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DeCAF: a novel method to identify cell-type specific regulatory variants and their role in cancer risk.

ABSTRACT: Here, we propose DeCAF (DEconvoluted cell type Allele specific Function), a new method to identify cell-fraction (cf) QTLs in tumors by leveraging both allelic and total expression information. Applying DeCAF to RNA-seq data from TCGA, we identify 3664 genes with cfQTLs (at 10% FDR) in 14 cell types, a 5.63× increase in discovery over conventional interaction-eQTL mapping. cfQTLs replicated in external cell-type-specific eQTL data are more enriched for cancer risk than conventional eQTLs. Our new method, DeCAF, empowers the discovery of biologically meaningful cfQTLs from bulk RNA-seq data in moderately sized studies.

SUBMITTER: Kalita CA

PROVIDER: S-EPMC9264694 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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DeCAF: a novel method to identify cell-type specific regulatory variants and their role in cancer risk.

Kalita Cynthia A CA Gusev Alexander A

Genome biology 20220708 1

Here, we propose DeCAF (DEconvoluted cell type Allele specific Function), a new method to identify cell-fraction (cf) QTLs in tumors by leveraging both allelic and total expression information. Applying DeCAF to RNA-seq data from TCGA, we identify 3664 genes with cfQTLs (at 10% FDR) in 14 cell types, a 5.63× increase in discovery over conventional interaction-eQTL mapping. cfQTLs replicated in external cell-type-specific eQTL data are more enriched for cancer risk than conventional eQTLs. Our ne ...[more]

PMID: 35804456

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Project description:BackgroundThe highly dimensional data produced by functional genomic (FG) studies makes it difficult to visualize relationships between gene products and experimental conditions (i.e., assays). Although dimensionality reduction methods such as principal component analysis (PCA) have been very useful, their application to identify assay-specific signatures has been limited by the lack of appropriate methodologies. This article proposes a new and powerful PCA-based method for the identification of assay-specific gene signatures in FG studies.ResultsThe proposed method (PM) is unique for several reasons. First, it is the only one, to our knowledge, that uses gene contribution, a product of the loading and expression level, to obtain assay signatures. The PM develops and exploits two types of assay-specific contribution plots, which are new to the application of PCA in the FG area. The first type plots the assay-specific gene contribution against the given order of the genes and reveals variations in distribution between assay-specific gene signatures as well as outliers within assay groups indicating the degree of importance of the most dominant genes. The second type plots the contribution of each gene in ascending or descending order against a constantly increasing index. This type of plots reveals assay-specific gene signatures defined by the inflection points in the curve. In addition, sharp regions within the signature define the genes that contribute the most to the signature. We proposed and used the curvature as an appropriate metric to characterize these sharp regions, thus identifying the subset of genes contributing the most to the signature. Finally, the PM uses the full dataset to determine the final gene signature, thus eliminating the chance of gene exclusion by poor screening in earlier steps. The strengths of the PM are demonstrated using a simulation study, and two studies of real DNA microarray data--a study of classification of human tissue samples and a study of E. coli cultures with different medium formulations.ConclusionWe have developed a PCA-based method that effectively identifies assay-specific signatures in ranked groups of genes from the full data set in a more efficient and simplistic procedure than current approaches. Although this work demonstrates the ability of the PM to identify assay-specific signatures in DNA microarray experiments, this approach could be useful in areas such as proteomics and metabolomics.

Dataset Information

DeCAF: a novel method to identify cell-type specific regulatory variants and their role in cancer risk.

Publications

DeCAF: a novel method to identify cell-type specific regulatory variants and their role in cancer risk.

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