1. Computational and Systems Biology
  2. Genetics and Genomics
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Genetic effects on promoter usage are highly context-specific and contribute to complex traits

  1. Kaur Alasoo  Is a corresponding author
  2. Julia Rodrigues
  3. John Danesh
  4. Daniel F Freitag
  5. Dirk S Paul
  6. Daniel J Gaffney
  1. University of Tartu, Estonia
  2. Wellcome Sanger Institute, United Kingdom
  3. University of Cambridge, United Kingdom
Research Article
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Cite this article as: eLife 2019;8:e41673 doi: 10.7554/eLife.41673

Abstract

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 3ʹ 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 3ʹ end usage. We found that promoters, splicing and 3ʹ 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.

Data availability

RNA-seq data from the acLDL stimulation study is available from ENA (PRJEB20734) and EGA (EGAS00001000876). RNA-seq data from the IFNɣ + Salmonella study is available from ENA (PRJEB18997) and EGA (EGAS00001002236). The imputed genotype data for HipSci cell lines is available from ENA (PRJEB11749) and EGA (EGAD00010000773). Processed data and QTL summary statistics are available from Zenodo: https://zenodo.org/communities/macrophage-tuqtls/.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Kaur Alasoo

    Institute of Computer Science, University of Tartu, Tartu, Estonia
    For correspondence
    kaur.alasoo@ut.ee
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1761-8881
  2. Julia Rodrigues

    Cellular Genetics, Wellcome Sanger Institute, Hinxton, United Kingdom
    Competing interests
    No competing interests declared.
  3. John Danesh

    Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  4. Daniel F Freitag

    Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    Daniel F Freitag, Since October 2015, Daniel F. Freitag has been a full-time employee of Bayer AG, Germany.
  5. Dirk S Paul

    Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8230-0116
  6. Daniel J Gaffney

    Cellular Genetics, Wellcome Sanger Institute, Hinxton, United Kingdom
    Competing interests
    No competing interests declared.

Funding

Wellcome (WT09805)

  • Kaur Alasoo
  • Julia Rodrigues
  • Daniel J Gaffney

British Heart Foundation (RG/13/13/30194)

  • John Danesh
  • Daniel F Freitag
  • Dirk S Paul

Estonian Research Council (MOBJD67)

  • Kaur Alasoo

Wellcome (WT099754/Z/12/Z)

  • Kaur Alasoo

Estonian Research Council (IUT34-4)

  • Kaur Alasoo

Wellcome (WT098503)

  • Daniel J Gaffney

British Heart Foundation Cambridge Centre of Excellence (RE/13/6/30180)

  • John Danesh
  • Daniel F Freitag
  • Dirk S Paul

Medical Research Council (MR/L003120/1)

  • John Danesh
  • Daniel F Freitag
  • Dirk S Paul

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Human induced pluripotent stem cells (iPSCs) lines from 123 healthy donors (72 female and 51 male) (Supplementary file 1) were obtained from the HipSci project (Kilpinen et al., 2017). Of these lines, 57 were initially grown in feeder-dependent medium and 66 were grown in feeder-free E8 medium. The cell lines were screened for mycoplasma by the HipSci project (Kilpinen et al., 2017). All samples for the HipSci project (Kilpinen et al., 2017) were collected from consented research volunteers recruited from the NIHR Cambridge BioResource (http://www.cambridgebioresource.org.uk). Samples were initially collected under ethics for iPSC derivation (REC Ref: 09/H0304/77, V2 04/01/2013), which require managed data access for all genetically identifying data. Later samples were collected under a revised consent (REC Ref: 09/H0304/77, V3 15/03/2013) under which all data, except from the Y chromosome from males, can be made openly available. The ethics approval was obtained from East of England - Cambridge East Research Ethics Committee. The iPSC lines used in this study are commercially available via the European Collection of Authenticated Cell Cultures. No new primary human samples were collected for this study.

Reviewing Editor

  1. Stephen Parker, University of Michigan, United States

Publication history

  1. Received: September 5, 2018
  2. Accepted: January 8, 2019
  3. Accepted Manuscript published: January 8, 2019 (version 1)
  4. Version of Record published: January 28, 2019 (version 2)

Copyright

© 2019, Alasoo et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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