Background:Heritable breast cancer (BC) predisposition is strongly influenced by high-penetrance genes such as BRCA1 and BRCA2, but many moderate- and low-penetrance genes remain poorly characterized. Although over 100 loci have been reported, the causal genes often include false positives or uncertain associations.Methods:We applied a gene-centric, integrative approach to multi-ethnic genomic datasets, including the UK Biobank (UKB) and FinnGen (FG). We assessed consistency across multiple GWAS in Open Targets (OT) and additional complementary genetic association approaches, including ExPheWAS, TWAS, and PWAS. Collapsing variant-level effects to a gene-level view enhanced confidence and reaffirmed contributions from genes such as BRCA1, BRCA2, PALB2, CHEK2, and other DNA repair genes.Results:Using this integrative framework, we identified 38 high-confidence BC predisposition genes, including 8 previously reported drivers, 13 supported by multiple lines of evidence, and additional candidates (e.g., APOBEC3A, TNS1, PEX14) with emerging evidence. PWAS revealed several genes with potential recessive effects often missed by standard GWAS. Multi-cohort replication showed robust findings in European ancestry populations, while transferability to other populations was more limited.Conclusions:This work demonstrates the value of a gene-centric, integrative framework for prioritizing high-confidence BC predisposition genes, highlighting associated cellular pathways, and uncovering new candidates for further functional study, providing a reliable foundation for future research.
背景：遗传性乳腺癌易感性主要受BRCA1、BRCA2等高外显率基因影响，但许多中低外显率基因的特征仍不明确。尽管已有超过100个相关位点被报道，其中所涉及的致病基因常包含假阳性或关联性不确定的结果。 方法：我们采用以基因为中心的整合分析方法，对包括英国生物样本库和FinnGen在内的多族群基因组数据集进行分析。通过评估Open Targets中多个全基因组关联研究的一致性，并结合ExPheWAS、TWAS及PWAS等补充性遗传关联分析方法，将变异水平效应整合至基因层面，从而增强结果的可信度，并再次确认了BRCA1、BRCA2、PALB2、CHEK2及其他DNA修复基因的贡献。 结果：通过该整合分析框架，我们鉴定出38个高置信度乳腺癌易感基因，其中包括8个先前报道的主要驱动基因、13个获多证据支持的基因，以及APOBEC3A、TNS1、PEX14等具有新兴证据的候选基因。PWAS分析揭示了多个可能具有隐性效应的基因，这些基因在标准GWAS中常被忽略。多队列验证表明，该发现在欧洲血统人群中具有稳健性，但在其他人群中的可迁移性较为有限。 结论：本研究证明了以基因为中心的整合分析框架在筛选高置信度乳腺癌易感基因、揭示相关细胞通路以及发现新候选基因用于后续功能研究方面的价值，为未来研究提供了可靠基础。
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