., Cebulla, C. M., Beasley, A. B., Bechrakis, N. E., Pritchard, A. L., Wadt, K. W., Johansson, P. A., Mobuchon, L., Barlow, S., Brooks, K., Beckman, T., Olsen, C. M., Warrier, S. K., Byrne, L., Kalirai, H., Mustard, C., . . . Law, M. H. (2026). GWAS meta-analysis provides new insights into uveal melanoma risk. British Journal of Cancer. Advance online publication. https://doi.org/10.1038/s41416-026-03499-7