ORCID Profile
0000-0001-9934-8602
Current Organisation
University of St Andrews
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Publisher: Public Library of Science (PLoS)
Date: 28-11-2012
Publisher: Oxford University Press (OUP)
Date: 06-12-2007
DOI: 10.1093/HMG/DDM358
Abstract: The KIAA0319 gene has been recently associated with developmental dyslexia and shown to be involved in neuronal migration. The deduced KIAA0319 protein contains several polycystic kidney disease (PKD) domains which may mediate the interaction between neurons and glial fibres during neuronal migration. We have previously reported the presence of several alternative splicing variants, some of which are predicted to affect the deduced protein. In this study, we over-expressed constructs containing the main form (A) and two alternative variants (B and C) of KIAA0319. We show that the full-length KIAA0319 (A) is a type I plasma membrane protein, a topology consistent with its proposed function in neuronal migration. The oligomeric status of KIAA0319 is mainly dimeric, and this condition depends on the cysteine-rich regions of the protein, especially the transmembrane (TM) domain and surrounding sequence. KIAA0319 is highly glycosylated in different mammalian cell lines. The central region including the PKD domains is N-glycosylated. Furthermore, a short fragment N-terminal to the PKD domains contains mucin-type O-glycosylation. The two alternative isoforms are soluble proteins lacking the TM domain and, interestingly, only isoform B is secreted. KIAA0319-deletion proteins lacking the TM domain were also secreted. These results suggest that KIAA0319 could be involved not only in cell-cell interactions, but also in signalling.
Publisher: Proceedings of the National Academy of Sciences
Date: 23-08-2022
Abstract: The use of spoken and written language is a fundamental human capacity. In idual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed in idually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in s les of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10 −8 ) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.
Publisher: Springer Science and Business Media LLC
Date: 29-11-2022
DOI: 10.1038/S41398-022-02250-Z
Abstract: Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were located near to or in genes involved in neuronal migration/axon guidance (NM/AG) or loci implicated in autism spectrum disorder (ASD). A prominent theory of RD etiology posits that it involves disturbed neuronal migration, while potential links between RD-ASD have not been extensively investigated. To improve power to identify associated loci, we up-weighted variants involved in NM/AG or ASD, separately, and performed a new Hypothesis-Driven (HD)–GWAS. The approach was applied to a Toronto RD s le and a meta-analysis of the GenLang Consortium. For the Toronto s le ( n = 624), no SNPs reached significance however, by gene-set analysis, the joint contribution of ASD-related genes passed the threshold ( p ~1.45 × 10 –2 , threshold = 2.5 × 10 –2 ). For the GenLang Cohort ( n = 26,558), SNPs in DOCK7 and CDH4 showed significant association for the NM/AG hypothesis (sFDR q = 1.02 × 10 –2 ). To make the GenLang dataset more similar to Toronto, we repeated the analysis restricting to s les selected for reading/language deficits ( n = 4152). In this GenLang selected subset, we found significant association for a locus intergenic between BTG3 - C21orf91 for both hypotheses (sFDR q 9.00 × 10 –4 ). This study contributes candidate loci to the genetics of word reading. Data also suggest that, although different variants may be involved, alleles implicated in ASD risk may be found in the same genes as those implicated in word reading. This finding is limited to the Toronto s le suggesting that ascertainment influences genetic associations.
Publisher: Wiley
Date: 13-02-2023
DOI: 10.1111/CDEV.13914
Abstract: Handedness has been studied for association with language‐related disorders because of its link with language hemispheric dominance. No clear pattern has emerged, possibly because of small s les, publication bias, and heterogeneous criteria across studies. Non‐right‐handedness (NRH) frequency was assessed in N = 2503 cases with reading and/or language impairment and N = 4316 sex‐matched controls identified from 10 distinct cohorts (age range 6–19 years old European ethnicity) using a priori set criteria. A meta‐analysis ( N cases = 1994) showed elevated NRH % in in iduals with language/reading impairment compared with controls (OR = 1.21, CI = 1.06–1.39, p = .01). The association between reading/language impairments and NRH could result from shared pathways underlying brain lateralization, handedness, and cognitive functions.
Publisher: Public Library of Science (PLoS)
Date: 12-09-2013
Publisher: Cold Spring Harbor Laboratory
Date: 04-11-2021
DOI: 10.1101/2021.11.04.466897
Abstract: The use of spoken and written language is a capacity that is unique to humans. In idual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30-80%, depending on the trait. The relevant genetic architecture is complex, heterogeneous, and multifactorial, and yet to be investigated with well-powered studies. Here, we present a multicohort genome-wide association study (GWAS) of five traits assessed in idually using psychometric measures: word reading, nonword reading, spelling, phoneme awareness, and nonword repetition, with total s le sizes ranging from 13,633 to 33,959 participants aged 5-26 years (12,411 to 27,180 for those with European ancestry, defined by principal component analyses). We identified a genome-wide significant association with word reading (rs11208009, p=1.098 × 10 −8 ) independent of known loci associated with intelligence or educational attainment. All five reading-/language-related traits had robust SNP-heritability estimates (0.13–0.26), and genetic correlations between them were modest to high. Using genomic structural equation modelling, we found evidence for a shared genetic factor explaining the majority of variation in word and nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence and educational attainment. A multivariate GWAS was performed to jointly analyse word and nonword reading, spelling, and phoneme awareness, maximizing power for follow-up investigation. Genetic correlation analysis of multivariate GWAS results with neuroimaging traits identified association with cortical surface area of the banks of the left superior temporal sulcus, a brain region with known links to processing of spoken and written language. Analysis of evolutionary annotations on the lineage that led to modern humans showed enriched heritability in regions depleted of Neanderthal variants. Together, these results provide new avenues for deciphering the biological underpinnings of these uniquely human traits.
Publisher: Springer Science and Business Media LLC
Date: 20-10-2022
DOI: 10.1038/S41588-022-01192-Y
Abstract: Reading and writing are crucial life skills but roughly one in ten children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70%, yet few convincing genetic markers have been found. Here we performed a genome-wide association study of 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls and identified 42 independent genome-wide significant loci: 15 in genes linked to cognitive ability/educational attainment, and 27 new and potentially more specific to dyslexia. We validated 23 loci (13 new) in independent cohorts of Chinese and European ancestry. Genetic etiology of dyslexia was similar between sexes, and genetic covariance with many traits was found, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Dyslexia polygenic scores explained up to 6% of variance in reading traits, and might in future contribute to earlier identification and remediation of dyslexia.
Publisher: Wiley
Date: 19-10-2010
Publisher: Wiley
Date: 29-08-2014
DOI: 10.1111/GBB.12158
Publisher: Wiley
Date: 04-2015
DOI: 10.1111/GBB.12213
Publisher: Springer Science and Business Media LLC
Date: 11-09-2007
DOI: 10.1007/S00335-007-9051-3
Abstract: The KIAA0319 gene in chromosome 6p22 has been strongly associated with developmental dyslexia. In this article we show a wide expression pattern of this gene in human adult brain by Northern blot analysis. We also performed RT-PCR analysis to detect alternative splicing variants in human brain. Most of the detected variants involve alternative splicing of the exons at the 5' and the 3' ends. Two main forms differing in the length of the 5' UTR are detected at approximately the same rate. Two variants (B and C) lacking exon 19, which encodes the transmembrane domain, are the main alternative forms detected among those predicted to encode protein. These two variants could be secreted and might be involved in signaling functions. A similar RT-PCR analysis performed in mouse and rat adult brains showed that only some of the alternative splicing variants are equivalent to those found in the human gene.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Silvia Paracchini.