Genetic effects on promoter usage are highly context-specific and contribute to complex traits
- University of Tartu, Estonia
- Wellcome Sanger Institute, United Kingdom
- University of Cambridge, United Kingdom
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/.
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Genetic effects on promoter usage are highly context-specific and contribute to complex traitsEuropean Nucleotide Archive, PRJEB20734.
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Genetic effects on promoter usage are highly context-specific and contribute to complex traitsEuropean Genome-phenome Archive, EGAS00001000876.
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Shared genetic effects on chromatin and gene expression indicate a role for enhancer priming in immune responseEuropean Nucleotide Archive, PRJEB18997.
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Shared genetic effects on chromatin and gene expression indicate a role for enhancer priming in immune responseEuropean Genome-phenome Archive, EGAS00001002236.
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Common genetic variation drives molecular heterogeneity in human iPSCsEuropean Nucleotide Archive, PRJEB11749.
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Common genetic variation drives molecular heterogeneity in human iPSCsEuropean Genome-phenome Archive, EGAD00010000773.
Article and author information
Author details
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.
Reviewing Editor
- Stephen Parker, University of Michigan, United States
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.
Version history
- Received: September 5, 2018
- Accepted: January 8, 2019
- Accepted Manuscript published: January 8, 2019 (version 1)
- 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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Genetic effects on promoter usage are highly context-specific and contribute to complex traits
eLife 8:e41673.
https://doi.org/10.7554/eLife.41673
Further reading
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- Computational and Systems Biology
- Medicine
Background:
Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Most cases of preterm birth occur spontaneously and result from preterm labor with intact (spontaneous preterm labor [sPTL]) or ruptured (preterm prelabor rupture of membranes [PPROM]) membranes. The prediction of spontaneous preterm birth (sPTB) remains underpowered due to its syndromic nature and the dearth of independent analyses of the vaginal host immune response. Thus, we conducted the largest longitudinal investigation targeting vaginal immune mediators, referred to herein as the immunoproteome, in a population at high risk for sPTB.
Methods:
Vaginal swabs were collected across gestation from pregnant women who ultimately underwent term birth, sPTL, or PPROM. Cytokines, chemokines, growth factors, and antimicrobial peptides in the samples were quantified via specific and sensitive immunoassays. Predictive models were constructed from immune mediator concentrations.
Results:
Throughout uncomplicated gestation, the vaginal immunoproteome harbors a cytokine network with a homeostatic profile. Yet, the vaginal immunoproteome is skewed toward a pro-inflammatory state in pregnant women who ultimately experience sPTL and PPROM. Such an inflammatory profile includes increased monocyte chemoattractants, cytokines indicative of macrophage and T-cell activation, and reduced antimicrobial proteins/peptides. The vaginal immunoproteome has improved predictive value over maternal characteristics alone for identifying women at risk for early (<34 weeks) sPTB.
Conclusions:
The vaginal immunoproteome undergoes homeostatic changes throughout gestation and deviations from this shift are associated with sPTB. Furthermore, the vaginal immunoproteome can be leveraged as a potential biomarker for early sPTB, a subset of sPTB associated with extremely adverse neonatal outcomes.
Funding:
This research was conducted by the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS) under contract HHSN275201300006C. ALT, KRT, and NGL were supported by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health.
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- Computational and Systems Biology
- Genetics and Genomics
Runs of homozygosity (ROH) segments, contiguous homozygous regions in a genome were traditionally linked to families and inbred populations. However, a growing literature suggests that ROHs are ubiquitous in outbred populations. Still, most existing genetic studies of ROH in populations are limited to aggregated ROH content across the genome, which does not offer the resolution for mapping causal loci. This limitation is mainly due to a lack of methods for the efficient identification of shared ROH diplotypes. Here, we present a new method, ROH-DICE, to find large ROH diplotype clusters, sufficiently long ROHs shared by a sufficient number of individuals, in large cohorts. ROH-DICE identified over 1 million ROH diplotypes that span over 100 SNPs and are shared by more than 100 UK Biobank participants. Moreover, we found significant associations of clustered ROH diplotypes across the genome with various self-reported diseases, with the strongest associations found between the extended HLA region and autoimmune disorders. We found an association between a diplotype covering the HFE gene and hemochromatosis, even though the well-known causal SNP was not directly genotyped or imputed. Using a genome-wide scan, we identified a putative association between carriers of an ROH diplotype in chromosome 4 and an increase in mortality among COVID-19 patients (P-value=1.82×10-11). In summary, our ROH-DICE method, by calling out large ROH diplotypes in a large outbred population, enables further population genetics into the demographic history of large populations. More importantly, our method enables a new genome-wide mapping approach for finding disease-causing loci with multi-marker recessive effects at a population scale.
