| 1. |
- Anthoni, Heidi, et al.
(författare)
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A locus on 2p12 containing the co-regulated MRPL19 and C2ORF3 genes is associated to dyslexia.
- 2007
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 16:6, s. 667-77
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Tidskriftsartikel (refereegranskat)abstract
- DYX3, a locus for dyslexia, resides on chromosome 2p11-p15. We have refined its location on 2p12 to a 157 kb region in two rounds of linkage disequilibrium (LD) mapping in a set of Finnish families. The observed association was replicated in an independent set of 251 German families. Two overlapping risk haplotypes spanning 16 kb were identified in both sample sets separately as well as in a joint analysis. In the German sample set, the odds ratio for the most significantly associated haplotype increased with dyslexia severity from 2.2 to 5.2. The risk haplotypes are located in an intergenic region between FLJ13391 and MRPL19/C2ORF3. As no novel genes could be cloned from this region, we hypothesized that the risk haplotypes might affect long-distance regulatory elements and characterized the three known genes. MRPL19 and C2ORF3 are in strong LD and were highly co-expressed across a panel of tissues from regions of adult human brain. The expression of MRPL19 and C2ORF3, but not FLJ13391, were also correlated with the four dyslexia candidate genes identified so far (DYX1C1, ROBO1, DCDC2 and KIAA0319). Although several non-synonymous changes were identified in MRPL19 and C2ORF3, none of them significantly associated with dyslexia. However, heterozygous carriers of the risk haplotype showed significantly attenuated expression of both MRPL19 and C2ORF3, as compared with non-carriers. Analysis of C2ORF3 orthologues in four non-human primates suggested different evolutionary rates for primates when compared with the out-group. In conclusion, our data support MRPL19 and C2ORF3 as candidate susceptibility genes for DYX3.
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| 2. |
- 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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| 3. |
- 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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| 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. |
- Dumontheil, Iroise, et al.
(författare)
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Influence of the COMT genotype on working memory and brain activity changes during development.
- 2011
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 70:3, s. 222-9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Valine158Methionine (Val158Met) polymorphism of the COMT gene leads to lower enzymatic activity and higher dopamine availability in Met carriers. The Met allele is associated with better performance and reduced prefrontal cortex activation during working memory (WM) tasks in adults. Dopaminergic system changes during adolescence may lead to a reduction of basal dopamine levels, potentially affecting Met allele benefits during development.METHODS: We investigated the association of COMT genotype with behavioral (n = 322) and magnetic resonance imaging data (n = 81-84) collected during performance of a visuospatial WM task and potential changes in these effects during development (reflected in age × genotype interactions). Data were collected from a cross-sectional and longitudinal typically developing sample of 6- to 20-year-olds.RESULTS: Visuospatial WM capacity exhibited an age × genotype interaction, with a benefit of the Met allele emerging after 10 years of age. There was a parallel age × genotype interaction on WM-related activation in the right inferior frontal gyrus and intraparietal sulcus (IPS), with increases in activation with age in the Val/Val group only. Main effects of COMT genotype were also observed in the IPS, with greater gray matter volumes bilaterally and greater right IPS activation in the Val/Val group compared with the Met carriers.CONCLUSIONS: These results suggest that COMT genotype effects on WM brain activity and behavior are not static during development. The full developmental picture should be considered when trying to understand the impact of genetic polymorphisms on the mature cognition of healthy adult or psychiatric populations.
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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. |
- Kalnak, Nelli, et al.
(författare)
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Nonword Repetition - A Clinical Marker for Specific Language Impairment in Swedish Associated with Parents' Language-Related Problems
- 2014
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:2
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Tidskriftsartikel (refereegranskat)abstract
- First, we explore the performance of nonword repetition (NWR) in children with specific language impairment (SLI) and typically developing children (TD) in order to investigate the accuracy of NWR as a clinical marker for SLI in Swedishspeaking school-age children. Second, we examine the relationship between NWR, family aggregation, and parental level of education in children with SLI. A sample of 61 children with SLI, and 86 children with TD, aged 8-12 years, were administered an NWR test. Family aggregation, measured as the prevalence of language and/or literacy problems (LLP) in parents of the children with SLI, was based on family history interviews. The sensitivity and specificity of nonword repetition was analyzed in a binary logistic regression, cut-off values were established with ROC curves, and positive and negative likelihood ratios reported. Results from the present study show that NWR distinguishes well between Swedish-speaking school-children with and without SLI. We found 90.2% sensitivity and 97.7% specificity at a cut-off level of -2 standard deviations for binary scoring of nonwords. Differences between the SLI and TD groups showed large effect sizes for the two scoring measures binary (d = 2.11) and percent correct consonants (PCC) (d = 1.79). The children with SLI were split into two subgroups: those with no parents affected with LLP (n = 12), and those with one or both parents affected (n = 49). The subgroup consisting of affected parents had a significantly lower score on NWR binary (p =.037), and there was a great difference between the subgroups (d = 0.7). When compared to the TD group, the difference from the subgroup with affected parents was almost one standard deviation larger (d = 2.47) than the difference from the TD to the subgroup consisting of non-affected parents (d = 1.57). Our study calls for further exploration of the complex interaction between family aggregation, language input, and phenotypes of SLI.
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| 9. |
- Massinen, Satu, et al.
(författare)
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Increased expression of the dyslexia candidate gene DCDC2 affects length and signaling of primary cilia in neurons.
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:6
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Tidskriftsartikel (refereegranskat)abstract
- DCDC2 is one of the candidate susceptibility genes for dyslexia. It belongs to the superfamily of doublecortin domain containing proteins that bind to microtubules, and it has been shown to be involved in neuronal migration. We show that the Dcdc2 protein localizes to the primary cilium in primary rat hippocampal neurons and that it can be found within close proximity to the ciliary kinesin-2 subunit Kif3a. Overexpression of DCDC2 increases ciliary length and activates Shh signaling, whereas downregulation of Dcdc2 expression enhances Wnt signaling, consistent with a functional role in ciliary signaling. Moreover, DCDC2 overexpression in C. elegans causes an abnormal neuronal phenotype that can only be seen in ciliated neurons. Together our results suggest a potential role for DCDC2 in the structure and function of primary cilia.
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| 10. |
- Matsson, Hans, et al.
(författare)
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Polymorphisms in DCDC2 and S100B associate with developmental dyslexia.
- 2015
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Ingår i: Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1434-5161 .- 1435-232X. ; 60:7, s. 399-401
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Tidskriftsartikel (refereegranskat)abstract
- Genetic studies of complex traits have become increasingly successful as progress is made in next-generation sequencing. We aimed at discovering single nucleotide variation present in known and new candidate genes for developmental dyslexia: CYP19A1, DCDC2, DIP2A, DYX1C1, GCFC2 (also known as C2orf3), KIAA0319, MRPL19, PCNT, PRMT2, ROBO1 and S100B. We used next-generation sequencing to identify single-nucleotide polymorphisms in the exons of these 11 genes in pools of 100 DNA samples of Finnish individuals with developmental dyslexia. Subsequent individual genotyping of those 100 individuals, and additional cases and controls from the Finnish and German populations, validated 92 out of 111 different single-nucleotide variants. A nonsynonymous polymorphism in DCDC2 (corrected P = 0.002) and a noncoding variant in S100B (corrected P = 0.016) showed a significant association with spelling performance in families of German origin. No significant association was found for the variants neither in the Finnish case-control sample set nor in the Finnish family sample set. Our findings further strengthen the role of DCDC2 and implicate S100B, in the biology of reading and spelling.
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| 11. |
- Matsson, Hans, et al.
(författare)
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SNP variations in the 7q33 region containing DGKI are associated with dyslexia in the Finnish and German populations.
- 2011
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Ingår i: Behavior Genetics. - : Springer Science and Business Media LLC. - 0001-8244 .- 1573-3297. ; 41:1, s. 134-40
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Tidskriftsartikel (refereegranskat)abstract
- Four genes, DYX1C1, ROBO1, DCDC2 and KIAA0319 have been studied both genetically and functionally as candidate genes for developmental dyslexia, a common learning disability in children. The identification of novel genes is crucial to better understand the molecular pathways affected in dyslectic individuals. Here, we report results from a fine-mapping approach involving linkage and association analysis in Finnish and German dyslexic cohorts. We restrict a candidate region to 0.3 Mb on chromosome 7q33. This region harbours the gene diacylglycerol kinase, iota (DGKI) which contains overlapping haplotypes associated with dyslexia in both Finnish and German sample sets.
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| 12. |
- Peyrard-Janvid, Myriam, et al.
(författare)
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Dominant Mutations in GRHL3 Cause Van der Woude Syndrome and Disrupt Oral Periderm Development
- 2014
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 94:1, s. 23-32
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in interferon regulatory factor 6 (IRF6) account for similar to 70% of cases of Van der Woude syndrome (VWS), the most common syndromic form of cleft lip and palate. In 8 of 45 VWS-affected families lacking a mutation in IRF6, we found coding mutations in grainyhead-like 3 (GRHL3). According to a zebrafish-based assay, the disease-associated GRHL3 mutations abrogated periderm development and were consistent with a dominant-negative effect, in contrast to haploinsufficiency seen in most VWS cases caused by IRF6 mutations. In mouse, all embryos lacking Grhl3 exhibited abnormal oral periderm and 17% developed a cleft palate. Analysis of the oral phenotype of double heterozygote (Irf6(+/-);Grhl3(+/-)) murine embryos failed to detect epistasis between the two genes, suggesting that they function in separate but convergent pathways during palatogenesis. Taken together, our data demonstrated that mutations in two genes, IRF6 and GRHL3, can lead to nearly identical phenotypes of orofacial cleft. They supported the hypotheses that both genes are essential for the presence of a functional oral periderm and that failure of this process contributes to VWS.
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| 13. |
- Scerri, Thomas S, et al.
(författare)
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The dyslexia candidate locus on 2p12 is associated with general cognitive ability and white matter structure.
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:11
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Tidskriftsartikel (refereegranskat)abstract
- Independent studies have shown that candidate genes for dyslexia and specific language impairment (SLI) impact upon reading/language-specific traits in the general population. To further explore the effect of disorder-associated genes on cognitive functions, we investigated whether they play a role in broader cognitive traits. We tested a panel of dyslexia and SLI genetic risk factors for association with two measures of general cognitive abilities, or IQ, (verbal and non-verbal) in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (N>5,000). Only the MRPL19/C2ORF3 locus showed statistically significant association (minimum P = 0.00009) which was further supported by independent replications following analysis in four other cohorts. In addition, a fifth independent sample showed association between the MRPL19/C2ORF3 locus and white matter structure in the posterior part of the corpus callosum and cingulum, connecting large parts of the cortex in the parietal, occipital and temporal lobes. These findings suggest that this locus, originally identified as being associated with dyslexia, is likely to harbour genetic variants associated with general cognitive abilities by influencing white matter structure in localised neuronal regions.
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| 14. |
- Söderqvist, Stina, et al.
(författare)
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Dopamine, working memory, and training induced plasticity : implications for developmental research.
- 2012
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Ingår i: Developmental Psychology. - : American Psychological Association (APA). - 0012-1649 .- 1939-0599. ; 48:3, s. 836-43
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Tidskriftsartikel (refereegranskat)abstract
- Cognitive deficits and particularly deficits in working memory (WM) capacity are common features in neuropsychiatric disorders. Understanding the underlying mechanisms through which WM capacity can be improved is therefore of great importance. Several lines of research indicate that dopamine plays an important role not only in WM function but also for improving WM capacity. For example, pharmacological interventions acting on the dopaminergic system, such as methylphenidate, improve WM performance. In addition, behavioral interventions for improving WM performance in the form of intensive computerized training have recently been associated with changes in dopamine receptor density. These two different means of improving WM performance--pharmacological and behavioral--are thus associated with similar biological mechanisms in the brain involving dopaminergic systems. This article reviews some of the evidence for the role of dopamine in WM functioning, in particular concerning the link to WM development and cognitive plasticity. Novel data are presented showing that variation in the dopamine transporter gene (DAT1) influences improvements in WM and fluid intelligence in preschool-age children following cognitive training. Our results emphasize the importance of the role of dopamine in determining cognitive plasticity.
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| 15. |
- Söderqvist, Stina, et al.
(författare)
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Polymorphisms in the dopamine receptor 2 gene region influence improvements during working memory training in children and adolescents.
- 2014
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Ingår i: Journal of cognitive neuroscience. - : MIT Press - Journals. - 0898-929X .- 1530-8898. ; 26:1, s. 54-62
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Tidskriftsartikel (refereegranskat)abstract
- Studying the effects of cognitive training can lead to finding better treatments, but it can also be a tool for investigating factors important for brain plasticity and acquisition of cognitive skills. In this study, we investigated how single-nucleotide polymorphisms (SNPs) and ratings of intrinsic motivation were associated to interindividual differences in improvement during working memory training. The study included 256 children aged 7-19 years who were genotyped for 13 SNPs within or near eight candidate genes previously implicated in learning: COMT, SLC6A3 (DAT1), DRD4, DRD2, PPP1R1B (DARPP32), MAOA, LMX1A, and BDNF. Ratings on the intrinsic motivation inventory were also available for 156 of these children. All participants performed at least 20 sessions of working memory training, and performance during the training was logged and used as the outcome variable. We found that two SNPs, rs1800497 and rs2283265, located near and within the dopamine receptor 2 (DRD2) gene, respectively, were significantly associated with improvements during training (p < .003 and p < .0004, respectively). Scores from a questionnaire regarding intrinsic motivation did not correlate with training outcome. However, we observed both the main effect of genotype at those two loci as well as the interaction between genotypes and ratings of intrinsic motivation (perceived competence). Both SNPs have previously been shown to affect DRD2 receptor density primarily in the BG. Our results suggest that genetic variation is accounting for some interindividual differences in how children acquire cognitive skills and that part of this effect is also seen on intrinsic motivation. Moreover, they suggest that dopamine D2 transmission in the BG is a key factor for cognitive plasticity.
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| 16. |
- Söderqvist, Stina, et al.
(författare)
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The SNAP25 gene is linked to working memory capacity and maturation of the posterior cingulate cortex during childhood.
- 2010
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 68:12, s. 1120-5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Working memory (WM) is the ability to retain task relevant information. This ability is important for a wide range of cognitive tasks, and WM deficits are a central cognitive impairment in neurodevelopment disorders such as attention-deficit/hyperactivity disorder (ADHD). Although WM capacity is known to be highly heritable, most genes involved remain unidentified.METHODS: Single nucleotide polymorphisms in genes previously associated with cognitive functions or ADHD were selected for genotyping. Associations of these with WM tasks were investigated in a community sample of 330 children and young adults. One single nucleotide polymorphisms was also investigated in an independent sample of 88 4-year-old children. Furthermore, association between brain structure and activity, as measured by magnetic resonance imaging techniques, and single nucleotide polymorphisms alleles were estimated in 88 participants.RESULTS: Genotype at rs363039, located in the gene coding for synaptosomal-associated protein, 25 kDa (SNAP25) was associated to WM capacity in both samples. Associations in the community sample were also found with measures of other cognitive functions. In addition, this polymorphism affected the gray matter and brain activity in the posterior cingulate cortex, an area included in the so-called default mode network previously correlated to regulation of attention and hypothesized to be implicated in ADHD.CONCLUSIONS: A novel gene-brain-behavior network was identified in which a genotype located in SNAP25 affects WM and has age-dependent effects on both brain structure and brain activity. Identifying such networks could be a key to better understanding cognitive development as well as some of its disorders.
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