Introduction: Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46), showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify SNPs that might improve performance in this population. Material and Methods: Anonymized genotypic data were obtained from the PRACTICAL consortium for 6,253 men with African genetic ancestry. Ten iterations of a ten-fold cross-validation search were conducted, to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African were compared using the same cross-validated approach. Results: Three SNPs (rs76229939, rs74421890, and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47 to 4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65 to 0.53). Conclusions: We identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans and Asians. A strategy of building on established statistical models might benefit ancestral groups generally under-represented in genome-wide association studies.

中文翻译：

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非洲人对前列腺癌诊断年龄的多基因危险评分的特定改善

简介：多基因危险评分（PHS）模型与前列腺癌诊断时的年龄有关。我们在欧洲人中开发的模型（PHS46）在具有非洲遗传血统的男性中表现出下降的表现。我们使用交叉验证的搜索来确定可能改善该人群的表现的SNP。材料和方法：匿名基因型数据是从PRACTICAL财团获得的6,253名具有非洲遗传血统的男性的数据。进行了十次交叉验证搜索的十次迭代，以选择将包含在最终PHS46 + African模型中的SNP。在Cox比例风险框架中，使用诊断时的年龄作为因变量和PHS46，并选择SNP作为预测因子，估算了PHS46 + African的系数。使用相同的交叉验证方法比较了PHS46和PHS46 + African的性能。结果：选择了三个SNP（rs76229939，rs74421890和rs5013678）以包含在PHS46 + African中。所有三个SNP均位于染色体8q24上。PHS46 + African在所测得的所有绩效指标上均取得了显着改善，包括高收入20％人群的相对危害比最低的20％（2.47至4.34）增加了75％，而相对较低的20％（2.47至4.34）底部20％则与中间40％（0.65至0.53）相比。结论：我们鉴定了三种SNP，它们在非洲遗传血统的男性中诊断出前列腺癌时显着改善了PHS46与年龄的关联，其水平可与欧洲人和亚洲人相提并论。