White matter connections : developmental neuroimaging studies of the associations between genes, brain and behavior

Development of cognitive abilities across childhood and adulthood parallels brain maturation in typically developing samples. Cognitive abilities such as reading and working memory have been linked to neuroimaging measures in relevant brain regions. Though the correlations between inter-individual brain differences and their related cognitive abilities are well established, the cause of this inter-individual variability is still not fully known. This thesis aims to understand the neural bases of the inter-individual variability in reading ability by studying the associations between dyslexia susceptibility genes and white and gray matter brain structures, and determine whether the measures of associated regions correlate with variability in reading ability. Moreover, it aims to identify the brain measures that correlate with concurrent measures of working memory and those that are predictive of future working memory, using a longitudinal cohort of typically developing children and young adults. Studies I and II: Three genes, DYX1C1, DCDC2 and KIAA0319, have been previously associated with dyslexia, neuronal migration, and ciliary function. We investigated whether the polymorphisms within these genes would affect variability in white and gray matter brain structures. Rs3743204 (DYX1C1), rs793842 (DCDC2), and rs6935076 (KIAA0319) were associated with left temporo-parietal white matter volume connecting middle temporal cortex to angular and supramarginal gyri as well as lateral occipital cortex. Rs793842 was significantly associated with thickness of left parietal areas and the lateral occipital cortex. Both white and gray matter measures correlated with current reading ability, but only white matter predicted future reading. Study III: We aimed to investigate whether MRPL19/C2ORF3 dyslexia genes, found to be correlated with verbal and non-verbal IQ, have a significant influence on white matter brain structures. Rs917235 showed a significant association with white matter volume in bilateral posterior parts of the corpus callosum and the cingulum, with connections to parietal, occipital and temporal cortices that are involved in both language and general cognitive abilities. Study IV: ROBO1 is a dyslexia gene that has been associated with axonal guidance and midline crossing. We assessed whether the polymorphisms within this gene have an influence on structure of the corpus callosum. Rs7631357 was associated with probability of connections within the fibers extending through the body of corpus callosum to parietal brain regions. The results fit well with previous reports on the role of Robo1 in axonal path finding in mice. Study V: Working memory has been associated with greater brain activity, thinner cortex, and white matter maturation in cross-sectional studies of children and young adults. Here, we aimed to investigate the role of differences in brain structure and function in the development of working memory. We assessed the concurrent and predictive relationships between working memory performance and neuroimaging measures in the fronto-parietal and fronto-striatal networks important for working memory. Working memory performance correlated with brain activity in frontal and parietal regions, cortical thickness in parietal cortex, and white matter volume of fronto-parietal and fronto-striatal tracts. White matter microstructure and brain activity in the caudate predicted future working memory. This work highlights the impact of imaging genetics research, revealing important associations between genes, brain and behavior. The results identify the neural mechanism underlying two cognitive abilities, reading and working memory. Specifically, the findings identify the important role of white matter in driving the development of working memory and reading ability, connecting the related cortical areas, as well as bridging the gap between genes and behavior

Human ROBO1 regulates white matter structure in corpus callosum

The axon guidance receptor, Robo1, controls the pathfinding of callosal axons in mice. To determine whether the orthologous ROBO1 gene is involved in callosal development also in humans, we studied polymorphisms in the ROBO1 gene and variation in the white matter structure in the corpus callosum using both structural magnetic resonance imaging and diffusion tensor magnetic resonance imaging. We found that five polymorphisms in the regulatory region of ROBO1 were associated with white matter density in the posterior part of the corpus callosum pathways. One of the polymorphisms, rs7631357, was also significantly associated with the probability of connections to the parietal cortical regions. Our results demonstrate that human ROBO1 may be involved in the regulation of the structure and connectivity of posterior part of corpus callosum.Peer reviewe

Mutation in CEP63 co-segregating with developmental dyslexia in a Swedish family

Developmental dyslexia is the most common learning disorder in children. Problems in reading and writing are likely due to a complex interaction of genetic and environmental factors, resulting in reduced power of studies of the genetic factors underlying developmental dyslexia. Our approach in the current study was to perform exome sequencing of affected and unaffected individuals within an extended pedigree with a familial form of developmental dyslexia. We identified a two-base mutation, causing a p.R229L amino acid substitution in the centrosomal protein 63 kDa (CEP63), co-segregating with developmental dyslexia in this pedigree. This mutation is novel, and predicted to be highly damaging for the function of the protein. 3D modelling suggested a distinct conformational change caused by the mutation. CEP63 is localised to the centrosome in eukaryotic cells and is required for maintaining normal centriole duplication and control of cell cycle progression. We found that a common polymorphism in the CEP63 gene had a significant association with brain white matter volume. The brain regions were partly overlapping with the previously reported region influenced by polymorphisms in the dyslexia susceptibility genes DYX1C1 and KIAA0319. We hypothesise that CEP63 is particularly important for brain development and might control the proliferation and migration of cells when those two events need to be highly coordinated.Peer reviewe

Identification of NCAN as a candidate gene for developmental dyslexia

A whole-genome linkage analysis in a Finnish pedigree of eight cases with developmental dyslexia (DD) revealed several regions shared by the affected individuals. Analysis of coding variants from two affected individuals identified rs146011974G >A (Ala1039Thr), a rare variant within the NCAN gene co-segregating with DD in the pedigree. This variant prompted us to consider this gene as a putative candidate for DD. The RNA expression pattern of the NCAN gene in human tissues was highly correlated (R > 0.8) with that of the previously suggested DD susceptibility genes KIAA0319, CTNND2, CNTNAP2 and GRIN2B. We investigated the association of common variation in NCAN to brain structures in two data sets: young adults (Brainchild study, Sweden) and infants (FinnBrain study, Finland). In young adults, we found associations between a common genetic variant in NCAN, rs1064395, and white matter volume in the left and right temporoparietal as well as the left inferior frontal brain regions. In infants, this same variant was found to be associated with cingulate and prefrontal grey matter volumes. Our results suggest NCAN as a new candidate gene for DD and indicate that NCAN variants affect brain structure.Peer reviewe

The Dyslexia Candidate Locus on 2p12 Is Associated with General Cognitive Ability and White Matter Structure

Peer reviewe

T1-Weighted/T2-Weighted Ratio Mapping at 5 Months Captures Individual Differences in Behavioral Development and Differentiates Infants at Familial Risk for Autism from Controls

Identifying structural measures that capture early brain development and are sensitive to individual differences in behavior is a priority in developmental neuroscience, with potential implications for our understanding of both typical and atypical populations. T1-weighted/T2-weighted (T1w/T2w) ratio mapping, which previously has been linked to myelination, represents an interesting candidate measure in this respect, as an accessible measure from standard magnetic resonance imaging (MRI) sequences. Yet, its value as an early infancy measure remains largely unexplored. Here, we compared T1w/T2w ratio in 5-month-old infants at familial risk (n = 27) for autism spectrum disorder (ASD) to those without elevated autism risk (n =16). We found lower T1w/T2w ratio in infants at high risk for ASD within widely distributed regions, spanning both white and gray matter. In regions differing between groups, higher T1w/T2w ratio was robustly associated with higher age at scan (range: similar to 4-6.5 months), implying sensitivity to maturation at short developmental timescales. Further, higher T1w/T2w ratio within these regions was associated with higher scores on measures of concurrent developmental level. These findings suggest that T1w/T2w ratio is a developmentally sensitive measure that should be explored further in future studies of both typical and atypical infant populations

Mutation in CEP63 co-segregating with developmental dyslexia in a Swedish family

Developmental dyslexia is the most common learning disorder in children. Problems in reading and writing are likely due to a complex interaction of genetic and environmental factors, resulting in reduced power of studies of the genetic factors underlying developmental dyslexia. Our approach in the current study was to perform exome sequencing of affected and unaffected individuals within an extended pedigree with a familial form of developmental dyslexia. We identified a two-base mutation, causing a p.R229L amino acid substitution in the centrosomal protein 63 kDa (CEP63), co-segregating with developmental dyslexia in this pedigree. This mutation is novel, and predicted to be highly damaging for the function of the protein. 3D modelling suggested a distinct conformational change caused by the mutation. CEP63 is localised to the centrosome in eukaryotic cells and is required for maintaining normal centriole duplication and control of cell cycle progression. We found that a common polymorphism in the CEP63 gene had a significant association with brain white matter volume. The brain regions were partly overlapping with the previously reported region influenced by polymorphisms in the dyslexia susceptibility genes DYX1C1 and KIAA0319. We hypothesise that CEP63 is particularly important for brain development and might control the proliferation and migration of cells when those two events need to be highly coordinated