Background Genetic variants identified through genome-wide association studies (GWAS) are predominantly non-coding and typically attributed to altered regulatory elements such as enhancers and promoters. However, the contribution of non-coding RNAs to complex traits is not clear. Results Using targeted RNA sequencing, we systematically annotated multi-exonic non-coding RNA (mencRNA) genes transcribed from 1.5-Mb intervals surrounding 139 breast cancer GWAS signals and assessed their contribution to breast cancer risk. We identify more than 4000 mencRNA genes and show their expression distinguishes normal breast tissue from tumors and different breast cancer subtypes. Importantly, breast cancer risk variants, identified through genetic fine-mapping, are significantly enriched in mencRNA exons, but not the promoters or introns. eQTL analyses identify mencRNAs whose expression is associated with risk variants. Furthermore, chromatin interaction data identify hundreds of mencRNA promoters that loop to regions that contain breast cancer risk variants. Conclusions We have compiled the largest catalog of breast cancer-associated mencRNAs to date and provide evidence that modulation of mencRNAs by GWAS variants may provide an alternative mechanism underlying complex traits.

中文翻译：

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非编码 RNA 是乳腺癌遗传易感性的基础

背景 通过全基因组关联研究 (GWAS) 鉴定的遗传变异主要是非编码的，通常归因于改变的调控元件，例如增强子和启动子。然而，非编码 RNA 对复杂性状的贡献尚不清楚。结果使用靶向 RNA 测序，我们系统地注释了从 139 个乳腺癌 GWAS 信号周围的 1.5-Mb 间隔转录的多外显子非编码 RNA (mencRNA) 基因，并评估了它们对乳腺癌风险的贡献。我们鉴定了 4000 多个 mencRNA 基因，并显示它们的表达将正常乳腺组织与肿瘤和不同的乳腺癌亚型区分开来。重要的是，通过遗传精细定位确定的乳腺癌风险变异在 mencRNA 外显子中显着富集，但在启动子或内含子中没有。eQTL 分析可识别表达与风险变异相关的 mencRNA。此外，染色质相互作用数据确定了数百个 mencRNA 启动子，这些启动子循环到包含乳腺癌风险变异的区域。结论 我们编制了迄今为止最大的乳腺癌相关 mencRNA 目录，并提供证据表明 GWAS 变体对 mencRNA 的调节可能提供了复杂性状的替代机制。