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A powerful and versatile colocalization test.

ABSTRACT: Transcriptome-wide association studies (TWAS and PrediXcan) have been increasingly applied to detect associations between genetically predicted gene expressions and GWAS traits, which may suggest, however do not completely determine, causal genes for GWAS traits, due to the likely violation of their imposed strong assumptions for causal inference. Testing colocalization moves it closer to establishing causal relationships: if a GWAS trait and a gene's expression share the same associated SNP, it may suggest a regulatory (and thus putative causal) role of the SNP mediated through the gene on the GWAS trait. Accordingly, it is of interest to develop and apply various colocalization testing approaches. The existing approaches may each have some severe limitations. For instance, some methods test the null hypothesis that there is colocalization, which is not ideal because often the null hypothesis cannot be rejected simply due to limited statistical power (with too small sample sizes). Some other methods arbitrarily restrict the maximum number of causal SNPs in a locus, which may lead to loss of power in the presence of wide-spread allelic heterogeneity. Importantly, most methods cannot be applied to either GWAS/eQTL summary statistics or cases with more than two possibly correlated traits. Here we present a simple and general approach based on conditional analysis of a locus on multiple traits, overcoming the above and other shortcomings of the existing methods. We demonstrate that, compared with other methods, our new method can be applied to a wider range of scenarios and often perform better. We showcase its applications to both simulated and real data, including a large-scale Alzheimer's disease GWAS summary dataset and a gene expression dataset, and a large-scale blood lipid GWAS summary association dataset. An R package "jointsum" implementing the proposed method is publicly available at github.

SUBMITTER: Deng Y

PROVIDER: S-EPMC7176287 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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A powerful and versatile colocalization test.

Deng Yangqing Y Pan Wei W

PLoS computational biology 20200410 4

Transcriptome-wide association studies (TWAS and PrediXcan) have been increasingly applied to detect associations between genetically predicted gene expressions and GWAS traits, which may suggest, however do not completely determine, causal genes for GWAS traits, due to the likely violation of their imposed strong assumptions for causal inference. Testing colocalization moves it closer to establishing causal relationships: if a GWAS trait and a gene's expression share the same associated SNP, it ...[more]

PMID: 32275709

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Project description:MotivationColocalization of structures in biomedical images can lead to insights into biological behaviors. One class of colocalization problems is examining an annular structure (disk-shaped such as a cell, vesicle or molecule) interacting with a network structure (vascular, neuronal, cytoskeletal, organellar). Examining colocalization events across conditions is often complicated by changes in density of both structure types, confounding traditional statistical approaches since colocalization cannot be normalized to the density of both structure types simultaneously. We have developed a technique to measure colocalization independent of structure density and applied it to characterizing intercellular colocation with blood vessel networks. This technique could be used to analyze colocalization of any annular structure with an arbitrarily shaped network structure.ResultsWe present the circular colocalization affinity with network structures test (CIRCOAST), a novel statistical hypothesis test to probe for enriched network colocalization in 2D z-projected multichannel images by using agent-based Monte Carlo modeling and image processing to generate the pseudo-null distribution of random cell placement unique to each image. This hypothesis test was validated by confirming that adipose-derived stem cells (ASCs) exhibit enriched colocalization with endothelial cells forming arborized networks in culture and then applied to show that locally delivered ASCs have enriched colocalization with murine retinal microvasculature in a model of diabetic retinopathy. We demonstrate that the CIRCOAST test provides superior power and type I error rates in characterizing intercellular colocalization compared to generic approaches that are confounded by changes in cell or vessel density.Availability and implementationCIRCOAST source code available at: https://github.com/uva-peirce-cottler-lab/ARCAS.Supplementary informationSupplementary data are available at Bioinformatics online.

Dataset Information

A powerful and versatile colocalization test.

Publications

A powerful and versatile colocalization test.

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