气候变化领域集成服务门户(CCPortal): A model and test for coordinated polygenic epistasis in complex traits

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DOI	10.1073/pnas.1922305118
	A model and test for coordinated polygenic epistasis in complex traits
	Sheppard B.; Rappoport N.; Loh P.-R.; Sanders S.J.; Zaitlen N.; Dahl A.
发表日期	2021
ISSN	00278424
卷号	118 期号:15
英文摘要	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. © This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
英文关键词	Epistasis; Genetics; Polygenic risk
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179921
作者单位	Department of Psychiatry and Behavioral Sciences, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94143, United States; Bakar Computational Health Sciences Institute, University of California San Francisco, San Francisco, CA 94143, United States; Program in Medical and Population Genetics, Broad Institute of Massachusetts, Institute of Technology and Harvard, Cambridge, MA 02142, United States; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States; Department of Neurology, University of California Los Angeles, Los Angeles, CA 90095, United States; Department of Computational Medicine, University of California Los Angeles, Los Angeles, CA 90095, United States; Section of Genetic Medicine, University of Chicago, Chicago, IL 60637, United States
推荐引用方式 GB/T 7714	Sheppard B.,Rappoport N.,Loh P.-R.,et al. A model and test for coordinated polygenic epistasis in complex traits[J],2021,118(15).
APA	Sheppard B.,Rappoport N.,Loh P.-R.,Sanders S.J.,Zaitlen N.,&Dahl A..(2021).A model and test for coordinated polygenic epistasis in complex traits.Proceedings of the National Academy of Sciences of the United States of America,118(15).
MLA	Sheppard B.,et al."A model and test for coordinated polygenic epistasis in complex traits".Proceedings of the National Academy of Sciences of the United States of America 118.15(2021).