You are here

Article Text

Article menu
Complex traits
Original article
The regulatory element READ1 epistatically influences reading and language, with both deleterious and protective alleles
  1. Natalie R Powers1,2,
  2. John D Eicher1,
  3. Laura L Miller3,
  4. Yong Kong4,5,
  5. Shelley D Smith6,
  6. Bruce F Pennington7,
  7. Erik G Willcutt8,9,
  8. Richard K Olson8,9,
  9. Susan M Ring3,10,
  10. Jeffrey R Gruen1,2,11
  1. 1Investigate Medicine, Yale University, New Haven, Connecticut, USA
  2. 2Department of Pediatrics, Yale University, New Haven, Connecticut, USA
  3. 3School of Social and Community Medicine, University of Bristol, Bristol, UK
  4. 4Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA
  5. 5W.M. Keck Foundation Biotechnology Resource Laboratory, Yale University, New Haven, Connecticut, USA
  6. 6Departments of Pediatrics and Developmental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA
  7. 7Department of Psychology, University of Denver, Denver, Colorado, USA
  8. 8Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, USA
  9. 9Departments of Psychology and Neuroscience, University of Colorado, Boulder, Colorado, USA
  10. 10MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
  11. 11Department of Investigative Medicine, Yale University, New Haven, Connecticut, USA
  1. Correspondence to Dr Jeffrey R Gruen, Yale Child Health Research Center, Yale University School of Medicine, 464 Congress Avenue, New Haven, CT, 06520-8081, USA; jeffrey.gruen{at}yale.edu

Abstract

Background Reading disability (RD) and language impairment (LI) are heritable learning disabilities that obstruct acquisition and use of written and spoken language, respectively. We previously reported that two risk haplotypes, each in strong linkage disequilibrium (LD) with an allele of READ1, a polymorphic compound short tandem repeat within intron 2 of risk gene DCDC2, are associated with RD and LI. Additionally, we showed a non-additive genetic interaction between READ1 and KIAHap, a previously reported risk haplotype in risk gene KIAA0319, and that READ1 binds the transcriptional regulator ETV6.

Objective To examine the hypothesis that READ1 is a transcriptional regulator of KIAA0319.

Methods We characterised associations between READ1 alleles and RD and LI in a large European cohort, and also assessed interactions between READ1 and KIAHap and their effect on performance on measures of reading, language and IQ. We also used family-based data to characterise the genetic interaction, and chromatin conformation capture (3C) to investigate the possibility of a physical interaction between READ1 and KIAHap.

Results and conclusions READ1 and KIAHap show interdependence—READ1 risk alleles synergise with KIAHap, whereas READ1 protective alleles act epistatically to negate the effects of KIAHap. The family data suggest that these variants interact in trans genetically, while the 3C results show that a region of DCDC2 containing READ1 interacts physically with the region upstream of KIAA0319. These data support a model in which READ1 regulates KIAA0319 expression through KIAHap and in which the additive effects of READ1 and KIAHap alleles are responsible for the trans genetic interaction.

  • dyslexia
  • reading disability
  • language impairment
  • Complex traits
  • READ1

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1136/jmedgenet-2015-103418

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    View Full Text

    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.