Transcriptome-wide association study of prostate cancer in the Chinese population

Wenyan Hu; Xiaoya Zeng; Jingjing Zhang; Xiaohao Ruan; Yongle Zhan; Chi Yao; Xiufeng Xin; Haitao Chen; Rong Na

doi:10.1016/j.ajur.2025.05.002

Transcriptome-wide association study of prostate cancer in the Chinese population

Asian J Urol. 2026 Apr;13(2):145-153. doi: 10.1016/j.ajur.2025.05.002. Epub 2025 Jul 29.

Authors

Wenyan Hu¹, Xiaoya Zeng¹, Jingjing Zhang¹, Xiaohao Ruan², Yongle Zhan³, Chi Yao³, Xiufeng Xin⁴, Haitao Chen¹, Rong Na³

Affiliations

¹ Department of Epidemiology, School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China.
² Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
⁴ Department of Neurology, The First Affiliated Hospital of Jinan University, Guangzhou, China.

Abstract

Objective: Prostate cancer (PCa) is among the most prevalent malignancies in men, with a substantial genetic predisposition. Despite extensive genome-wide association studies (GWAS) identifying numerous risk loci, the causal target genes remain largely undetermined. To address this knowledge gap, we conducted the first transcriptome-wide association study (TWAS) of PCa in the Chinese population to systematically identify putative target genes.

Methods: This study included 5048 participants, comprising 2425 individuals from the Chinese Prostate Cancer Genetics Consortium cohort (1417 PCa cases and 1008 healthy controls) and 2623 from the Ruijin Biopsy cohort (1133 cases and 1490 controls). We employed both single-tissue and cross-tissue TWAS approaches to prioritize candidate genes. Causal inference was performed using two-sample Mendelian randomization, while differential mRNA expression and methylation analyses were conducted to investigate potential regulatory mechanisms. The prognostic significance of the identified genes was further assessed through survival analysis.

Results: A total of 179 and 114 putative target genes were identified in the ChinaPCa and Ruijin Biopsy cohorts, respectively. The meta-analysis of the single-tissue TWAS revealed 23 genes achieving false discovery rate significance, while cross-tissue TWAS identified nine additional significant genes (one gene previously reported in the single-tissue TWAS was excluded). GRAM domain-containing protein 2 (GRAMD2) emerged as the most consistently associated gene across analyses. Furthermore, the Mendelian randomization analysis provided evidence supporting a causal role for trafficking protein particle complex subunit 6B (TRAPPC6B) and patatin-like phospholipase domain-containing 6 (PNPLA6) in PCa etiology.

Conclusion: This study represents the first comprehensive TWAS of PCa in the Chinese population, identifying 290 putative causal genes. These findings enhance our understanding of PCa pathogenesis and may inform future research on molecular mechanisms, therapeutic targets, and prognostic biomarkers.

Keywords: Genetic mechanism; Genome-wide association study; Prostate cancer; Single nucleotide polymorphism; Transcriptome-wide association study.