Variant-specific priors clarify colocalisation analysis.

IF 4 2区 生物学 Q1 GENETICS & HEREDITY
Jeffrey M Pullin, Chris Wallace
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引用次数: 0

Abstract

Linking GWAS variants to their causal gene and context remains an ongoing challenge. A widely used method for performing this analysis is the coloc package for statistical colocalisation analysis, which can be used to link GWAS and eQTL associations. Currently, coloc assumes that all variants in a region are equally likely to be causal, despite the success of fine-mapping methods that use additional information to adjust their prior probabilities. In this paper we propose and implement an approach for specifying variant-specific prior probabilities in the coloc method. We describe and compare six source of information for specifying prior probabilities: non-coding constraint, enhancer-gene link scores, the output of the PolyFun method and three estimates of eQTL-TSS distance densities. Using simulations and analysis of ground-truth pQTL-eQTL colocalisations we show that variant-specific priors, particularly the eQTL-TSS distance density priors, can improve colocalisation performance. Furthermore, across GWAS-eQTL colocalisations variant-specific priors changed colocalisation significance in up to 14.1% of colocalisations, at some loci revealing the likely causal gene.

变异特异性先验澄清了共定位分析。
将GWAS变异与其致病基因和环境联系起来仍然是一个持续的挑战。用于执行此分析的广泛使用的方法是用于统计共定位分析的colc包,它可用于连接GWAS和eQTL关联。目前,coloc假设一个地区的所有变异都同样可能是因果关系,尽管使用附加信息来调整其先验概率的精细映射方法取得了成功。在本文中,我们提出并实现了一种在coloc方法中指定特定变量先验概率的方法。我们描述并比较了用于指定先验概率的六种信息来源:非编码约束、增强基因链接分数、PolyFun方法的输出和eQTL-TSS距离密度的三种估计。通过对基真pQTL-eQTL共定位的仿真和分析,我们发现变异特异性先验,特别是eQTL-TSS距离密度先验,可以提高共定位性能。此外,在GWAS-eQTL共定位中,变异特异性先验改变了多达14.1%的共定位意义,在一些位点上揭示了可能的因果基因。
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来源期刊
PLoS Genetics
PLoS Genetics GENETICS & HEREDITY-
自引率
2.20%
发文量
438
期刊介绍: PLOS Genetics is run by an international Editorial Board, headed by the Editors-in-Chief, Greg Barsh (HudsonAlpha Institute of Biotechnology, and Stanford University School of Medicine) and Greg Copenhaver (The University of North Carolina at Chapel Hill). Articles published in PLOS Genetics are archived in PubMed Central and cited in PubMed.
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