Department of Psychiatry and Behavioral Sciences, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94143.
Bakar Computational Health Sciences Institute, University of California San Francisco, San Francisco, CA 94143.
Proc Natl Acad Sci U S A. 2021 Apr 13;118(15). doi: 10.1073/pnas.1922305118.
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.
遗传变异的相互作用-上位性-在模型系统中普遍存在，并且可以深刻影响进化适应、群体疾病动态、遗传图谱和精准医学的努力。在这项工作中，我们开发了一种结构多基因上位性模型，称为协调上位性（CE），并证明了最近的几种遗传结构理论都属于 CE 的正式范畴。与假设上位性和主效是独立的标准上位性模型不同，CE 捕捉了由于途径水平上位性而导致的上位性和主效之间的系统相关性，从而平衡地改变了遗传效应的外显率。为了检验 CE 的存在，我们提出了偶数-奇数（EO）检验，并证明它在一系列现实的生物学模型中是校准的。我们在英国生物库中应用 EO 检验，在 26 个疾病、人体测量和血液分类特征中发现了 18 个具有 CE 的证据。最后，我们将 EO 检验扩展到组织特异性富集，并确定了几个合理的组织-特征对。总的来说，CE 是遗传结构的一个维度，它可以捕捉复杂人类特征中结构化、系统性的上位性形式。
