A model and test for coordinated polygenic epistasis in complex traits.
A model and test for coordinated polygenic epistasis in complex traits.
复制标题
DOI：
10.1073/pnas.1922305118
复制
发表时间：
2021-04-13
影响因子：
11.1
通讯作者：
Dahl A
中科院分区：
文献类型：
--
作者：
Sheppard B;Rappoport N;Loh PR;Sanders SJ;Zaitlen N;Dahl A
跨生理途径、细胞类型和组织的系统级相互作用是跨不同领域广泛研究的核心生物学元素，包括进化、系统生物学和模式生物遗传学。然而，它们在人类遗传学中基本上被忽视，现有的方法无法解释大量复杂的性状遗传力。在这里，我们提出了协调上位性模型的复杂表型，概括了最近提出的几个理论上位性架构的人类性状。广义地说，协调衡量上位效应与边际效应协同作用的程度。它总结了一个维度的多基因效应正交的参数，如遗传力和上位性的标准估计。遗传变异之间的相互作用-上位性-在模型系统中普遍存在，并可能深刻影响进化适应，群体疾病动力学，遗传图谱和精准医学工作。在这项工作中，我们开发了一个模型结构化的多基因上位性，称为协调上位性（CE），并证明了最近的遗传结构的几个理论属于CE的正式保护伞。与假设上位性和主效应是独立的标准上位性模型不同，CE捕获了上位性和主效应之间的系统相关性，这些相关性是由路径水平的上位性引起的，平衡地扭曲了遗传效应的随机性。为了检验CE的存在，我们提出了奇偶（EO）检验，并证明它是校准在一系列现实的生物模型。应用EO测试在英国生物银行，我们发现CE的证据在18的26个性状跨越疾病，人体测量，和血液类别。最后，我们将EO测试扩展到组织特异性富集，并确定了几个合理的组织性状对。总的来说，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的系统上位性形式。
Systems-level interactions across physiological pathways, cell types, and tissues are core biological elements widely studied across diverse fields including evolution, systems biology, and model-organism genetics. However, they are essentially ignored in human genetics, and existing approaches fail to interpretably explain substantial complex trait heritability. Here, we propose the coordinated epistasis model of complex phenotypes that generalizes several recently proposed theoretical epistatic architectures of human traits. Broadly, coordination measures the degree to which epistasis effects act in concert with respect to marginal effects. It summarizes a dimension of polygenic effects orthogonal to parameters like heritability and standard estimates of epistasis. 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.
登录
查看更多内容
影响因子：
4.5
作者：
Chen A;Liu Y;Williams SM;Morris N;Buchner DA
通讯作者：
Buchner DA
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
DOI：
10.1093/bioinformatics/btu848
发表时间：
2015-05-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Euesden J;Lewis CM;O'Reilly PF
通讯作者：
O'Reilly PF
影响因子：
30.8
作者：
Finucane HK;Reshef YA;Anttila V;Slowikowski K;Gusev A;Byrnes A;Gazal S;Loh PR;Lareau C;Shoresh N;Genovese G;Saunders A;Macosko E;Pollack S;Brainstorm Consortium;Perry JRB;Buenrostro JD;Bernstein BE;Raychaudhuri S;McCarroll S;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
64.5
作者：
Boyle EA;Li YI;Pritchard JK
通讯作者：
Pritchard JK