Journal
BIOINFORMATICS
Volume 37, Issue 8, Pages 1125-1134Publisher
OXFORD UNIV PRESS
DOI: 10.1093/bioinformatics/btaa927
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Funding
- NIH from the National Institute of Human Genome Research [R01-HG008146]
- Flinn Foundation
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This study developed a novel algorithm, TreeMap, which accurately detects co-regulating variants in eQTL and enables genome-wide analysis of long-range eQTL with high computational efficiency. Applied to brain and colon samples data, numerous distal eQTL were discovered along with consistent long-range regulation of gene expression in both tissues.
Motivation: Expression quantitative trait loci (eQTL) harbor genetic variants modulating gene transcription. Fine mapping of regulatory variants at these loci is a daunting task due to the juxtaposition of causal and linked variants at a locus as well as the likelihood of interactions among multiple variants. This problem is exacerbated in genes with multiple cis-acting eQTL, where superimposed effects of adjacent loci further distort the association signals. Results: We developed a novel algorithm, TreeMap, that identifies putative causal variants in cis-eQTL accounting for multisite effects and genetic linkage at a locus. Guided by the hierarchical structure of linkage disequilibrium, TreeMap performs an organized search for individual and multiple causal variants. Via extensive simulations, we show that TreeMap detects co-regulating variants more accurately than current methods. Furthermore, its high computational efficiency enables genome-wide analysis of long-range eQTL. We applied TreeMap to GTEx data of brain hippocampus samples and transverse colon samples to search for eQTL in gene bodies and in 4 Mbps gene-flanking regions, discovering numerous distal eQTL. Furthermore, we found concordant distal eQTL that were present in both brain and colon samples, implying long-range regulation of gene expression.
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