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

Abstract

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.

Translating dyslexia across species

“…For example, KIAA0319, within 200 kb of DCDC2 on the DYX2 locus, has been shown to contribute to RD based on human, animal, and cellular studies (Scerri et al, 2011;Eicher et al, 2014;Che, Girgenti, & Loturco, 2013;Ludwig et al, 2008;Meng et al, 2011Meng et al, , 2005Peschansky et al, 2010;Truong et al, 2014). In addition, the three-marker risk haplotype in KIAA0319 (KIAHap) interacts with deleterious alleles of READ1 in a nonadditive manner to adversely affect reading and language performance, while protective alleles of READ1 epistatically negate the effect of KIAHap (Powers et al, 2013(Powers et al, , 2015. Biologically, assays using chromatin conformation capture (3C) demonstrate that the genomic region containing READ1 in DCDC2 physically interacts with a region upstream of KIAA0319 (promoter region), suggesting that READ1 regulates KIAA0319 expression (Powers et al, 2015).…”

“…In addition, the three-marker risk haplotype in KIAA0319 (KIAHap) interacts with deleterious alleles of READ1 in a nonadditive manner to adversely affect reading and language performance, while protective alleles of READ1 epistatically negate the effect of KIAHap (Powers et al, 2013(Powers et al, , 2015. Biologically, assays using chromatin conformation capture (3C) demonstrate that the genomic region containing READ1 in DCDC2 physically interacts with a region upstream of KIAA0319 (promoter region), suggesting that READ1 regulates KIAA0319 expression (Powers et al, 2015). These studies are essential in order to understand the link between CDSG risk variants, behavioral, and cognitive processing deficits reported in individuals with RD, so that more comprehensive interventions can be developed.…”

Visual motion and rapid auditory processing are solid endophenotypes of developmental dyslexia

“…; Powers et al . , ). Taking into account these effects has been shown to improve the phenotypic variance explained by etiological risk factors (Plomin ).…”

“…It is unlikely that a single model connects all the DD-candidate genes and their corresponding proteins at the molecular level; instead, several etiopathogenetic cascades involved in neuronal migration and neurite outgrowth is perhaps a more comprehensive and plausible model for DD (Poelmans et al 2011). Second, the pathways from genes to DD are not straightforward (cf., 'the missing heritability problem') (Maher 2008), and can be influenced by several events, such as incomplete linkage disequilibrium between causal variants and genotyped SNPs (Yang et al 2011), environmental effects, as well as gene-by-gene and gene-by-environment phenomena (Harold et al 2006;Ludwig et al 2008;Mascheretti et al 2013Mascheretti et al , 2015McGrath et al 2007;Powers et al 2013Powers et al , 2016. Taking into account these effects has been shown to improve the phenotypic variance explained by etiological risk factors (Plomin 2013).…”

Effect of READ1 on latent profiles of reading disability and comorbid attention and language learning disability subtypes

“…A univariate linkage analysis for ADHD and bivariate linkage analysis for ADHD and reading measures in a sample of sibling-pairs selected for co-occurrence identified a significant linkage signal in the region of 6p22 (Willcutt et al, 2002). This was further supported by genetic analyses variants within DCDC2 Meng et al, 2005;Powers et al, 2013;Powers et al, 2016). Quantitative measures of language (Cope et al, 2012), inattention and hyperactivity/impulsivity (Couto et al, 2009;Willcutt et al, 2002) have also been associated with variants of DCDC2, as well as a gene-bygene interaction between DCDC2 and KIAA0319, another candidate risk gene for RD Riva et al, 2015).…”