Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Center for Functional Cancer Epigenetics Dana-Farber Cancer Institute, Boston, MA, USA.
Nat Genet. 2022 Sep;54(9):1364-1375. doi: 10.1038/s41588-022-01168-y. Epub 2022 Sep 7.
Many genetic variants affect disease risk by altering context-dependent gene regulation. Such variants are difficult to study mechanistically using current methods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs). To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for identifying genotypic and allele-specific effects on chromatin that are also associated with disease. In prostate cancer, CWAS identified regulatory elements and androgen receptor-binding sites that explained the association at 52 of 98 known prostate cancer risk loci and discovered 17 additional risk loci. CWAS implicated key developmental transcription factors in prostate cancer risk that are overlooked by eQTL-based approaches due to context-dependent gene regulation. We experimentally validated associations and demonstrated the extensibility of CWAS to additional epigenomic datasets and phenotypes, including response to prostate cancer treatment. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting transcriptional regulation.
许多遗传变异通过改变与上下文相关的基因调控来影响疾病风险。目前的方法（如表达数量性状基因座 (eQTL)）将遗传变异与稳态基因表达水平联系起来，很难从机制上研究这些变异。为了解决这一挑战，我们开发了全染色质关联研究 (CWAS)，这是一种识别染色质上基因型和等位基因特异性效应的框架，这些效应也与疾病相关。在前列腺癌中，CWAS 鉴定了调控元件和雄激素受体结合位点，这些元件和结合位点解释了 98 个已知前列腺癌风险位点中的 52 个的关联，并发现了 17 个额外的风险位点。CWAS 将关键的发育转录因子纳入前列腺癌风险，而这些转录因子由于基因调控的上下文依赖性，被基于 eQTL 的方法所忽视。我们通过实验验证了关联，并证明了 CWAS 可扩展到其他表观基因组数据集和表型，包括对前列腺癌治疗的反应。CWAS 是一种强大且具有生物学解释力的范例，可用于研究通过影响转录调控来影响性状的变异。
