Evaluation of visual motion perception ability in mice with knockout of the dyslexia candidate susceptibility gene Dcdc2

Developmental dyslexia is a heritable disability characterized by difficulties in learning to read and write. The neurobiological and genetic mechanisms underlying dyslexia remain poorly understood; however, several dyslexia candidate risk genes have been identified. One of these candidate risk genes—doublecortin domain containing 2 (DCDC2)—has been shown to play a role in neuronal migration and cilia function. At a behavioral level, variants of DCDC2 have been associated with impairments in phonological processing, working memory and reading speed. Additionally, a specific mutation in DCDC2 has been strongly linked to deficits in motion perception—a skill subserving reading abilities. To further explore the relationship between DCDC2 and dyslexia, a genetic knockout (KO) of the rodent homolog of DCDC2 (Dcdc2) was created. Initial studies showed that Dcdc2 KOs display deficits in auditory processing and working memory. The current study was designed to evaluate the association between DCDC2 and motion perception, as these skills have not yet been assessed in the Dcdc2 KO mouse model. We developed a novel motion perception task, utilizing touchscreen technology and operant conditioning. Dcdc2 KOs displayed deficits on the Pairwise Discrimination task specifically as motion was added to visual stimuli. Following behavioral assessment, brains were histologically prepared for neuroanatomical analysis of the lateral geniculate nucleus (LGN). The cumulative distribution showed that Dcdc2 KOs exhibited more small neurons and fewer larger neurons in the LGN. Results compliment findings that DCDC2 genetic alteration results in anomalies in visual motion pathways in a subpopulation of dyslexic patients.     

Mutation of the dyslexia-associated gene Dcdc2 impairs LTM and visuo-spatial performance in mice

Developmental reading disorder (RD) affects 5-10% of school aged children, with a heritability of approximately 60%. Genetic association studies have identified several candidate RD susceptibility genes, including DCDC2; however, a direct connection between the function of these genes and cognitive or learning impairments remains unclear. Variants in DCDC2, a member of the doublecortin family of genes, have been associated in humans with RD and ADHD and Dcdc2 may play a role in neuronal migration in rats. In this study, we examined the effect of Dcdc2 mutation on cognitive abilities in mice using a visual attention and visuo-spatial learning and memory task. We show that both heterozygous and homozygous mutations of Dcdc2 result in persistent visuo-spatial memory deficits, as well as visual discrimination and long-term memory deficits. These behavioral deficits occur in the absence of neuronal migration disruption in the mutant mice, and may be comorbid with an anxiety phenotype. These are the first results to suggest a direct relationship between induced mutation in Dcdc2 and changes in behavioral measures. Dcdc2 mutant mice should prove useful in future studies designed to further dissect the underlying neural mechanisms that are impaired following Dcdc2 mutation.     

DCDC2 Mutations Cause a Renal-Hepatic Ciliopathy by Disrupting Wnt Signaling

Nephronophthisis-related ciliopathies (NPHP-RC) are recessive diseases characterized by renal dysplasia or degeneration. We here identify mutations of DCDC2 as causing a renal-hepatic ciliopathy. DCDC2 localizes to the ciliary axoneme and to mitotic spindle fibers in a cell-cycle-dependent manner. Knockdown of Dcdc2 in IMCD3 cells disrupts ciliogenesis, which is rescued by wild-type (WT) human DCDC2, but not by constructs that reflect human mutations. We show that DCDC2 interacts with DVL and DCDC2 overexpression inhibits β-catenin-dependent Wnt signaling in an effect additive to Wnt inhibitors. Mutations detected in human NPHP-RC lack these effects. A Wnt inhibitor likewise restores ciliogenesis in 3D IMCD3 cultures, emphasizing the importance of Wnt signaling for renal tubulogenesis. Knockdown of dcdc2 in zebrafish recapitulates NPHP-RC phenotypes, including renal cysts and hydrocephalus, which is rescued by a Wnt inhibitor and by WT, but not by mutant, DCDC2. We thus demonstrate a central role of Wnt signaling in the pathogenesis of NPHP-RC, suggesting an avenue for potential treatment of NPHP-RC.     

Long‐term perturbation of spine plasticity results in distinct impairments of cognitive function

Dendritic spines serve as the post‐synaptic structural component of synapses. The structure and function of dendritic spines are dynamically regulated by a number of signaling pathways and allow for normal neural processing, whereas aberrant spine changes are thought to contribute to cognitive impairment in neuropsychiatric and neurodegenerative disorders. However, spine changes within different brain regions and their contribution to specific cognitive functions, especially later in adulthood, is not well understood. In this study, we used late‐adult KALRN‐deficient mice as a tool to investigate the vulnerability of different cognitive functions to long‐term perturbations in spine plasticity in different forebrain regions. We found that in these mice, loss of one or both copies of KALRN lead to genotype and brain region‐dependent reductions in spine density. Surprisingly, heterozygote and knockout mice showed differential impairments in cognitive phenotypes, including working memory, social recognition, and social approach. Correlation analysis between the site and magnitude of spine loss and behavioral alterations suggests that the interplay between brain regions is critical for complex cognitive processing and underscores the importance of spine plasticity in normal cognitive function. Long‐term perturbation of spine plasticity results in distinct impairments of cognitive function. Using genetically modified mice deficient in a central regulator of spine plasticity, we investigated the brain region‐specific contribution of spine numbers to various cognitive functions. We found distinct cognitive functions display differential sensitivity to spine loss in the cortex and hippocampus. Our data support spines as neuronal structures important for cognition and suggest interplay between brain regions is critical for complex cognitive processing.     

Single point mutation on the gene encoding dysbindin results in recognition deficits

The dystrobrevin‐binding protein 1 (DTNBP1) gene is a candidate risk factor for schizophrenia and has been associated with cognitive ability in both patient populations and healthy controls. DTNBP1 encodes dysbindin protein, which is localized to synaptic sites and is reduced in the prefrontal cortex and hippocampus of patients with schizophrenia, indicating a potential role in schizophrenia etiology. Most studies of dysbindin function have focused on the sandy (sdy) mice that lack dysbindin protein and have a wide range of abnormalities. In this study, we examined dysbindin salt and pepper (spp) mice that possess a single point mutation on the Dtnbp1 gene predicted to reduce, but not eliminate, dysbindin expression. By western blot analysis, we found that spp homozygous (spp ?/?) mutants had reduced dysbindin and synaptosomal‐associated protein 25 (SNAP‐25) in the prefrontal cortex, but unaltered levels in hippocampus. Behaviorally, spp mutants performed comparably to controls on a wide range of tasks assessing locomotion, anxiety, spatial recognition and working memory. However, spp ?/? mice had selective deficits in tasks measuring novel object recognition and social novelty recognition. Our results indicate that reduced dysbindin and SNAP‐25 protein in the prefrontal cortex of spp ?/? is associated with selective impairments in recognition processing. These spp mice may prove useful as a novel mouse model to study cognitive deficits linked to dysbindin alterations. Our findings also suggest that aspects of recognition memory may be specifically influenced by DTNBP1 single nucleotide polymorphisms or risk haplotypes in humans and this connection should be further investigated.     

Association of DCDC2 Polymorphisms with Normal Variations in Reading Abilities in a Chinese Population

The doublecortin domain-containing 2 (DCDC2) gene, which is located on chromosome 6p22.1, has been widely suggested to be a candidate gene for dyslexia, but its role in typical reading development over time remains to be clarified. In the present study, we explored the role of DCDC2 in contributing to the individual differences in reading development from ages 6 to 11 years by analysing data from 284 unrelated children who were participating in the Chinese Longitudinal Study of Reading Development (CLSRD). The associations of eight single nucleotide polymorphisms (SNPs) in DCDC2 with the latent intercept and slope of children’s reading scores were examined in the first step. There was significant support for an association of rs807724 with the intercept for the reading comprehension measure of reading fluency, and the minor “G” allele was associated with poor reading performance. Next, we further tested the rs807724 SNP in association with the reading ability at each tested time and revealed that, in addition to significant associations with the two main reading measures (reading fluency and Chinese character reading) over multiple testing occasions, this SNP also showed associations with reading-related cognitive skills, including morphological production, orthographic judgment and phonological processing skills (rapid number naming, phoneme deletion, and tone detection). This study provides support for DCDC2 as a risk gene for reading disability and suggests that this gene is also operative for typical reading development in the Han population.     

The DYX2 locus and neurochemical signaling genes contribute to speech sound disorder and related neurocognitive domains

A major milestone of child development is the acquisition and use of speech and language. Communication disorders, including speech sound disorder (SSD), can impair a child's academic, social and behavioral development. Speech sound disorder is a complex, polygenic trait with a substantial genetic component. However, specific genes that contribute to SSD remain largely unknown. To identify associated genes, we assessed the association of the DYX2 dyslexia risk locus and markers in neurochemical signaling genes (e.g., nicotinic and dopaminergic) with SSD and related endophenotypes. We first performed separate primary associations in two independent samples – Cleveland SSD (210 affected and 257 unaffected individuals in 127 families) and Denver SSD (113 affected individuals and 106 unaffected individuals in 85 families) – and then combined results by meta‐analysis. DYX2 markers, specifically those in the 3′ untranslated region of DCDC2 (P = 1.43 × 10^?4), showed the strongest associations with phonological awareness. We also observed suggestive associations of dopaminergic‐related genes ANKK1 (P = 1.02 × 10^?2) and DRD2 (P = 9.22 × 10^?3) and nicotinic‐related genes CHRNA3 (P = 2.51 × 10^?3) and BDNF (P = 8.14 × 10^?3) with case–control status and articulation. Our results further implicate variation in putative regulatory regions in the DYX2 locus, particularly in DCDC2, influencing language and cognitive traits. The results also support previous studies implicating variation in dopaminergic and nicotinic neural signaling influencing human communication and cognitive development. Our findings expand the literature showing genetic factors (e.g., DYX2) contributing to multiple related, yet distinct neurocognitive domains (e.g., dyslexia, language impairment, and SSD). How these factors interactively yield different neurocognitive and language‐related outcomes remains to be elucidated.     

Genetic and behavioral characterization of a Kmt2d mouse mutant,a new model for Kabuki Syndrome

The recessive mutant mice bate palmas (bapa) ‐ claps in Portuguese arose from N‐ethyl‐N‐nitrosourea mutagenesis. A single nucleotide, T > C, change in exon 13, leading to a Thr₁₂₈₉Ala substitution, was identified in the lysine (K)‐specific methyltransferase 2D gene (Kmt2d) located on chromosome 15. Mutations with a loss‐of‐function in the KMT2D gene on chromosome 12 in humans are responsible for Kabuki syndrome (KS). Phenotypic characterization of the bapa mutant was performed using a behavioral test battery to evaluate the parameters related to general activity, the sensory nervous system, the psychomotor system, and the autonomous nervous system, as well as to measure motor function and spatial memory. Relative to BALB/cJ mice, the bapa mutant showed sensory and psychomotor impairments, such as hypotonia denoted by a surface righting reflex impairment and hindquarter fall, and a reduction in the auricular reflex, suggesting hearing impairment. Additionally, the enhanced general activity showed by the increased rearing and grooming frequency, distance traveled and average speed possibly presupposes the presence of hyperactivity of bapa mice compared with the control group. A slight motor coordination dysfunction was showed in bapa mice, which had a longer crossing time on the balance beam compared with BALB/cJ controls. Male bapa mice also showed spatial gait pattern changes, such as a shorter stride length and shorter step length. In conclusion, the bapa mouse may be a valuable animal model to study the mechanisms involved in psychomotor and behavior impairments, such as hypotonia, fine motor coordination and hyperactivity linked to the Kmt2d mutation.     

Altered low-γ sampling in auditory cortex accounts for the three main facets of dyslexia

It has recently been conjectured that dyslexia arises from abnormal auditory sampling. What sampling rate is altered and how it affects reading remains unclear. We hypothesized that by impairing phonemic parsing abnormal low-gamma sampling could yield phonemic representations of unusual format and disrupt phonological processing and verbal memory. Using magnetoencephalography and behavioral tests, we show in dyslexic subjects a reduced left-hemisphere bias for phonemic processing, reflected in less entrainment to ≈30?Hz acoustic modulations in left auditory cortex. This deficit correlates with measures of phonological processing and rapid naming. We further observed enhanced cortical entrainment at rates beyond 40?Hz in dyslexics and show that this particularity is associated with a verbal memory deficit. These data suggest that a single auditory anomaly, i.e., phonemic oversampling in left auditory cortex, accounts for three main facets of the linguistic deficit in dyslexia.     

Male and female Fmr1 knockout mice on C57 albino background exhibit spatial learning and memory impairments

Impaired spatial learning is a prominent deficit in fragile X syndrome (FXS). Previous studies using the Fmr1 knockout (KO) mouse model of FXS have not consistently reported a deficit in spatial learning. Fmr1 KO mice bred onto an albino C57BL/6J‐Tyr^c‐Brd background showed significant deficits in several primary measures of performance during place navigation and probe trials in the Morris water maze. Fmr1 KO mice were also impaired during a serial reversal version of the water maze task. We examined fear conditioning as an additional cognitive screen. Knockout mice exhibited contextual memory deficits when trained with unsignaled shocks; however, deficits were not found in a separate group of KO mice trained with signaled shocks. No potentially confounding genotypic differences in locomotor activity were observed. A decreased anxiety‐like profile was apparent in the open field, as others have noted, and also in the platform test. Also as previously reported, startle reactivity to loud auditory stimuli was decreased, prepulse inhibition and social interaction increased in KO mice. Female Fmr1 KO mice were tested along with male KO mice in all assays, except for social interaction. The female and male KO exhibited very similar impairments indicating that sex does not generally drive the behavioral symptoms of the disorder. Our results suggest that procedural factors, such as the use of albino mice, may help to reliably detect spatial learning and memory impairments in both sexes of Fmr1 KO mice, making it more useful for understanding FXS and a platform for evaluating potential therapeutics.     

He hears,she hears: Are there sex differences in auditory processing?

Songbirds learn individually unique songs through vocal imitation and use them in courtship and territorial displays. Previous work has identified a forebrain auditory area, the caudomedial nidopallium (NCM), that appears specialized for discriminating and remembering conspecific vocalizations. In zebra finches (ZFs), only males produce learned vocalizations, but both sexes process these and other signals. This study assessed sex differences in auditory processing by recording extracellular multiunit activity at multiple sites within NCM. Juvenile female ZFs (n = 46) were reared in individual isolation and artificially tutored with song. In adulthood, songs were played back to assess auditory responses, stimulus‐specific adaptation, neural bias for conspecific song, and memory for the tutor's song, as well as recently heard songs. In a subset of females (n = 36), estradiol (E2) levels were manipulated to test the contribution of E2, known to be synthesized in the brain, to auditory responses. Untreated females (n = 10) showed significant differences in response magnitude and stimulus‐specific adaptation compared to males reared in the same paradigm (n = 9). In hormone‐manipulated females, E2 augmentation facilitated the memory for recently heard songs in adulthood, but neither E2 augmentation (n = 15) nor E2 synthesis blockade (n = 9) affected tutor song memory or the neural bias for conspecific song. The results demonstrate subtle sex differences in processing communication signals, and show that E2 levels in female songbirds can affect the memory for songs of potential suitors, thus contributing to the process of mate selection. The results also have potential relevance to clinical interventions that manipulate E2 in human patients. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 75: 302–314, 2015     

Association of the ROBO1 gene with reading disabilities in a family‐based analysis

Linkage studies have identified a locus on chromosome 3 as reading disabilities (RD) and speech and sound disorder (SSD) susceptibility region, with both RD and SSD sharing similar phonological processing and phonological memory difficulties. One gene in this region, roundabout homolog 1 (ROBO1), has been indicated as a RD candidate and has shown significant association with measures of phonological memory in a population‐based sample. In this study, we conducted a family‐based association analysis using two independent samples collected in Toronto and Calgary, Canada. Using the two samples, we tested for association between ROBO1 single nucleotide polymorphisms (SNPs) and RD, along with quantitative measures for reading, spelling and phonological memory. One SNP, rs331142, which was selected based on its correlation with ROBO1 expression in brain tissue, was found to be significantly associated with RD in the Toronto sample with over transmission of the minor C allele (P = 0.001), correlated with low expression. This SNP is located ～200 bp from a putative enhancer and results for a marker within the enhancer, rs12495133, showed evidence for association with the same allele in both the Toronto and Calgary samples (P = 0.005 and P = 0.007). These results support previous associations between ROBO1 and RD, as well as correlation with low gene expression, suggesting a possible mechanism of risk conferred by this gene.     

Novel variants in the BLOC1S3 gene in patients presenting a mild form of Hermansky–Pudlak syndrome

Hermansky–Pudlak syndrome (HPS) associates oculocutaneous albinism and systemic affections including platelet dense granules anomalies leading to bleeding diathesis and, depending on the form, pulmonary fibrosis, immunodeficiency, and/or granulomatous colitis. So far, 11 forms of autosomal recessive HPS caused by pathogenic variants in 11 different genes have been reported. We describe three HPS‐8 consanguineous families with different homozygous pathogenic variants in BLOC1S3 (NM_212550.3), one of which is novel. These comprise two deletions leading to a reading frameshift (c.385_403del, c.338_341del) and one in frame deletion (c.444_467del). All patients have moderate oculocutaneous albinism and bleeding diathesis, but other HPS symptoms are not described. One patient diagnosed with HPS‐8 suffered from lymphocyte‐predominant Hodgkin lymphoma. The mild severity of HPS‐8 is consistent with other HPS forms caused by variants in BLOC‐1 complex coding genes (HPS‐7, DTNBP1; HPS‐9, BLOC1S6, HPS‐11, BLOC1S5).     

TIP39 modulates effects of novelty‐induced arousal on memory

Tuberoinfundibular peptide of 39 residues (TIP39) is a neuropeptide localized to neural circuits subserving emotional processing. Recent work showed that mice with null mutation for the gene coding TIP39 (TIP39‐KO mice) display increased susceptibility to environmental provocation. Based on this stressor‐dependent phenotype, the neuroanatomical distribution of TIP39, and knowledge that novelty‐induced arousal modulates memory functions via noradrenergic activation, we hypothesized that exposure to a novel environment differently affects memory performance of mice with or without TIP39 signaling, potentially by differences in sensitivity of the noradrenergic system. We tested TIP39‐KO mice and mice with null mutation of its receptor, the parathyroid hormone 2 receptor (PTH2‐R), in tasks of short‐term declarative and social memory (object recognition and social recognition tests, respectively), and of working memory (Y‐maze test) under conditions of novelty‐induced arousal or acclimation to the test conditions. Mice lacking TIP39 signaling showed memory impairment selectively under conditions of novelty‐induced arousal. Acute administration of a PTH2‐R antagonist in wild‐type mice had a similar effect. The restoration of memory functions in TIP39‐KO mice after injection of a β‐adrenoreceptor‐blocker, propranolol, suggested involvement of the noradrenergic system. Collectively, these results suggest that the TIP39/PTH2‐R system modulates the effects of novelty exposure on memory performance, potentially by acting on noradrenergic signaling.     

APP independent and dependent effects on neurite outgrowth are modulated by the receptor associated protein (RAP)

Amyloid precursor protein (APP) and its secreted form, sAPP, contribute to the development of neurons in hippocampus, a brain region critical for learning and memory. Full‐length APP binds the low‐density lipoprotein receptor‐related protein (LRP), which stimulates APP endocytosis. LRP also contributes to neurite growth. Furthermore, the receptor associated protein (RAP) binds LRP in a manner that blocks APP–LRP interactions. To elucidate APP contributions to neurite growth for full‐length APP and sAPP, we cultured wild type (WT) and APP knockout (KO) neurons in sAPPα and/or RAP and measured neurite outgrowth at 1 day in vitro. Our data reveal that WT neurons had less axonal outgrowth including less axon branching. RAP treatment potentiated the inhibitory effects of APP. KO neurons had significantly more outgrowth and branching, especially in response to RAP, effects which were also associated with ERK2 activation. Our results affirm a major inhibitory role by full‐length APP on all aspects of axonal and dendritic outgrowth, and show that RAP–LRP binding stimulated axon growth independently of APP. These findings support a major role for APP as an inhibitor of neurite growth and reveal novel signaling functions for LRP that may be disrupted by Alzheimer's pathology or therapies aimed at APP processing.     

Abnormal semantic processing in females with fragile X‐associated tremor/ataxia syndrome

Fragile X‐associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder, affects fragile X (FMR1) gene premutation carriers in late life. Studies have shown cognitive impairments in FXTAS including executive dysfunction, working memory and visuospatial deficits. However, less is known about cognition in females with FXTAS. Thus, we examined semantic processing and verbal memory in female FXTAS patients with event‐related potentials (ERPs) and neuropsychological testing. Sixty‐one females (34 FXTAS, M_age = 62.7; 27 controls, M_age = 60.4) were studied with 32‐channel ERPs during a category judgment task in which semantically congruous (50%) and incongruous items were repeated approximately 10–140 seconds later. N400 and P600 amplitude data were submitted to analysis of covariance. Neuropsychological testing demonstrated lower performance in verbal learning and executive function in females with FXTAS. Event‐related potential analyses showed a significant reduction of the N400 congruity effect (incongruous ? congruous) in the FXTAS group. The N400 congruity effect reduction in females with FXTAS was mainly due to increased N400 amplitude to congruous new words. No significant abnormalities of the N400 repetition effect or the P600 repetition effect were found, indicating preserved implicit memory and verbal memory, respectively, in females with FXTAS. The decreased N400 congruity effect suggests abnormal semantic expectancy and/or semantic network disorganization in female FXTAS patients. The enhanced N400 amplitude to congruous new words may reflect decreased cognitive flexibility among FXTAS women, making access to less typical category exemplar words more difficult .     

Isoform‐specific effects of apolipoprotein E on cognitive performance in targeted‐replacement mice overexpressing human APP

The ε4 allele of apolipoprotein E (apoE4) is the predominant genetic risk factor for late‐onset Alzheimer's disease (AD) and is also implicated in cognitive deficits associated with normal aging. The biological mechanisms by which APOE genotype affects cognitive processes or AD pathogenesis remain unclear, but interactions of apoE with amyloid β peptide (Aβ) are thought to play an important role in mediating apoE's isoform‐specific effects on brain function. Here, we investigated the potential isoform‐dependent effects of apoE on behavioral and cognitive performance in human apoE3 and apoE4 targeted‐replacement (TR) mice that also overexpress the human amyloid precursor protein (APP). Beginning at 6–7 months of age, female APP‐Yac/apoE3‐TR (‘poE3’) and APP‐Yac/apoE4‐TR (‘poE4’) mice were tested on a battery of tests to evaluate basic sensorimotor functioning, spatial working memory, spatial recognition, episodic‐like memory and attentional processing. Compared with apoE3 mice, a generalized reduction in locomotor activity was observed in apoE4 mice. Moderate, but significant, cognitive impairments were also detected in apoE4 mice in the novel object‐location preference task, the contextual fear conditioning test, and a two‐choice visual discrimination/detection test, however spontaneous alternation performance in the Y‐maze was spared. These results offer additional support for the negative impact of apoE4 on both memory and attention and further suggest that APP‐Yac/apoE‐TR mice provide a novel and useful model for investigating the role of apoE in mediating susceptibility to cognitive decline.     

Selective Alterations Within Executive Functions in Adolescents With Excess Weight

Increasing evidence underscores overlapping neurobiological pathways to addiction and obesity. In both conditions, reward processing of preferred stimuli is enhanced, whereas the executive control system that would normally regulate reward‐driven responses is altered. This abnormal interaction can be greater in adolescence, a period characterized by relative immaturity of executive control systems coupled with the relative maturity of reward processing systems. The aim of this study is to explore neuropsychological performance of adolescents with excess weight (n = 27, BMI range 24–51 kg/m²) vs. normal‐weight adolescents (n = 34, BMI range 17–24 kg/m²) on a comprehensive battery of executive functioning tests, including measures of working memory (letter‐number sequencing), reasoning (similarities), planning (zoo map), response inhibition (five‐digit test (FDT)–interference and Stroop), flexibility (FDT–switching and trail‐making test (TMT)), self‐regulation (revised‐strategy application test (R‐SAT)), and decision‐making (Iowa gambling task (IGT)). We also aimed to explore personality traits of impulsivity and sensitivity to reward. Independent sample t‐ and Z Kolmogorov–Smirnov tests showed significant differences between groups on indexes of inhibition, flexibility, and decision‐making (excess‐weight participants performed poorer than controls), but not on tests of working memory, planning, and reasoning, nor on personality measures. Moreover, regression models showed a significant association between BMI and flexibility performance. These results are indicative of selective alterations of particular components of executive functions in overweight adolescents.     

An assessment of gene‐by‐environment interactions in developmental dyslexia‐related phenotypes

While the genetic and environmental contributions to developmental dyslexia (DD) have been studied extensively, the effects of identified genetic risk susceptibility and of specified environmental hazardous factors have usually been investigated separately. We assessed potential gene‐by‐environment (GxE) interactions on DD‐related reading, spelling and memory phenotypes. The presence of GxE effects were investigated for the DYX1C1, DCDC2, KIAA0319 and ROBO1 genes, and for seven specified environmental moderators in 165 nuclear families in which at least one member had DD, by implementing a general test for GxE interaction in sib‐pair‐based association analysis of quantitative traits. Our results support a diathesis‐stress model for both reading and memory composites: GxE effects were found between some specified environmental moderators (i.e. maternal smoke during pregnancy, birth weight and socio‐economic status) and the DYX1C1‐1259C/G marker. We have provided initial evidence that the joint analysis of identified genetic risk susceptibility and measured putative risk factors can be exploited in the study of the etiology of DD and reading‐related neuropsychological phenotypes, and may assist in identifying/preventing the occurrence of DD.