前列腺癌（PrCa）是全球男性中第二常见的癌症。尽管有强烈的需求，但尤其是在其发展之前，对PrCa的死亡风险的预测是具有挑战性的。在这里，我们通过充分发挥遗传数据的统计能力，进行多祖先的荟萃分析，并着重研究雄激素受体（AR）的结合位点，该受体在PrCa中具有关键作用。在利用数十万大样本进行的多祖先荟萃分析中，确定了9个未报道的位点，包括肿瘤抑制基因ZFHX3，并相对于仅欧洲研究，成功缩小了统计精细映射变异体的范围，并且这些变异体在AR结合位点中显著富集。在仅限于AR结合位点中的统计精细映射变异体的多基因风险评分（PRS）分析中，我们发现在无癌症个体中，位于前10%的PRS的个体未来死于PrCa的风险明显增加（HR：5.57，P=4.2 × 10-10）。我们的研究结果表明，充分利用大规模遗传数据和先进的分析方法在预测PrCa的死亡风险方面具有潜在的实用价值。© 2023. Springer Nature Limited.

Prostate cancer (PrCa) is the second most common cancer worldwide in males. While strongly warranted, the prediction of mortality risk due to PrCa, especially before its development, is challenging. Here, we address this issue by maximizing the statistical power of genetic data with multi-ancestry meta-analysis and focusing on binding sites of the androgen receptor (AR), which has a critical role in PrCa. Taking advantage of large Japanese samples ever, a multi-ancestry meta-analysis comprising more than 300,000 subjects in total identifies 9 unreported loci including ZFHX3, a tumor suppressor gene, and successfully narrows down the statistically finemapped variants compared to European-only studies, and these variants strongly enrich in AR binding sites. A polygenic risk scores (PRS) analysis restricting to statistically finemapped variants in AR binding sites shows among cancer-free subjects, individuals with a PRS in the top 10% have a strongly higher risk of the future death of PrCa (HR: 5.57, P = 4.2 × 10-10). Our findings demonstrate the potential utility of leveraging large-scale genetic data and advanced analytical methods in predicting the mortality of PrCa.© 2023. Springer Nature Limited.