The regulatory element READ1 epistatically influences reading and language, with both deleterious and protective alleles

• Published in: Journal of medical genetics Vol. 53; no. 3; pp. 163 - 171
• Main Authors: Powers, Natalie R, Eicher, John D, Miller, Laura L, Kong, Yong, Smith, Shelley D, Pennington, Bruce F, Willcutt, Erik G, Olson, Richard K, Ring, Susan M, Gruen, Jeffrey R
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.03.2016; BMJ Publishing Group
• Series: Original article
• Subjects: Alleles; Complex Traits; Dyslexia; Epistasis, Genetic; Female; Gene expression; Haplotypes; Humans; Infant; Infant, Newborn; Influence; Introns; Language; Language Disorders - genetics; Language Disorders - physiopathology; Learning Disabilities - genetics; Learning Disabilities - physiopathology; Literacy; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Pregnancy; Reading; Regulatory Sequences, Nucleic Acid; Studies; Tandem Repeat Sequences; READ1; reading disability; Complex traits; language impairment; dyslexia
• ISSN: 0022-2593; 1468-6244
• DOI: 10.1136/jmedgenet-2015-103418

BackgroundReading 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.ObjectiveTo examine the hypothesis that READ1 is a transcriptional regulator of KIAA0319.MethodsWe 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 conclusionsREAD1 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.