GWAS meta-analysis provides new insights into uveal melanoma risk

Matthew D’Mellow; Huanwei Wang; Jane M. Palmer; Kari Hemminki; Colleen M. Cebulla; Aaron B. Beasley; Nikolaos E. Bechrakis; Antonia L. Pritchard; Karin W. Wadt; Peter A. Johansson; Lenha Mobuchon; Samantha Barlow; Kelly M. Brooks; Timothy Beckman; Catherine M. Olsen; Sunil K. Warrier; Lindsey Byrne; Helen Kalirai; Colette Mustard; Nathan Ingold; Asta Försti; Timothy Isaacs; G. J. M. Shanika R. Jayasinghe; William J. Glasson; Gayle Williamson; Lindsay A. McGrath; Ngoc-Quynh Le; Vikas Chadha; Elin S. Gray; Kevin M. Brown; Paul Cauchi; Hauke Thomsen; Julie Connolly; Stuart MacGregor; David C. Whiteman; Jens F. Kiilgaard; Marc-Henri Stern; Sarah E. Coupland; Mohamed H. Abdel-Rahman; Michael Zeschnigk; Nick Hayward; Matthew H. Law

doi:10.1038/s41416-026-03499-7

GWAS meta-analysis provides new insights into uveal melanoma risk

Matthew D’Mellow
, Huanwei Wang
, Jane M. Palmer
, Kari Hemminki
, Colleen M. Cebulla
, Aaron B. Beasley
, Nikolaos E. Bechrakis
, Antonia L. Pritchard
, Karin W. Wadt
, Peter A. Johansson
, Lenha Mobuchon
, Samantha Barlow
, Kelly M. Brooks
, Timothy Beckman
, Catherine M. Olsen
, Sunil K. Warrier
, Lindsey Byrne
, Helen Kalirai
, Colette Mustard
, Nathan Ingold

Asta Försti, Timothy Isaacs, G. J. M. Shanika R. Jayasinghe, William J. Glasson, Gayle Williamson, Lindsay A. McGrath, Ngoc-Quynh Le, Vikas Chadha, Elin S. Gray, Kevin M. Brown, Paul Cauchi, Hauke Thomsen, Julie Connolly, Stuart MacGregor, David C. Whiteman, Jens F. Kiilgaard, Marc-Henri Stern, Sarah E. Coupland, Mohamed H. Abdel-Rahman, Michael Zeschnigk, Nick Hayward, Matthew H. Law

Producción científica: Article › revisión exhaustiva

Resumen

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.

Idioma original	English
Publicación	British Journal of Cancer
DOI	https://doi.org/10.1038/s41416-026-03499-7
Estado	Published - 16 jun 2026

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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. M., 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. https://doi.org/10.1038/s41416-026-03499-7

@article{8ef5f75c5de0426695f07423845c1633,

title = "GWAS meta-analysis provides new insights into uveal melanoma risk",

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{\textquoteright}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.",

author = "Matthew D{\textquoteright}Mellow and Huanwei Wang and Palmer, \{Jane M.\} and Kari Hemminki 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 Lenha Mobuchon and Samantha Barlow and Brooks, \{Kelly M.\} and Timothy Beckman and Olsen, \{Catherine M.\} and Warrier, \{Sunil K.\} and Lindsey Byrne and Helen Kalirai and Colette Mustard and Nathan Ingold and Asta F{\"o}rsti and Timothy Isaacs and Jayasinghe, \{G. J. M. Shanika R.\} and Glasson, \{William J.\} and Gayle Williamson and McGrath, \{Lindsay A.\} and Ngoc-Quynh Le and Vikas Chadha and Gray, \{Elin S.\} and Brown, \{Kevin M.\} and Paul Cauchi and Hauke Thomsen and Julie Connolly and Stuart MacGregor and Whiteman, \{David C.\} and Kiilgaard, \{Jens F.\} and Marc-Henri Stern and Coupland, \{Sarah E.\} and Abdel-Rahman, \{Mohamed H.\} and Michael Zeschnigk and Nick Hayward and Law, \{Matthew H.\}",

note = "{\textcopyright} Copyright 2026 The Author(s). Published by Springer Nature Limited This is an open access article under the terms of the Creative Commons Attribution License CC BY, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.",

year = "2026",

month = jun,

day = "16",

doi = "10.1038/s41416-026-03499-7",

language = "English",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Springer Nature",

}

D’Mellow, M, Wang, H, Palmer, JM, Hemminki, K, Cebulla, CM, Beasley, AB, Bechrakis, NE, Pritchard, AL, Wadt, KW, Johansson, PA, Mobuchon, L, Barlow, S, Brooks, KM, Beckman, T, Olsen, CM, Warrier, SK, Byrne, L, Kalirai, H, Mustard, C, Ingold, N, Försti, A, Isaacs, T, Jayasinghe, GJMSR, Glasson, WJ, Williamson, G, McGrath, LA, Le, N-Q, Chadha, V, Gray, ES, Brown, KM, Cauchi, P, Thomsen, H, Connolly, J, MacGregor, S, Whiteman, DC, Kiilgaard, JF, Stern, M-H, Coupland, SE, Abdel-Rahman, MH, Zeschnigk, M, Hayward, N & Law, MH 2026, 'GWAS meta-analysis provides new insights into uveal melanoma risk', British Journal of Cancer. https://doi.org/10.1038/s41416-026-03499-7

TY - JOUR

T1 - GWAS meta-analysis provides new insights into uveal melanoma risk

AU - D’Mellow, Matthew

AU - Wang, Huanwei

AU - Palmer, Jane M.

AU - Hemminki, Kari

AU - Cebulla, Colleen M.

AU - Beasley, Aaron B.

AU - Bechrakis, Nikolaos E.

AU - Pritchard, Antonia L.

AU - Wadt, Karin W.

AU - Johansson, Peter A.

AU - Mobuchon, Lenha

AU - Barlow, Samantha

AU - Brooks, Kelly M.

AU - Beckman, Timothy

AU - Olsen, Catherine M.

AU - Warrier, Sunil K.

AU - Byrne, Lindsey

AU - Kalirai, Helen

AU - Mustard, Colette

AU - Ingold, Nathan

AU - Försti, Asta

AU - Isaacs, Timothy

AU - Jayasinghe, G. J. M. Shanika R.

AU - Glasson, William J.

AU - Williamson, Gayle

AU - McGrath, Lindsay A.

AU - Le, Ngoc-Quynh

AU - Chadha, Vikas

AU - Gray, Elin S.

AU - Brown, Kevin M.

AU - Cauchi, Paul

AU - Thomsen, Hauke

AU - Connolly, Julie

AU - MacGregor, Stuart

AU - Whiteman, David C.

AU - Kiilgaard, Jens F.

AU - Stern, Marc-Henri

AU - Coupland, Sarah E.

AU - Abdel-Rahman, Mohamed H.

AU - Zeschnigk, Michael

AU - Hayward, Nick

AU - Law, Matthew H.

N1 - © Copyright 2026 The Author(s). Published by Springer Nature Limited This is an open access article under the terms of the Creative Commons Attribution License CC BY, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

PY - 2026/6/16

Y1 - 2026/6/16

N2 - 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.

AB - 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.

U2 - 10.1038/s41416-026-03499-7

DO - 10.1038/s41416-026-03499-7

M3 - Article

SN - 0007-0920

JO - British Journal of Cancer

JF - British Journal of Cancer

ER -

GWAS meta-analysis provides new insights into uveal melanoma risk

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