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GWAS meta-analysis provides new insights into uveal melanoma risk

D’Mellow, Matthew ; Wang, Huanwei ; Palmer, Jane M. ; Hemminki, Kari LU ; Cebulla, Colleen M. ; Beasley, Aaron B. ; Bechrakis, Nikolaos E. ; Pritchard, Antonia L. ; Wadt, Karin W. and Johansson, Peter A. , et al. (2026) In British Journal of Cancer p.1-9
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:... (More)

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.

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publishing date
type
Contribution to journal
publication status
epub
in
British Journal of Cancer
pages
1 - 9
publisher
Nature Publishing Group
external identifiers
  • pmid:42303830
  • scopus:105042068531
ISSN
0007-0920
DOI
10.1038/s41416-026-03499-7
language
English
LU publication?
no
additional info
Publisher Copyright: © The Author(s) 2026.
id
7408be56-8be8-4dbb-b160-9b0d83e22942
date added to LUP
2026-06-28 10:58:19
date last changed
2026-06-30 03:02:18
@article{7408be56-8be8-4dbb-b160-9b0d83e22942,
  abstract     = {{<p>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<sup>−8</sup>. 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.</p>}},
  author       = {{D’Mellow, Matthew and Wang, Huanwei and Palmer, Jane M. and Hemminki, Kari and Cebulla, Colleen M. and Beasley, Aaron B. and Bechrakis, Nikolaos E. and Pritchard, Antonia L. and Wadt, Karin W. and Johansson, Peter A. and Mobuchon, Lenha and Barlow, Samantha and Brooks, Kelly and Beckman, Timothy and Olsen, Catherine M. and Warrier, Sunil K. and Byrne, Lindsey and Kalirai, Helen and Mustard, Colette and Ingold, Nathan and Försti, Asta and Isaacs, Timothy and Jayasinghe, G. J.M.Shanika R. and Glasson, William J. and Williamson, Gayle and McGrath, Lindsay A. and Le, Ngoc Quynh and Chadha, Vikas and Gray, Elin S. and Brown, Kevin M. and Cauchi, Paul and Thomsen, Hauke and Connolly, Julie and MacGregor, Stuart and Whiteman, David C. and Kiilgaard, Jens F. and Stern, Marc Henri and Coupland, Sarah E. and Abdel-Rahman, Mohamed H. and Zeschnigk, Michael and Hayward, Nick and Law, Matthew H.}},
  issn         = {{0007-0920}},
  language     = {{eng}},
  pages        = {{1--9}},
  publisher    = {{Nature Publishing Group}},
  series       = {{British Journal of Cancer}},
  title        = {{GWAS meta-analysis provides new insights into uveal melanoma risk}},
  url          = {{http://dx.doi.org/10.1038/s41416-026-03499-7}},
  doi          = {{10.1038/s41416-026-03499-7}},
  year         = {{2026}},
}