In the last decade, a large number of genome-wide association studies have uncovered many single-nucleotide polymorphisms (SNPs) that are associated with complex traits and confer susceptibility to diseases, such as cancer. However, so far only a few heritable traits with medium-to-high penetrance have been identified. The vast majority of the discovered variants only leads to disease in combination with other still unknown factors. Furthermore, while many studies aimed to link the effect of SNPs to changes in molecular phenotypes, the analysis has been often focused on testing associations between a single SNP and a transcript, hence disregarding the dysregulation of gene regulatory networks that has been shown to play an essential role in disease onset, notably in cancer. Here we take a systems biology approach and develop GVITamIN (Genetic VarIaTIoN functional analysis tool), a new statistical and computational approach to characterize the effect of a SNP on both genes and transcriptional regulatory programs. GVITamIN exploits a novel statistical approach to combine the usually small effect of disease-susceptibility SNPs, and reveals important potential oncogenic mechanisms, hence taking one step further in the direction of understanding the SNP mechanism of action. We apply GVITamIN on a breast cancer cohort and identify well-known cancer-related transcription factors, such as CTCF, LEF1, and FOXA1, as TFs dysregulated by breast cancer-associated SNPs. Furthermore, our results reveal that SNPs located on the RAD51B gene are significantly associated with an abnormal regulatory activity, suggesting a pivotal role for homologous recombination repair mechanisms in breast cancer.

中文翻译：

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用 GVITamIN 鉴定与乳腺癌易感性相关的 SNP 的潜在作用机制

在过去的十年中，大量的全基因组关联研究发现了许多与复杂性状相关的单核苷酸多态性 (SNP)，这些单核苷酸多态性 (SNP) 与癌症等疾病易感性有关。然而，到目前为止，只有少数具有中高外显率的遗传性状被鉴定出来。绝大多数已发现的变异与其他仍然未知的因素相结合只会导致疾病。此外，虽然许多研究旨在将 SNP 的影响与分子表型的变化联系起来，但分析往往集中在测试单个 SNP 和转录本之间的关联，因此忽略了已被证明发挥重要作用的基因调控网络的失调。在疾病发作中起重要作用，尤其是在癌症中。在这里，我们采用系统生物学方法并开发 GVITamIN（遗传变异功能分析工具），这是一种新的统计和计算方法，用于表征 SNP 对基因和转录调控程序的影响。GVITamIN 利用一种新的统计方法来结合疾病易感性 SNP 通常较小的影响，并揭示重要的潜在致癌机制，从而在了解 SNP 作用机制的方向上又迈进了一步。我们将 GVITamIN 应用于乳腺癌队列，并确定众所周知的癌症相关转录因子，如 CTCF、LEF1 和 FOXA1，作为受乳腺癌相关 SNP 失调的 TF。此外，我们的结果表明，位于 RAD51B 基因上的 SNP 与异常调节活动显着相关，