Complex effects of dyslexia risk factors account for ADHD-traits : evidence from two independent samples

Background: Developmental dyslexia (DD) and attention deficit/hyperactivity disorder (ADHD) are among the most common neurodevelopmental disorders, whose etiology involves multiple risk factors. DD and ADHD co-occur in the same individuals much more often than would be expected by chance. Several studies have found significant bivariate heritability, and specific genes associated with either DD or ADHD have been investigated for association in the other disorder. Moreover, there are likely to be gene-by-gene and gene-by-environment interaction effects (GxG and GxE, respectively) underlying the comorbidity between DD and ADHD. We investigated the pleiotropic effects of 19 SNPs spanning five DD genes (DYX1C1, DCDC2, KIAA0319, ROBO1 and GRIN2B) and seven DD environmental factors (smoke, miscarriage, birth weight, breastfeeding, parental age, socioeconomic status and parental education) for main, either 1) genetic or 2) environmental, 3) G×G, and 4) G×E upon inattention and hyperactivity/impulsivity. We then attempted replication of these findings in an independent twin cohort. Methods: Marker-trait association was analyzed by implementing the Quantitative Transmission Disequilibrium Test (QTDT). Environmental associations were tested by partial correlations. GxG were investigated by a general linear model equation and a family-based association test. GxE were analyzed through a general test for GxE in sib-pair-based association analysis of quantitative traits. Results: DCDC2-rs793862 was associated with hyperactivity/impulsivity via G×G (KIAA0319) and G×E (miscarriage). Smoke was significantly correlated with hyperactivity/impulsivity. We replicated the DCDC2×KIAA0319 interaction upon hyperactivity/impulsivity in the twin cohort. Conclusions: DD genetic (DCDC2) and environmental factors (smoke and miscarriage) underlie ADHD-traits supporting a potential pleiotropic effect

Strong motion deficits in dyslexia associated with DCDC2 gene alteration

Dyslexia is a specific impairment in reading that affects 1 in 10 people. Previous studies have failed to isolate a single cause of the disorder, but several candidate genes have been reported. We measured motion perception in two groups of dyslexics, with and without a deletion within the DCDC2 gene, a risk gene for dyslexia. We found impairment for motion particularly strong at high spatial frequencies in the population carrying the deletion. The data suggest that deficits in motion processing occur in a specific genotype, rather than the entire dyslexia population, contributing to the large variability in impairment of motion thresholds in dyslexia reported in the literature

Working memory mediates the effects of gestational age at birth on expressive language development in children

Objective: This study tested the role of temporary memory, measured by phonological short-term memory (pSTM) and verbal working memory (vWM), as a mediator of the effect of 3 putative risk factors (i.e., socioeconomic status, home literacy environment, birth gestational age) upon expressive and receptive language. Method: A community-based sample of 646 Italian children aged 6-11 years was assessed with a comprehensive battery of language and cognitive tests. A mediation analysis was used to examine whether memory mediates environmental/biological effects on language. Results: The results demonstrated a developmental cascade of effects, whereby the duration of pregnancy drives vWM functioning that, in turn, may affect expressive linguistic outcome Conclusion: Treatments focused on vWM, specifically to preterm children, may improve their language development, with enduring consequences on educational and psychosocial outcome

Selecting the Most Relevant Brain Regions to Classify Children with Developmental Dyslexia and Typical Readers by Using Complex Magnocellular Stimuli and Multiple Kernel Learning

Increasing evidence supports the presence of deficits in the visual magnocellular (M) system in developmental dyslexia (DD). The M system is related to the fronto-parietal attentional network. Previous neuroimaging studies have revealed reduced/absent activation within the visual M pathway in DD, but they have failed to characterize the extensive brain network activated by M stimuli. We performed a multivariate pattern analysis on a Region of Interest (ROI) level to differentiate between children with DD and age-matched typical readers (TRs) by combining full-field sinusoidal gratings, controlled for spatial and temporal frequencies and luminance contrast, and a coherent motion (CM) sensitivity task at 6%-CML6, 15%-CML15 and 40%-CML40. ROIs spanning the entire visual dorsal stream and ventral attention network (VAN) had higher discriminative weights and showed higher act1ivation in TRs than in children with DD. Of the two tasks, CM had the greatest weight when classifying TRs and children with DD in most of the ROIs spanning these streams. For the CML6, activation within the right superior parietal cortex positively correlated with reading skills. Our approach highlighted the dorsal stream and the VAN as highly discriminative areas between children with DD and TRs and allowed for a better characterization of the “dorsal stream vulnerability” underlying DD

Selecting the Most Relevant Brain Regions to Classify Children with Developmental Dyslexia and Typical Readers by Using Complex Magnocellular Stimuli and Multiple Kernel Learning

Increasing evidence supports the presence of deficits in the visual magnocellular (M) system in developmental dyslexia (DD). The M system is related to the fronto-parietal attentional network. Previous neuroimaging studies have revealed reduced/absent activation within the visual M pathway in DD, but they have failed to characterize the extensive brain network activated by M stimuli. We performed a multivariate pattern analysis on a Region of Interest (ROI) level to differentiate between children with DD and age-matched typical readers (TRs) by combining full-field sinusoidal gratings, controlled for spatial and temporal frequencies and luminance contrast, and a coherent motion (CM) sensitivity task at 6%-CML6, 15%-CML15 and 40%-CML40. ROIs spanning the entire visual dorsal stream and ventral attention network (VAN) had higher discriminative weights and showed higher act1ivation in TRs than in children with DD. Of the two tasks, CM had the greatest weight when classifying TRs and children with DD in most of the ROIs spanning these streams. For the CML6, activation within the right superior parietal cortex positively correlated with reading skills. Our approach highlighted the dorsal stream and the VAN as highly discriminative areas between children with DD and TRs and allowed for a better characterization of the “dorsal stream vulnerability” underlying DD

Complex effects of dyslexia risk factors account for ADHD traits: evidence from two independent samples

Backgroun

The Mediation Role of Dynamic Multisensory Processing Using Molecular Genetic Data in Dyslexia

Although substantial heritability has been reported and candidate genes have been identified, we are far from understanding the etiopathogenetic pathways underlying developmental dyslexia (DD). Reading-related endophenotypes (EPs) have been established. Until now it was unknown whether they mediated the pathway from gene to reading (dis)ability. Thus, in a sample of 223 siblings from nuclear families with DD and 79 unrelated typical readers, we tested four EPs (i.e., rapid auditory processing, rapid automatized naming, multisensory nonspatial attention and visual motion processing) and 20 markers spanning five DD-candidate genes (i.e., DYX1C1, DCDC2, KIAA0319, ROBO1 and GRIN2B) using a multiple-predictor/multiple-mediator framework. Our results show that rapid auditory and visual motion processing are mediators in the pathway from ROBO1-rs9853895 to reading. Specifically, the T/T genotype group predicts impairments in rapid auditory and visual motion processing which, in turn, predict poorer reading skills. Our results suggest that ROBO1 is related to reading via multisensory temporal processing. These findings support the use of EPs as an effective approach to disentangling the complex pathways between candidate genes and behavior

The Mediation Role of Dynamic Multisensory Processing Using Molecular Genetic Data in Dyslexia

Although substantial heritability has been reported and candidate genes have been identified, we are far from understanding the etiopathogenetic pathways underlying developmental dyslexia (DD). Reading-related endophenotypes (EPs) have been established. Until now it was unknown whether they mediated the pathway from gene to reading (dis)ability. Thus, in a sample of 223 siblings from nuclear families with DD and 79 unrelated typical readers, we tested four EPs (i.e., rapid auditory processing, rapid automatized naming, multisensory nonspatial attention and visual motion processing) and 20 markers spanning five DD-candidate genes (i.e., DYX1C1, DCDC2, KIAA0319, ROBO1 and GRIN2B) using a multiple-predictor/multiple-mediator framework. Our results show that rapid auditory and visual motion processing are mediators in the pathway from ROBO1-rs9853895 to reading. Specifically, the T/T genotype group predicts impairments in rapid auditory and visual motion processing which, in turn, predict poorer reading skills. Our results suggest that ROBO1 is related to reading via multisensory temporal processing. These findings support the use of EPs as an effective approach to disentangling the complex pathways between candidate genes and behavior