特定变异先验信息阐明了共定位分析。

Variant-specific priors clarify colocalisation analysis.

作者信息

Pullin Jeffrey M, Wallace Chris

机构信息

MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom.

Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom.

出版信息

PLoS Genet. 2025 May 27;21(5):e1011697. doi: 10.1371/journal.pgen.1011697. eCollection 2025 May.

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.

摘要

将全基因组关联研究(GWAS)变异与其因果基因及背景联系起来仍然是一项持续存在的挑战。进行此类分析的一种广泛使用的方法是用于统计共定位分析的coloc软件包,它可用于关联GWAS和表达数量性状基因座(eQTL)关联。目前,coloc假定一个区域内的所有变异成为因果变异的可能性相同,尽管精细定位方法利用额外信息来调整其先验概率已取得成功。在本文中,我们提出并实现了一种在coloc方法中指定变异特异性先验概率的方法。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、增强子-基因链接分数、PolyFun方法的输出以及eQTL-转录起始位点(TSS)距离密度的三种估计值。通过模拟以及对真实蛋白质数量性状基因座(pQTL)-eQTL共定位的分析,我们表明变异特异性先验,特别是eQTL-TSS距离密度先验,可提高共定位性能。此外,在全基因组关联研究-表达数量性状基因座共定位中,变异特异性先验在高达14.1%的共定位中改变了共定位显著性,在某些基因座揭示了可能的因果基因。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7451/12140431/624bd6a3faac/pgen.1011697.g001.jpg

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