Genetic interactions affecting human gene expression identified by variance association mapping

  1. Andrew A Brown
  2. Alfonso Buil
  3. Ana Viñuela
  4. Tuuli Lappalainen
  5. Hou-Feng Zheng
  6. John B Richards
  7. Kerrin S Small
  8. Timothy D Spector
  9. Emmanouil T Dermitzakis
  10. Richard Durbin  Is a corresponding author
  1. Wellcome Trust Sanger Institute, United Kingdom
  2. University of Geneva, Switzerland
  3. King's College London, United Kingdom
  4. McGill University, Canada
  5. The Wellcome Trust Sanger Institute, United Kingdom

Abstract

Non-additive interaction between genetic variants, or epistasis, is a possible explanation for the gap between heritability of complex traits and the variation explained by identified genetic loci. Interactions give rise to genotype dependent variance, and therefore the identification of variance quantitative trait loci can be an intermediate step to discover both epistasis and gene by environment effects (GxE). Using RNA-sequence data from lymphoblastoid cell lines (LCLs) from the TwinsUK cohort, we identify a candidate set of 508 variance associated SNPs. Exploiting the twin design we show that GxE plays a role in ~70% of these associations. Further investigation of these loci reveals 57 epistatic interactions that replicated in a smaller dataset, explaining on average 4.3% of phenotypic variance. In 24 cases, more variance is explained by the interaction than their additive contributions. Using molecular phenotypes in this way may provide a route to uncovering genetic interactions underlying more complex traits.

Article and author information

Author details

  1. Andrew A Brown

    Wellcome Trust Sanger Institute, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  2. Alfonso Buil

    University of Geneva, Geneva, Switzerland
    Competing interests
    No competing interests declared.
  3. Ana Viñuela

    King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  4. Tuuli Lappalainen

    University of Geneva, Geneva, Switzerland
    Competing interests
    No competing interests declared.
  5. Hou-Feng Zheng

    McGill University, Montreal, Canada
    Competing interests
    No competing interests declared.
  6. John B Richards

    King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  7. Kerrin S Small

    King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  8. Timothy D Spector

    King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  9. Emmanouil T Dermitzakis

    University of Geneva, Geneva, Switzerland
    Competing interests
    Emmanouil T Dermitzakis, Reviewing editor, eLife.
  10. Richard Durbin

    The Wellcome Trust Sanger Institute, Cambridge, United Kingdom
    For correspondence
    rd@sanger.ac.uk
    Competing interests
    No competing interests declared.

Reviewing Editor

  1. Philipp Khaitovich, Partner Institute for Computational Biology, China

Ethics

Human subjects: This project was approved by the ethics committee at St Thomas' Hospital London, where all the biopsies were carried out. Volunteers gave informed consent and signed an approved consent form prior to the biopsy procedure. Volunteers were supplied with an appropriate detailed information sheet regarding the research project and biopsy procedure by post prior to attending for the biopsy. The St. Thomas' Research Ethics Committee (REC) approved on 20th September 2007 the protocol for dissemination of data, including DNA, with the REC reference number RE04/015. On 12th of March of 2008, the St Thomas' REC confirmed this approval extends to expression data.

Version history

  1. Received: August 21, 2013
  2. Accepted: March 13, 2014
  3. Accepted Manuscript published: April 25, 2014 (version 1)
  4. Version of Record published: May 20, 2014 (version 2)

Copyright

© 2014, Brown et al.

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

Metrics

  • 7,250
    views
  • 485
    downloads
  • 99
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Andrew A Brown
  2. Alfonso Buil
  3. Ana Viñuela
  4. Tuuli Lappalainen
  5. Hou-Feng Zheng
  6. John B Richards
  7. Kerrin S Small
  8. Timothy D Spector
  9. Emmanouil T Dermitzakis
  10. Richard Durbin
(2014)
Genetic interactions affecting human gene expression identified by variance association mapping
eLife 3:e01381.
https://doi.org/10.7554/eLife.01381

Share this article

https://doi.org/10.7554/eLife.01381

Further reading

    1. Chromosomes and Gene Expression
    2. Immunology and Inflammation
    Rajan M Thomas, Matthew C Pahl ... Andrew D Wells
    Research Article

    Ikaros is a transcriptional factor required for conventional T cell development, differentiation, and anergy. While the related factors Helios and Eos have defined roles in regulatory T cells (Treg), a role for Ikaros has not been established. To determine the function of Ikaros in the Treg lineage, we generated mice with Treg-specific deletion of the Ikaros gene (Ikzf1). We find that Ikaros cooperates with Foxp3 to establish a major portion of the Treg epigenome and transcriptome. Ikaros-deficient Treg exhibit Th1-like gene expression with abnormal production of IL-2, IFNg, TNFa, and factors involved in Wnt and Notch signaling. While Ikzf1-Treg-cko mice do not develop spontaneous autoimmunity, Ikaros-deficient Treg are unable to control conventional T cell-mediated immune pathology in response to TCR and inflammatory stimuli in models of IBD and organ transplantation. These studies establish Ikaros as a core factor required in Treg for tolerance and the control of inflammatory immune responses.

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Lucie Crhak Khaitova, Pavlina Mikulkova ... Karel Riha
    Research Article

    Heat stress is a major threat to global crop production, and understanding its impact on plant fertility is crucial for developing climate-resilient crops. Despite the known negative effects of heat stress on plant reproduction, the underlying molecular mechanisms remain poorly understood. Here, we investigated the impact of elevated temperature on centromere structure and chromosome segregation during meiosis in Arabidopsis thaliana. Consistent with previous studies, heat stress leads to a decline in fertility and micronuclei formation in pollen mother cells. Our results reveal that elevated temperature causes a decrease in the amount of centromeric histone and the kinetochore protein BMF1 at meiotic centromeres with increasing temperature. Furthermore, we show that heat stress increases the duration of meiotic divisions and prolongs the activity of the spindle assembly checkpoint during meiosis I, indicating an impaired efficiency of the kinetochore attachments to spindle microtubules. Our analysis of mutants with reduced levels of centromeric histone suggests that weakened centromeres sensitize plants to elevated temperature, resulting in meiotic defects and reduced fertility even at moderate temperatures. These results indicate that the structure and functionality of meiotic centromeres in Arabidopsis are highly sensitive to heat stress, and suggest that centromeres and kinetochores may represent a critical bottleneck in plant adaptation to increasing temperatures.