Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease

PLoS Computational Biology
J Kenneth BaillieDavid A Hume

Abstract

Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns of transcriptional activity. Accordingly, shared transcriptional activity (coexpression) may help prioritise loci associated with a given trait, and help to identify underlying biological processes. Using cap analysis of gene expression (CAGE) profiles of promoter- and enhancer-derived RNAs across 1824 human samples, we have analysed coexpression of RNAs originating from trait-associated regulatory regions using a novel quantitative method (network density analysis; NDA). For most traits studied, phenotype-associated variants in regulatory regions were linked to tightly-coexpressed networks that are likely to share important functional characteristics. Coexpression provides a new signal, independent of phenotype association, to enable fine mapping of causative variants. The NDA coexpression approach identifies new genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and gen...Continue Reading

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Citations

Dec 13, 2018·American Journal of Respiratory and Critical Care Medicine·Brendon P Scicluna, J Kenneth Baillie
Sep 7, 2019·Critical Care : the Official Journal of the Critical Care Forum·Sara Clohisey, John Kenneth Baillie
Nov 22, 2018·Frontiers in Cardiovascular Medicine·Maria F HughesHelen M Roche

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Methods Mentioned

BETA
RNAseq
genotyping

Software Mentioned

FANTOM5
CAGE
LiftOver
ENSEMBL Perl API
GIANT
NDA
PASCAL

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