| 1. |
- Gialluisi, A, et al.
(författare)
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Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia
- 2019
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 9:1, s. 77-
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Tidskriftsartikel (refereegranskat)abstract
- Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562–3468). We observed a genome-wide significant effect (p < 1 × 10−8) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10−9), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10−8). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10−8) and with all the cognitive traits tested (p = 3.07 × 10−8), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10−5–10−7]) and negatively associated with ADHD PRS (p ~ [10−8−10−17]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.
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| 2. |
- Kalnak, N., et al.
(författare)
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Enrichment of rare copy number variation in children with developmental language disorder
- 2018
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 94:3-4, s. 313-320
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Tidskriftsartikel (refereegranskat)abstract
- Developmental language disorder (DLD) is a common neurodevelopmental disorder with largely unknown etiology. Rare copy number variants (CNVs) have been implicated in the genetic architecture of other neurodevelopmental disorders (NDDs), which have led to clinical genetic testing recommendations for these disorders; however, the evidence is still lacking for DLD. We analyzed rare and de novo CNVs in 58 probands with severe DLD, their 159 family members and 76 Swedish typically developing children using high-resolution microarray. DLD probands had larger rare CNVs as measured by total length (P =.05), and average length (P =.04). In addition, the rate of rare CNVs overlapping coding genes was increased (P =.03 and P =.01) and in average more genes were affected (P =.006 and P =.03) in the probands and their siblings, respectively. De novo CNVs were found in 4.8% DLD probands (2/42) and 2.4% (1/42) siblings. Clinically significant CNVs or chromosomal anomalies were found in 6.9% (4/58) of the probands of which 2 carried 16p11.2 deletions. We provide further evidence that rare CNVs contribute to the etiology of DLD in loci that overlap with other NDDs. Based on our results and earlier literature, families with DLD should be offered molecular genetic testing as a routine in their clinical follow-up.
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| 3. |
- 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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| 4. |
- 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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| 5. |
- 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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