Purpose: To assess the association of a polygenic risk score (PRS) for functional genetic variants with the risk of developing breast cancer. Methods: Summary data-based Mendelian randomization (SMR) and heterogeneity in dependent instruments (HEIDI) were used to identify breast cancer risk variants associated with gene expression and DNA methylation levels. A new SMR-based PRS was computed from the identified variants (functional PRS) and compared to an established 313-variant breast cancer PRS (GWAS PRS). The two scores were evaluated in 3560 breast cancer cases and 3383 non-cancer controls and also in a prospective study (n= 10,213) comprising 418 cases. Results: We identified 149 variants showing pleiotropic association with breast cancer risk (eQTLHEIDI> 0.05 = 9, mQTLHEIDI> 0.05 = 165). The discriminatory ability of the functional PRS (AUCcontinuous[95% CI]: 0.540 [0.526 to 0.553]) was found to be lower than that of the GWAS PRS (AUCcontinuous[95% CI]: 0.609 [0.596 to 0.622]). Even when utilizing 457 distinct variants from both the functional and GWAS PRS, the combined discriminatory performance remained below that of the GWAS PRS (AUCcontinuous, combined [95% CI]: 0.561 [0.548 to 0.575]). A binary high/low-risk classification based on the 80th centile PRS in controls revealed a 6% increase in cases using the GWAS PRS compared to the functional PRS. The functional PRS identified an additional 12% of high-risk cases but also led to a 13% increase in high-risk classification among controls. Similar findings were observed in the SCHS prospective cohort, where the GWAS PRS outperformed the functional PRS, and the highest-performing PRS, a combined model, did not significantly improve over the GWAS PRS. Conclusions: While this study identified potentially functional variants associated with breast cancer risk, their inclusion did not substantially enhance the predictive accuracy of the GWAS PRS.
目的：评估基于功能性遗传变异的多基因风险评分（PRS）与乳腺癌发病风险的关联性。方法：采用基于汇总数据的孟德尔随机化（SMR）及工具变量异质性检验（HEIDI）方法，筛选与基因表达及DNA甲基化水平相关的乳腺癌风险变异。基于鉴定出的变异构建新型SMR-PRS（功能性PRS），并与已建立的313个变异位点的乳腺癌PRS（GWAS-PRS）进行比较。两项评分在3560例乳腺癌患者与3383例非癌对照中接受评估，同时在一个包含418例病例的前瞻性研究队列（n=10,213）中进行验证。结果：共鉴定出149个与乳腺癌风险存在多效性关联的变异位点（eQTL-HEIDI>0.05=9个，mQTL-HEIDI>0.05=165个）。功能性PRS的判别能力（连续AUC[95% CI]：0.540[0.526-0.553]）低于GWAS-PRS（连续AUC[95% CI]：0.609[0.596-0.622]）。即使联合使用功能性PRS与GWAS-PRS中的457个独立变异位点，其综合判别性能仍低于GWAS-PRS（联合连续AUC[95% CI]：0.561[0.548-0.575]）。基于对照组PRS第80百分位数的高/低风险二分类分析显示，相较于功能性PRS，GWAS-PRS可使高风险病例比例提升6%。功能性PRS虽能额外识别12%的高风险病例，但同时导致对照组中高风险分类比例增加13%。在新加坡华人健康研究前瞻性队列中观察到相似结果：GWAS-PRS表现优于功能性PRS，而表现最佳的联合模型PRS并未较GWAS-PRS产生显著提升。结论：本研究虽鉴定出与乳腺癌风险相关的潜在功能性变异，但其纳入并未显著提升GWAS-PRS的预测准确性。
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