Meta-analysis of uveal melanoma genome-wide association studies identifies novel risk loci and population effect size heterogeneity
Mies, Georgia ; Tsao, Noah L. ; Houy, Alexandre ; Coupland, Sarah E. ; Kalirai, Helen ; Försti, Asta LU ; Hemminki, Kari LU ; Thomsen, Hauke LU
; Stern, Marc Henri
and Shields, Carol L.
, et al.
(2025)
In Human Genetics and Genomics Advances
6(3).
- Abstract
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... (More)
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.
(Less)
- author
- Mies, Georgia
; Tsao, Noah L.
; Houy, Alexandre
; Coupland, Sarah E.
; Kalirai, Helen
; Försti, Asta
LU
; Hemminki, Kari
LU
; Thomsen, Hauke
LU
; Stern, Marc Henri
and Shields, Carol L.
, et al. (More)
- Mies, Georgia
; Tsao, Noah L.
; Houy, Alexandre
; Coupland, Sarah E.
; Kalirai, Helen
; Försti, Asta
LU
; Hemminki, Kari
LU
; Thomsen, Hauke
LU
; Stern, Marc Henri
; Shields, Carol L.
; Damrauer, Scott M.
; Ewens, Katheryn G.
; Ganguly, Arupa
and Mathieson, Iain
(Less)
- publishing date
- 2025-07-10
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- eye pigmentation, genome-wide association study, uveal melanoma
- in
- Human Genetics and Genomics Advances
- volume
- 6
- issue
- 3
- article number
- 100465
- publisher
- Elsevier
- external identifiers
-
- scopus:105008824746
- pmid:40495383
- ISSN
- 2666-2477
- DOI
- 10.1016/j.xhgg.2025.100465
- language
- English
- LU publication?
- no
- additional info
- Publisher Copyright: © 2025
- id
- 9122c798-b464-42ae-a425-291b8bec75fe
- date added to LUP
- 2025-07-13 09:21:58
- date last changed
- 2025-07-15 03:08:17
@article{9122c798-b464-42ae-a425-291b8bec75fe,
abstract = {{<p>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.</p>}},
author = {{Mies, Georgia and Tsao, Noah L. and Houy, Alexandre and Coupland, Sarah E. and Kalirai, Helen and Försti, Asta and Hemminki, Kari and Thomsen, Hauke and Stern, Marc Henri and Shields, Carol L. and Damrauer, Scott M. and Ewens, Katheryn G. and Ganguly, Arupa and Mathieson, Iain}},
issn = {{2666-2477}},
keywords = {{eye pigmentation; genome-wide association study; uveal melanoma}},
language = {{eng}},
month = {{07}},
number = {{3}},
publisher = {{Elsevier}},
series = {{Human Genetics and Genomics Advances}},
title = {{Meta-analysis of uveal melanoma genome-wide association studies identifies novel risk loci and population effect size heterogeneity}},
url = {{http://dx.doi.org/10.1016/j.xhgg.2025.100465}},
doi = {{10.1016/j.xhgg.2025.100465}},
volume = {{6}},
year = {{2025}},
}