Interactions between genetic variants—epistasis—is pervasive in model systems and can profoundly impact evolutionary adaption, population disease dynamics, genetic mapping, and precision medicine efforts. In this work, we develop a model for structured polygenic epistasis, called coordinated epistasis (CE), and prove that several recent theories of genetic architecture fall under the formal umbrella of CE. Unlike standard epistasis models that assume epistasis and main effects are independent, CE captures systematic correlations between epistasis and main effects that result from pathway-level epistasis, on balance skewing the penetrance of genetic effects. To test for the existence of CE, we propose the even-odd (EO) test and prove it is calibrated in a range of realistic biological models. Applying the EO test in the UK Biobank, we find evidence of CE in 18 of 26 traits spanning disease, anthropometric, and blood categories. Finally, we extend the EO test to tissue-specific enrichment and identify several plausible tissue–trait pairs. Overall, CE is a dimension of genetic architecture that can capture structured, systemic forms of epistasis in complex human traits.

遗传变异之间的相互作用（上位性）在模型系统中普遍存在，可以深刻影响进化适应、群体疾病动态、遗传图谱和精准医疗工作。在这项工作中，我们开发了一种结构化多基因上位性模型，称为协调上位性（CE），并证明了最近的几种遗传结构理论属于 CE 的正式范畴。与假设上位性和主效应是独立的标准上位模型不同，CE 捕获了上位性和由通路水平上位性产生的主效应之间的系统相关性，平衡地扭曲了遗传效应的外显率。为了测试 CE 的存在，我们提出了偶奇 (EO) 测试，并证明它在一系列现实的生物模型中进行了校准。应用英国生物库中的 EO 测试，我们在涵盖疾病、人体测量和血液类别的 26 个性状中的 18 个中发现了 CE 证据。最后，我们将 EO 测试扩展到组织特异性富集，并识别出几个看似合理的组织性状对。总体而言，CE 是遗传结构的一个维度，可以捕获复杂人类特征中结构化、系统性的上位性形式。