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Elife. 2019 Jan 8;8. pii: e41673. doi: 10.7554/eLife.41673.

Genetic effects on promoter usage are highly context-specific and contribute to complex traits.

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Institute of Computer Science, University of Tartu, Tartu, Estonia.
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom.
BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom.
National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.


Genetic variants regulating RNA splicing and transcript usage have been implicated in both common and rare diseases. Although transcript usage quantitative trait loci (tuQTLs) have been mapped across multiple cell types and contexts, it is challenging to distinguish between the main molecular mechanisms controlling transcript usage: promoter choice, splicing and 3' end choice. Here, we analysed RNA-seq data from human macrophages exposed to three inflammatory and one metabolic stimulus. In addition to conventional gene-level and transcript-level analyses, we also directly quantified promoter usage, splicing and 3' end usage. We found that promoters, splicing and 3' ends were predominantly controlled by independent genetic variants enriched in distinct genomic features. Promoter usage QTLs were also 50% more likely to be context-specific than other tuQTLs and constituted 25% of the transcript-level colocalisations with complex traits. Thus, promoter usage might be an underappreciated molecular mechanism mediating complex trait associations in a context-specific manner.


RNA-seq; computational biology; genetics; genomics; human; macrophages; splicing; systems biology; transcription

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