| 1. |
- Darki, Fahimeh, et al.
(författare)
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DCDC2 polymorphism is associated with left temporoparietal gray and white matter structures during development.
- 2014
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Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 34:43, s. 14455-62
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Tidskriftsartikel (refereegranskat)abstract
- Three genes, DYX1C1, DCDC2, and KIAA0319, have been previously associated with dyslexia, neuronal migration, and ciliary function. Three polymorphisms within these genes, rs3743204 (DYX1C1), rs793842 (DCDC2), and rs6935076 (KIAA0319) have also been linked to normal variability of left temporoparietal white matter volume connecting the middle temporal cortex to the angular and supramarginal gyri. Here, we assessed whether these polymorphisms are also related to the cortical thickness of the associated regions during childhood development using a longitudinal dataset of 76 randomly selected children and young adults who were scanned up to three times each, 2 years apart. rs793842 in DCDC2 was significantly associated with the thickness of left angular and supramarginal gyri as well as the left lateral occipital cortex. The cortex was significantly thicker for T-allele carriers, who also had lower white matter volume and lower reading comprehension scores. There was a negative correlation between white matter volume and cortical thickness, but only white matter volume predicted reading comprehension 2 years after scanning. These results show how normal variability in reading comprehension is related to gene, white matter volume, and cortical thickness in the inferior parietal lobe. Possibly, the variability of gray and white matter structures could both be related to the role of DCDC2 in ciliary function, which affects both neuronal migration and axonal outgrowth.
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| 2. |
- Darki, Fahimeh, et al.
(författare)
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Human ROBO1 regulates white matter structure in corpus callosum.
- 2017
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Ingår i: Brain Structure and Function. - : Springer Science and Business Media LLC. - 1863-2653 .- 1863-2661. ; 222:2, s. 707-716
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Darki, Fahimeh, et al.
(författare)
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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
- 2021
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Ingår i: Cerebral Cortex. - : Oxford University Press. - 1047-3211 .- 1460-2199. ; 31:9, s. 4068-4077
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Darki, Fahimeh, et al.
(författare)
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Three dyslexia susceptibility genes, DYX1C1, DCDC2, and KIAA0319, affect temporo-parietal white matter structure.
- 2012
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 72:8, s. 671-6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Volume and integrity of white matter correlate with reading ability, but the underlying factors contributing to this variability are unknown.METHODS: We investigated single nucleotide polymorphisms in three genes previously associated with dyslexia and implicated in neuronal migration (DYX1C1, DCDC2, KIAA0319) and white matter volume in a cohort of 76 children and young adults from the general population.RESULTS: We found that all three genes contained polymorphisms that were significantly associated with white matter volume in the left temporo-parietal region and that white matter volume influenced reading ability.CONCLUSIONS: The identified region contained white matter pathways connecting the middle temporal gyrus with the inferior parietal lobe. The finding links previous neuroimaging and genetic results and proposes a mechanism underlying variability in reading ability in both normal and impaired readers.
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| 5. |
- Darki, Fahimeh
(författare)
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White matter connections : developmental neuroimaging studies of the associations between genes, brain and behavior
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 6. |
- Einarsdottir, Elisabet, et al.
(författare)
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Identification of NCAN as a candidate gene for developmental dyslexia.
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
- Einarsdottir, Elisabet, et al.
(författare)
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Mutation in CEP63 co-segregating with developmental dyslexia in a Swedish family
- 2015
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 134:11-12, s. 1239-1248
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 8. |
- Hofmeister, Wolfgang, et al.
(författare)
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CTNND2-a candidate gene for reading problems and mild intellectual disability.
- 2015
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 52:2, s. 111-22
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cytogenetically visible chromosomal translocations are highly informative as they can pinpoint strong effect genes even in complex genetic disorders.METHODS AND RESULTS: Here, we report a mother and daughter, both with borderline intelligence and learning problems within the dyslexia spectrum, and two apparently balanced reciprocal translocations: t(1;8)(p22;q24) and t(5;18)(p15;q11). By low coverage mate-pair whole-genome sequencing, we were able to pinpoint the genomic breakpoints to 2 kb intervals. By direct sequencing, we then located the chromosome 5p breakpoint to intron 9 of CTNND2. An additional case with a 163 kb microdeletion exclusively involving CTNND2 was identified with genome-wide array comparative genomic hybridisation. This microdeletion at 5p15.2 is also present in mosaic state in the patient's mother but absent from the healthy siblings. We then investigated the effect of CTNND2 polymorphisms on normal variability and identified a polymorphism (rs2561622) with significant effect on phonological ability and white matter volume in the left frontal lobe, close to cortical regions previously associated with phonological processing. Finally, given the potential role of CTNND2 in neuron motility, we used morpholino knockdown in zebrafish embryos to assess its effects on neuronal migration in vivo. Analysis of the zebrafish forebrain revealed a subpopulation of neurons misplaced between the diencephalon and telencephalon.CONCLUSIONS: Taken together, our human genetic and in vivo data suggest that defective migration of subpopulations of neuronal cells due to haploinsufficiency of CTNND2 contribute to the cognitive dysfunction in our patients.
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| 9. |
- Nyström, Pär, 1975-, et al.
(författare)
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Atypical Topographical Organization of Global Form and Motion Processing in 5-Month-Old Infants at Risk for Autism
- 2021
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Ingår i: Journal of autism and developmental disorders. - : Springer Science and Business Media LLC. - 0162-3257 .- 1573-3432. ; 51:1, s. 364-370
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Tidskriftsartikel (refereegranskat)abstract
- Research indicates that individuals with autism spectrum disorder (ASD) are superior at local processing while the integration of local features to global percepts is reduced. Here, we compared infants at familiar risk for ASD to typically developing infants in terms of global coherence processing at 5 months of age, using steady state visually evoked potentials (SSVEP). We found a different topographical organization for global form and motion processing in infants at risk (n = 50) than in controls (n = 23). In contrast, activation patterns for local visual change were strikingly similar between groups. Although preliminary, the results represent the first neurophysiological evidence supporting the view that basic atypicalities in perception may play a role in the developmental pathways leading to ASD.
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| 10. |
- Peter, Moa G., et al.
(författare)
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Lifelong olfactory deprivation-dependent cortical reorganization restricted to orbitofrontal cortex
- 2023
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Ingår i: Human Brain Mapping. - 1065-9471 .- 1097-0193. ; 44:18, s. 6459-6470
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Tidskriftsartikel (refereegranskat)abstract
- Prolonged sensory deprivation has repeatedly been linked to cortical reorganization. We recently demonstrated that individuals with congenital anosmia (CA, complete olfactory deprivation since birth) have seemingly normal morphology in piriform (olfactory) cortex despite profound morphological deviations in the orbitofrontal cortex (OFC), a finding contradictory to both the known effects of blindness on visual cortex and to the sparse literature on brain morphology in anosmia. To establish whether these unexpected findings reflect the true brain morphology in CA, we first performed a direct replication of our previous study to determine if lack of results was due to a deviant control group, a confound in cross sectional studies. Individuals with CA (n = 30) were compared to age and sex matched controls (n = 30) using voxel- and surface-based morphometry. The replication results were near identical to the original study: bilateral clusters of group differences in the OFC, including CA atrophy around the olfactory sulci and volume increases in the medial orbital gyri. Importantly, no group differences in piriform cortex were detected. Subsequently, to assess any subtle patterns of group differences not detectable by our mass-univariate analysis, we explored the data from a multivariate perspective. Combining the newly collected data with data from the replicated study (CA = 49, control = 49), we performed support vector machine classification based on gray matter volume. In line with the mass-univariate analyses, the multivariate analysis could accurately differentiate between the groups in bilateral OFC, whereas the classification accuracy in piriform cortex was at chance level. Our results suggest that despite lifelong olfactory deprivation, piriform (olfactory) cortex is morphologically unaltered and the morphological deviations in CA are confined to the OFC.
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