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Objective <p>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.</p> Methods <p>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.</p> Results <p>We identify nine linkage disequilibrium (LD)-independent loci (three novel) with an IVW <i>P</i> value of less than 5 × 10<sup>−8</sup>. TWAS analysis indicates five potential target genes, including <i>MOB3B</i>, <i>RBAK</i>, and <i>MTSS1</i>, which have established links to multiple cancer types. We note a significant genetic correlation (rg = 0.31, <i>P</i> = 0.01) between UM and cutaneous melanoma (CM), and a non-significant but consistent correlation with naevus count (rg = 0.25, <i>P</i> = 0.08).</p> Conclusions <p>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>

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GWAS meta-analysis provides new insights into uveal melanoma risk

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月16日

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  • 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 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

摘要

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.