Dyslexia and language impairment associated genetic markers influence cortical thickness and white matter in typically developing children

Dyslexia and language impairment (LI) are complex traits with substantial genetic components. We recently completed an association scan of the DYX2 locus, where we observed associations of markers in DCDC2, KIAA0319, ACOT13, and FAM65B with reading-, language-, and IQ-related traits. Additionally, the effects of reading-associated DYX3 markers were recently characterized using structural neuroimaging techniques. Here, we assessed the neuroimaging implications of associated DYX2 and DYX3 markers, using cortical volume, cortical thickness, and fractional anisotropy. To accomplish this, we examined eight DYX2 and three DYX3 markers in 332 subjects in the Pediatrics Imaging Neurocognition Genetics study. Imaging-genetic associations were examined by multiple linear regression, testing for influence of genotype on neuroimaging. Markers in DYX2 genes KIAA0319 and FAM65B were associated with cortical thickness in the left orbitofrontal region and global fractional anisotropy, respectively. KIAA0319 and ACOT13 were suggestively associated with overall fractional anisotropy and left pars opercularis cortical thickness, respectively. DYX3 markers showed suggestive associations with cortical thickness and volume measures in temporal regions. Notably, we did not replicate association of DYX3 markers with hippocampal measures. In summary, we performed a neuroimaging follow-up of reading-, language-, and IQ-associated DYX2 and DYX3 markers. DYX2 associations with cortical thickness may reflect variations in their role in neuronal migration. Furthermore, our findings complement gene expression and imaging studies implicating DYX3 markers in temporal regions. These studies offer insight into where and how DYX2 and DYX3 risk variants may influence neuroimaging traits. Future studies should further connect the pathways to risk variants associated with neuroimaging/neurocognitive outcomes

Age-Related Differences in Cortical Thickness Vary by Socioeconomic Status

Recent findings indicate robust associations between socioeconomic status (SES) and brain structure in children, raising questions about the ways in which SES may modify structural brain development. In general, cortical thickness and surface area develop in nonlinear patterns across childhood and adolescence, with developmental patterns varying to some degree by cortical region. Here, we examined whether age-related nonlinear changes in cortical thickness and surface area varied by SES, as indexed by family income and parental education. We hypothesized that SES disparities in age-related change may be particularly evident for language- and literacy-supporting cortical regions. Participants were 1148 typically-developing individuals between 3 and 20 years of age. Results indicated that SES factors moderate patterns of age-associated change in cortical thickness but not surface area. Specifically, at lower levels of SES, associations between age and cortical thickness were curvilinear, with relatively steep age-related decreases in cortical thickness earlier in childhood, and subsequent leveling off during adolescence. In contrast, at high levels of SES, associations between age and cortical thickness were linear, with consistent reductions across the age range studied. Notably, this interaction was prominent in the left fusiform gyrus, a region that is critical for reading development. In a similar pattern, SES factors significantly moderated linear age-related change in left superior temporal gyrus, such that higher SES was linked with steeper age-related decreases in cortical thickness in this region. These findings suggest that SES may moderate patterns of age-related cortical thinning, especially in language- and literacy-supporting cortical regions

Use of machine learning to determine deviance in neuroanatomical maturity associated with future psychosis in youths at clinically high risk

Importance: Altered neurodevelopmental trajectories are thought to reflect heterogeneity in the pathophysiologic characteristics of schizophrenia, but whether neural indicators of these trajectories are associated with future psychosis is unclear. Objective: To investigate distinct neuroanatomical markers that can differentiate aberrant neurodevelopmental trajectories among clinically high-risk (CHR) individuals. Design, Setting, and Participants: In this prospective longitudinal multicenter study, a neuroanatomical-based age prediction model was developed using a supervised machine learning technique with T1-weighted magnetic resonance imaging scans of 953 healthy controls 3 to 21 years of age from the Pediatric Imaging, Neurocognition, and Genetics (PING) study and then applied to scans of 275 CHR individuals (including 39 who developed psychosis) and 109 healthy controls 12 to 21 years of age from the North American Prodrome Longitudinal Study 2 (NAPLS 2) for external validation and clinical application. Scans from NAPLS 2 were collected from January 15, 2010, to April 30, 2012. Main Outcomes and Measures: Discrepancy between neuroanatomical-based predicted age (hereafter referred to as brain age) and chronological age. Results: The PING-derived model (460 females and 493 males; age range, 3-21 years) accurately estimated the chronological ages of the 109 healthy controls in the NAPLS 2 (43 females and 66 males; age range, 12-21 years), providing evidence of independent external validation. The 275 CHR individuals in the NAPLS 2 (111 females and 164 males; age range, 12-21 years) showed a significantly greater mean (SD) gap between model-predicted age and chronological age (0.64 [2.16] years) compared with healthy controls (P = .008). This outcome was significantly moderated by chronological age, with brain age systematically overestimating the ages of CHR individuals who developed psychosis at ages 12 to 17 years but not the brain ages of those aged 18 to 21 years. Greater brain age deviation was associated with a higher risk for developing psychosis (F = 3.70; P = .01) and a pattern of stably poor functioning over time, but only among younger CHR adolescents. Previously reported evidence of accelerated reduction in cortical thickness among CHR individuals who developed psychosis was found to apply only to those who were 18 years of age or older. Conclusions and Relevance: These results are consistent with the view that neuroanatomical markers of schizophrenia may help to explain some of the heterogeneity of this disorder, particularly with respect to early vs later age of onset of psychosis, with younger and older individuals having differing intercepts and trajectories in structural brain parameters as a function of age. The results also suggest that baseline neuroanatomical measures are likely to be useful in estimating onset of psychosis, especially (or only) among CHR individuals with an earlier age of onset of prodromal symptoms

Genome-wide association study of shared components of reading disability and language impairment

Written and verbal languages are neurobehavioral traits vital to the development of communication skills. Unfortunately, disorders involving these traits-specifically reading disability (RD) and language impairment (LI)-are common and prevent affected individuals from developing adequate communication skills, leaving them at risk for adverse academic, socioeconomic and psychiatric outcomes. Both RD and LI are complex traits that frequently co-occur, leading us to hypothesize that these disorders share genetic etiologies. To test this, we performed a genome-wide association study on individuals affected with both RD and LI in the Avon Longitudinal Study of Parents and Children. The strongest associations were seen with markers in ZNF385D (OR = 1.81, P = 5.45 × 10(-7) ) and COL4A2 (OR = 1.71, P = 7.59 × 10(-7) ). Markers within NDST4 showed the strongest associations with LI individually (OR = 1.827, P = 1.40 × 10(-7) ). We replicated association of ZNF385D using receptive vocabulary measures in the Pediatric Imaging Neurocognitive Genetics study (P = 0.00245). We then used diffusion tensor imaging fiber tract volume data on 16 fiber tracts to examine the implications of replicated markers. ZNF385D was a predictor of overall fiber tract volumes in both hemispheres, as well as global brain volume. Here, we present evidence for ZNF385D as a candidate gene for RD and LI. The implication of transcription factor ZNF385D in RD and LI underscores the importance of transcriptional regulation in the development of higher order neurocognitive traits. Further study is necessary to discern target genes of ZNF385D and how it functions within neural development of fluent language

Genome-wide association study of shared components of reading disability and language impairment

Written and verbal languages are neurobehavioral traits vital to the development of communication skills. Unfortunately, disorders involving these traits—specifically reading disability (RD) and language impairment (LI)—are common and prevent affected individuals from developing adequate communication skills, leaving them at risk for adverse academic, socioeconomic and psychiatric outcomes. Both RD and LI are complex traits that frequently co-occur, leading us to hypothesize that these disorders share genetic etiologies. To test this, we performed a genome-wide association study on individuals affected with both RD and LI in the Avon Longitudinal Study of Parents and Children. The strongest associations were seen with markers in ZNF385D (OR = 1.81, P = 5.45 × 10−7) and COL4A2 (OR = 1.71, P = 7.59 × 10−7). Markers within NDST4 showed the strongest associations with LI individually (OR = 1.827, P = 1.40 × 10−7). We replicated association of ZNF385D using receptive vocabulary measures in the Pediatric Imaging Neurocognitive Genetics study (P = 0.00245). We then used diffusion tensor imaging fiber tract volume data on 16 fiber tracts to examine the implications of replicated markers. ZNF385D was a predictor of overall fiber tract volumes in both hemispheres, as well as global brain volume. Here, we present evidence for ZNF385D as a candidate gene for RD and LI. The implication of transcription factor ZNF385D in RD and LI underscores the importance of transcriptional regulation in the development of higher order neurocognitive traits. Further study is necessary to discern target genes of ZNF385D and how it functions within neural development of fluent language

Long-term influence of normal variation in neonatal characteristics on human brain development

It is now recognized that a number of cognitive, behavioral, and mental health outcomes across the lifespan can be traced to fetal development. Although the direct mediation is unknown, the substantial variance in fetal growth, most commonly indexed by birth weight, may affect lifespan brain development. We investigated effects of normal variance in birth weight on MRI-derived measures of brain development in 628 healthy children, adolescents, and young adults in the large-scale multicenter Pediatric Imaging, Neurocognition, and Genetics study. This heterogeneous sample was recruited through geographically dispersed sites in the United States. The influence of birth weight on cortical thickness, surface area, and striatal and total brain volumes was investigated, controlling for variance in age, sex, household income, and genetic ancestry factors. Birth weight was found to exert robust positive effects on regional cortical surface area in multiple regions as well as total brain and caudate volumes. These effects were continuous across birth weight ranges and ages and were not confined to subsets of the sample. The findings show that (i) aspects of later child and adolescent brain development are influenced at birth and (ii) relatively small differences in birth weight across groups and conditions typically compared in neuropsychiatric research (e.g., Attention Deficit Hyperactivity Disorder, schizophrenia, and personality disorders) may influence group differences observed in brain parameters of interest at a later stage in life. These findings should serve to increase our attention to early influences

Multimodal imaging of the self-regulating developing brain

Self-regulation refers to the ability to control behavior, cognition, and emotions, and self-regulation failure is related to a range of neuropsychiatric problems. It is poorly understood how structural maturation of the brain brings about the gradual improvement in self-regulation during childhood. In a large-scale multicenter effort, 735 children (4-21 y) underwent structural MRI for quantification of cortical thickness and surface area and diffusion tensor imaging for quantification of the quality of major fiber connections. Brain development was related to a standardized measure of cognitive control (the flanker task from the National Institutes of Health Toolbox), a critical component of self-regulation. Ability to inhibit responses and impose cognitive control increased rapidly during preteen years. Surface area of the anterior cingulate cortex accounted for a significant proportion of the variance in cognitive performance. This finding is intriguing, because characteristics of the anterior cingulum are shown to be related to impulse, attention, and executive problems in neurodevelopmental disorders, indicating a neural foundation for self-regulation abilities along a continuum from normality to pathology. The relationship was strongest in the younger children. Properties of large-fiber connections added to the picture by explaining additional variance in cognitive control. Although cognitive control was related to surface area of the anterior cingulate independently of basic processes of mental speed, the relationship between white matter quality and cognitive control could be fully accounted for by speed. The results underscore the need for integration of different aspects of brain maturation to understand the foundations of cognitive development

Supplementary Material for: The Relationship between White Matter and Reading Acquisition, Refinement and Maintenance

Reading requires efficient communication between brain regions that are situated all over the cortex. These brain areas are structurally connected by white-matter pathways that develop over the period of reading acquisition. Here, we conducted a cross-sectional study to assess the relationship between white-matter tracts and reading performance across the lifespan. <b><i>Methods:</i></b> Behavioral (reading performance) and neuroimaging (diffusion tensor imaging [DTI]) data were collected from participants aged 3–21 years as a part of the multi-site project called the pediatric imaging neurocognition genetics study. DTI measures (fractional anisotropy [FA], mean diffusivity, radial diffusivity and axial diffusivity) of bilateral dorsal tracts (arcuate fasciculus, superior longitudinal fasciculus, and posterior superior longitudinal fasciculus) and ventral tracts (uncinate fasciculus, inferior fronto-occipital fasciculus, and inferior longitudinal fasciculus) were extracted. Reading performance was calculated as the number of items correctly read (words for older children and letters in the case of young children). Correlational and regression analyses were conducted between the DTI measures and reading scores. <b><i>Results:</i></b> During the early stages of reading acquisition (ages 3–6), the dorsal tracts were positively related to reading performance (as FA goes up, reading performance goes up). For ages 6–10, the dorsal tracts remain positively associated with reading performance and a relationship between ventral tracts and reading performance emerges. From the age of 10 onwards, the dorsal tracts no longer correlate with reading performance, and a brain-behavior relationship in the right ventral tracts begins to shift, whereby higher FA is associated with lower reading performance. In addition to the involvement of left hemispheric tracts, this study revealed the initial engagement of right hemispheric tracts during the early stages of reading acquisition. <b><i>Conclusion:</i></b> We discuss these different associations of white-matter tracts with reading during development in the context of the biological processes model of myelination and pruning

The Pediatric Imaging, Neurocognition, and Genetics (PING) Data Repository

The main objective of the multi-site Pediatric Imaging, Neurocognition, and Genetics (PING) study was to create a large repository of standardized measurements of behavioral and imaging phenotypes accompanied by whole genome genotyping acquired from typically-developing children varying widely in age (3 to 20 years). This cross-sectional study produced sharable data from 1493 children, and these data have been described in several publications focusing on brain and cognitive development. Researchers may gain access to these data by applying for an account on the PING portal and filing a data use agreement. Here we describe the recruiting and screening of the children and give a brief overview of the assessments performed, the imaging methods applied, the genetic data produced, and the numbers of cases for whom different data types are available. We also cite sources of more detailed information about the methods and data. Finally we describe the procedures for accessing the data and for using the PING data exploration portal