Mendelian Randomization Reveals Height as a Risk Factor and Potential Therapeutic Target for Testicular Cancer

Yuanbo Xu; Jieyu Xiong; Yikun Wu; Yuanlin Wang; Hua Shi; Shuxiong Xu; Yuangao Xu

doi:10.71321/sqcqnh24

Authors

Yuanbo Xu Southern Medical University
Jieyu Xiong University of Bern
Yikun Wu Guizhou University
Yuanlin Wang Guizhou Provincial People’s Hospital
Hua Shi Guizhou Provincial People’s Hospital
Shuxiong Xu Guizhou Provincial People’s Hospital
Yuangao Xu Guizhou Provincial People’s Hospital

DOI:

https://doi.org/10.71321/sqcqnh24

Keywords:

Height, Testicular cancer, Mendelian randomization, Bayesian colocalization, Susceptibility gene

Abstract

Objective

To investigate the potential causal relationship between height and the risk of developing testicular cancer using Mendelian Randomization analysis.

Methods

We utilized phenotype data on height and testicular cancer from two European ancestry cohorts, integrating data from the IEU, FinnGen, and UK Biobank databases. Linkage Disequilibrium Score regression and SNP-associated gene enrichment analyses were initially conducted to assess the association between SNPs and the phenotypes. A two-sample MR approach was then applied to evaluate the causal relationship between height and testicular cancer risk. An additional cohort was analyzed for validation, followed by a meta-analysis to combine results. Reverse MR and colocalization analyses were performed to investigate potential reverse causality. Gene enrichment analysis was conducted to elucidate the biological mechanisms linking height to testicular cancer, and potential eQTL targets for testicular cancer were explored using summary-data-based MR and colocalization analysis.

Results

The Inverse Variance Weighted method revealed a significant association between genetically predicted height and testicular cancer risk, with an odds ratio of 1.372 (95% CI: 1.024-1.837, p-value < 0.05). Gene enrichment analysis suggested that the extracellular matrix-related pathway might underlie the increased risk of testicular cancer associated with height. PMF1 and SLC9B2 were identified as potential targets for testicular cancer from summary-data-based MR, colocalization, and gene expression analysis.

Conclusions

This Mendelian randomization study provides evidence supporting a causal relationship between height and the risk of developing testicular cancer, with PMF1 and SLC9B2 identified as potential targets for further investigation.

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