Background Although genome-wide association studies (GWAS) of breast cancer (BC) identified common variants which differ between intrinsic subtypes, genes through which these variants act to impact BC risk have not been fully established. Transcriptome-wide association studies (TWAS) have identified genes associated with overall BC risk, but subtype-specific differences are largely unknown. Methods We performed two multi-tissue TWASs for each BC intrinsic subtype including an expression-based approach that collated TWAS signals from expression quantitative trait loci (eQTLs) across multiple tissues and a novel splicing-based approach that collated signals from splicing QTLs (sQTLs) across intron clusters and subsequently across tissues. We utilized summary statistics for five intrinsic subtypes including Luminal A-like, Luminal B-like, Luminal B/HER2-negative-like, HER2-enriched-like, and Triple-negative BC, generated from 106,278 BC cases and 91,477 controls in the Breast Cancer Association Consortium. Results Overall, we identified 235 genes in 88 loci across were associated with at least one of the five intrinsic subtypes. Most genes were subtype-specific, and many have not been reported in previous TWAS. We discovered common variants that modulate expression of CHEK2 confer increased risk to Luminal-A-like BC, in contrast to the viewpoint that CHEK2 primarily harbors rare, penetrant mutations. Additionally, our splicing-based TWAS provided population-level support for MDM4 splice variants that increased triple-negative BC risk. Conclusion Our comprehensive, multi-tissue TWAS corroborated previous GWAS loci for overall BC risk and intrinsic subtypes, while underscoring how common variation which impacts expression and splicing of genes in multiple tissue types can be used to further elucidate the etiology of BC.

中文翻译：

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多组织转录组范围关联研究确定了乳腺癌内在亚型的 235 个基因

背景 尽管乳腺癌 (BC) 的全基因组关联研究 (GWAS) 发现了内在亚型之间存在差异的常见变异，但这些变异影响 BC 风险的基因尚未完全确定。全转录组关联研究 (TWAS) 已确定与 BC 总体风险相关的基因，但亚型特异性差异很大程度上未知。方法 我们对每种 BC 内在亚型进行了两次多组织 TWAS，包括一种基于表达的方法，该方法整理来自跨多个组织的表达数量性状位点 (eQTL) 的 TWAS 信号，以及一种新颖的基于剪接的方法，该方法整理来自剪接 QTL (sQTL) 的信号穿过内含子簇，随后穿过组织。我们利用了五种内在亚型的汇总统计数据，包括 Luminal A 样、Luminal B 样、Luminal B/HER2 阴性样、HER2 富集样和三阴性 BC，这些亚型是从 106,278 例 BC 病例和 91,477 例对照中生成的。乳腺癌协会联盟。结果 总体而言，我们在 88 个基因座中确定了 235 个基因与五种内在亚型中的至少一种相关。大多数基因是亚型特异性的，并且许多基因在之前的 TWAS 中没有报道过。我们发现调节 CHEK2 表达的常见变异会增加 Luminal-A 样 BC 的风险，这与 CHEK2 主要含有罕见的渗透性突变的观点相反。此外，我们基于剪接的 TWAS 为增加三阴性 BC 风险的 MDM4 剪接变体提供了群体水平的支持。结论 我们全面的多组织 TWAS 证实了先前 GWAS 基因座的整体 BC 风险和内在亚型，同时强调了如何利用影响多种组织类型中基因表达和剪接的常见变异来进一步阐明 BC 的病因。