The role of READ1 and KIAA0319 genetic variations in developmental dyslexia: testing main and interactive effects

Abstract

Developmental dyslexia (DD) is a complex heritable condition characterized by impaired reading abilities. Two well-replicated candidate risk factors are as follows: (1) regulatory element associated with dyslexia 1 (READ1), which is located in intron 2 of DCDC2 and acts as a binding site for protein regulation of DCDC2 expression; and (2) a three-single-nucleotide polymorphism risk haplotype spanning KIAA0319. Phylogenetically similar READ1 variants showed synergistic effects with the KIAA0319 risk haplotype on reading-related phenotypes in a general population sample. Here we examine the association between different allele classes in READ1, the KIAA0319 risk haplotype and reading-related traits in a cohort of 368 Italian children with DD and their siblings (n=266) by testing both main and non-additive effects. We replicated the deleterious main effects upon both reading accuracy and speed exerted by the longer READ1 alleles. We further supported the interdependence through non-additive, possibly antagonistic, effects between READ1 and the KIAA0319 risk haplotype on reading accuracy. By suggesting the presence of common biological processes underlying reading (dis)ability, these findings represent initial support for a generalist effect of the non-additive interdependence between READ1 and the KIAA0319 risk haplotype. Moreover, our results confirm that using as much information as possible about genetic interdependence among dyslexia-candidate genes can help in clinically assessing the individual risk for DD.

Effect of READ1 on latent profiles of reading disorder and comorbid attention and language impairment subtypes

“…RU1-1 of READ1 in DCDC2 is significantly associated with impairments in processing speed and attention co-occurring with RD (class 4) in the GRaD sample, even after controlling for the significant effects of age and ADHD diagnosis. The results support prior evidence for a pleiotropic role of DCDC2 in reading and attention performance (Couto et al, 2009;Mascheretti et al, 2017;Riva et al, 2015). To date, there has only been one study that has examined the effects of different READ1 alleles on attention measures.…”

“…In Western Europeans, Powers et al (2016) observed a protective effect of RU1-1 when tested for association against severe RD status (Powers et al, 2016). In an Italian sample, Trezzi et al (2017) found no effect of RU1-1 on different reading measures collected in Italian. In the present analysis, the observed effects of RU1-1 were deleterious in Hispanic and African American subjects, though specifically for co-occurring RD with poor processing speed and attention.…”

“…This was further supported by genetic association of variants within DCDC2 (Meng et al, 2011(Meng et al, , 2005Powers et al, 2013Powers 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-by-gene interaction between DCDC2 and KIAA0319, another candidate risk gene for RD (Mascheretti et al, 2017;Riva, Marino, Giorda, Molteni, & Nobile, 2015). These studies provide compelling evidence that DCDC2 has pleiotropic effects on reading, language, and attention.…”

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

“…While we have not yet identified the other variants that help confer these differences, identifying these opposing effects of RU1-1 alleles will aid in the discovery of additional factors contributing to these complex traits. The present findings, together with those from Powers et al (2016), and Trezzi et al (2017), highlight that differences in effect of the RU1-1 group of READ1 alleles exist and warrant further investigation to understand why.…”

“…In Western Europeans, Powers et al (2016) observed a protective effect of RU1-1 when tested for association against severe RD status (Powers et al, 2016). In an Italian sample, Trezzi et al (2017) found no effect of RU1-1 on different reading measures collected in Italian. In the present analysis, the observed effects of RU1-1 were deleterious in Hispanic and African American subjects, though specifically for co-occurring RD with poor processing speed and attention.…”