title: The regulatory element READ1 epistatically influences reading and language, with both deleterious and protective alleles.
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.
  
  
  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.
authors.affiliation: Investigate Medicine, Yale University, New Haven, Connecticut, USA Department of Pediatrics, Yale University, New Haven, Connecticut, USA.
authors.forename: Natalie R
authors.initials: NR
authors.lastname: Powers
authors.affiliation: Investigate Medicine, Yale University, New Haven, Connecticut, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Eicher
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Miller
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA W.M. Keck Foundation Biotechnology Resource Laboratory, Yale University, New Haven, Connecticut, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Departments of Pediatrics and Developmental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Shelley D
authors.initials: SD
authors.lastname: Smith
authors.affiliation: Department of Psychology, University of Denver, Denver, Colorado, USA.
authors.forename: Bruce F
authors.initials: BF
authors.lastname: Pennington
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, USA Departments of Psychology and Neuroscience, University of Colorado, Boulder, Colorado, USA.
authors.forename: Erik G
authors.initials: EG
authors.lastname: Willcutt
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, USA Departments of Psychology and Neuroscience, University of Colorado, Boulder, Colorado, USA.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Olson
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ring
authors.affiliation: Investigate Medicine, Yale University, New Haven, Connecticut, USA Department of Pediatrics, Yale University, New Haven, Connecticut, USA Department of Investigative Medicine, Yale University, New Haven, Connecticut, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Gruen
mesh_terms: D000483:Alleles; D004843:Epistasis, Genetic; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007438:Introns; D007806:Language Disorders / Q000235:genetics* / Q000503:physiopathology; D007859:Learning Disabilities / Q000235:genetics* / Q000503:physiopathology; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy; D012045:Regulatory Sequences, Nucleic Acid; D020080:Tandem Repeat Sequences
chemical_list: C510451:DCDC2 protein, human; C500377:KIAA0319 protein, human; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins
keywords: Complex traits; READ1; dyslexia; language impairment; reading disability