Silvia Paracchini’s research while affiliated with University of St Andrews and other places

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Publications (164)


Genetics of human handedness: microtubules and beyond
  • Literature Review

February 2025

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14 Reads

Trends in Genetics

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Jutta Peterburs

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Silvia Paracchini

Whole-exome sequencing in children with dyslexia identifies rare variants in CLDN3 and ion channel genes
  • Preprint
  • File available

December 2024

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22 Reads

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[...]

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Silvia Paracchini

Dyslexia is a specific difficulty in learning to read that affects 5-10% of school-aged children and is strongly influenced by genetic factors. While previous studies have identified common genetic variants associated with dyslexia, the role of rare variants has only recently begun to emerge from pedigree studies and has yet to be systematically tested in larger cohorts. Here, we present a whole-exome sequencing (WES) study of 53 individuals with dyslexia, followed by replication analysis in 38 cases with reading difficulties and 82 controls assessed with reading measures. Our stringent bioinformatics filtering strategy highlighted five brain-expressed genes carrying rare variants: CACNA1D, CACNA1G, CLDN3, CNGB1, and CP. Notably, a specific variant (7-73769649-G-A) in the CLDN3 gene was identified in six independent cases, showing a four-fold higher frequency compared to population reference datasets. CACNA1D and CACNA1G encode subunits of voltage-gated calcium channels (VGCC) expressed in neurons, and variants in both genes have been implicated in neurodevelopmental disorders such as autism spectrum disorder (ASD) and epilepsy. Segregation analysis in available family members were consistent with patterns of dominant inheritance with variable expressivity. In total, high-impact variants in the five genes of interest were found in 26% (N = 14) of individuals of the discovery cohort. Overall, our findings support the involvement of rare variants in developmental dyslexia and indicate that larger WES studies may uncover additional associated genes.

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Genetics of Human Handedness

December 2024

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11 Reads

Around the world, about 10% of people prefer using their left hand. Handedness exhibits a consistent but modest (~25%) genetic component as reported across independent studies. Advances in genomic technologies combined with very large samples have led to the identification of specific genes associated with handedness. Most of these genes have a clear role in neurodevelopment, and the results provide evidence for shared biology contributing to handedness, cerebral asymmetries, and psychiatric disorders. It has become clear that human handedness is highly polygenic, and no individual gene is expected to play a major role. This chapter illustrates the methodology used in genomic studies and the implications of the most recent findings.


Distribution of grip strength with dominant (GSD) and grip strength with non‐dominant (GSND) scores stratified by sex in ALSPAC (A and B) and in the Raine Study (C and D). Females are represented in purple and males in orange.
Manhattan plots for (A) grip strength with dominant and (B) grip strength with non‐dominant in the meta‐analysed sample. See Figure S3 for QQ plots and Figure S4 for the regional plot of the top associated locus at chromosome 4.
Genetic correlation (rg) analysis for grip strength with dominant (GSD) and grip strength with non‐dominant (GSND). The colour of the rg values refers to the p‐value with red indicating nominal significance (p < 0.05), green indicating a non‐significant result, and blue indicating statistical significance with p < 0.0021. AD, Alzheimer's disease; ASD, autism spectrum disorder; BIP, bipolar disorder; HBD.left, heel bone density with the left foot; Grip.left.UKBB, grip strength with the left hand from UK Biobank; Grip.right.UKBB, grip strength with the right hand from UK Biobank; HBD.right, heel bone density with the right foot; SCZ, schizophrenia.
A GWAS for grip strength in cohorts of children—Advantages of analysing young participants for this trait

October 2024

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27 Reads

Grip strength (GS) is a proxy measure for muscular strength and a predictor for bone fracture risk among other diseases. Previous genome‐wide association studies (GWASs) have been conducted in large cohorts of adults focusing on scores collected for the dominant hand, therefore increasing the likelihood of confounding effects by environmental factors. Here, we perform the first GWAS meta‐analyses on maximal GS with the dominant (GSD) and non‐dominant (GSND) hand in two cohorts of children (ALSPAC, N = 5450; age range = 10.65–13.61; Raine Study, N = 1162, age range: 9.42–12.38 years). We identified a novel significant association for GSND (rs9546244, LINC02465, p = 3.43e−08) and replicated associations previously reported in adults including with a HOXB3 gene marker that shows an expression quantitative trait locus (eQTL) effect. Despite a much smaller sample (~3%) compared with the UK Biobank we replicated correlation analyses previously reported in this much larger adult cohort, such as a negative correlation with coronary artery disease. Although the results from the polygenic risk score (PRS) analyses did not survive multiple testing correction, we observed nominally significant associations between GS and risk of overall fracture, as previously reported, as well ADHD which will require further investigations. Finally, we observed a higher SNP‐heritability (24%–41%) compared with previous studies (4%–24%) in adults. Overall, our results suggest that cohorts of children might be better suited for genetic studies of grip strength, possibly due to the shorter exposure to confounding environmental factors compared with adults.




Figure 2 | Sex differences, parental genetic effects and parent-of-origin effects. Sex biased expression of genes can lead to a sex difference in incidence of left-handedness. Expression of parents' genes can lead to parental genetic effects in relation to lefthandedness. Parent-of-origin-specific gene expression can lead to parent-of-origin effects in relation to left-handedness.
Figure 3 | Predictions as to how dispersal pattern and gene function modulate the pattern of genomic imprinting. See Supplementary Material Figure S7 for additional predictions concerning the phenotypic consequences of gene deletions, gene duplications, epimutations and uniparental disomies.
Kin selection as a modulator of human handedness: sex-specific, parental and parent-of-origin effects

August 2024

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46 Reads

Evolutionary Human Sciences

The frequency of left-handedness in humans is ∼10% worldwide and slightly higher in males than females. Twin and family studies estimate the heritability of human handedness at around 25%. The low but substantial frequency of left-handedness has been suggested to imply negative frequency-dependent selection, e.g. owing to a “surprise” advantage of left-handers in combat against opponents more used to fighting right-handers. Because such game-theoretic hypotheses involve social interaction, here, we perform an analysis of the evolution of handedness based on kin-selection, which is understood to play a major role in the evolution of social behaviour generally. We show that: (1) relatedness modulates the balance of right-handedness versus left-handedness, according to whether left-handedness is marginally selfish versus marginally altruistic; (2) sex differences in relatedness to social partners may drive sex differences in handedness; (3) differential relatedness of parents and offspring may generate parent-offspring conflict and sexual conflict leading to the evolution of maternal and paternal genetic effects in relation to handedness; and (4) differential relatedness of maternal-origin versus paternal-origin genes may generate intragenomic conflict leading to the evolution of parent-of-origin-specific gene effects—such as “genomic imprinting”—and associated maladaptation.


Fig. 2 | Results of polygenic risk score (PRS) analysis using SBayesR on the 34 language-related phenotypes analyzed in this study, with PRS constructed from external GWAS data of different neuropsychiatric disorders/traits (training set).
Fig. 3 | Results of polygenic risk score (PRS) analysis on the 34 language-related phenotypes analyzed in this study, with PRS constructed from external GWAS data of reading and language-related traits from Eising et al. The following traits were included: word reading, nonword reading, spelling, phoneme awareness, and nonword repetition. In the heatmap, for each PRS analysis, we select the result with the lowest FDR-adjusted p-value (p.adjust), and show the regression coefficient in the graph. The PRS represent the average risk allele score per non-missing SNP. PT: the optimal p-value threshold at which the most significant association was observed.
Top 20 S-Multixcan results after correction of multiple testing
Overview of phenotypes included in the study
A genome-wide association study of Chinese and English language phenotypes in Hong Kong Chinese children

March 2024

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134 Reads

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1 Citation

npj Science of Learning

Dyslexia and developmental language disorders are important learning difficulties. However, their genetic basis remains poorly understood, and most genetic studies were performed on Europeans. There is a lack of genome-wide association studies (GWAS) on literacy phenotypes of Chinese as a native language and English as a second language (ESL) in a Chinese population. In this study, we conducted GWAS on 34 reading/language-related phenotypes in Hong Kong Chinese bilingual children (including both twins and singletons; total N = 1046). We performed association tests at the single-variant, gene, and pathway levels. In addition, we tested genetic overlap of these phenotypes with other neuropsychiatric disorders, as well as cognitive performance (CP) and educational attainment (EA) using polygenic risk score (PRS) analysis. Totally 5 independent loci (LD-clumped at r ² = 0.01; MAF > 0.05) reached genome-wide significance ( p < 5e-08; filtered by imputation quality metric Rsq>0.3 and having at least 2 correlated SNPs (r ² > 0.5) with p < 1e-3). The loci were associated with a range of language/literacy traits such as Chinese vocabulary, character and word reading, and rapid digit naming, as well as English lexical decision. Several SNPs from these loci mapped to genes that were reported to be associated with EA and other neuropsychiatric phenotypes, such as MANEA and PLXNC1 . In PRS analysis, EA and CP showed the most consistent and significant polygenic overlap with a variety of language traits, especially English literacy skills. To summarize, this study revealed the genetic basis of Chinese and English abilities in a group of Chinese bilingual children. Further studies are warranted to replicate the findings.


A GWAS for grip strength in cohorts of children – advantages of analysing young participants for this trait

February 2024

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14 Reads

Grip strength (GS) is a proxy measure for muscular strength and a predictor for bone fracture risk among other diseases. Previous genomewide association studies (GWAS) have been conducted in large cohorts of adults focusing on scores collected for the dominant hand, therefore increasing the likelihood of confounding effects by environmental factors. Here, we perform the first GWAS meta-analyses on maximal GS with the dominant (GSD) and non-dominant (GSND) hand in two cohorts of children (ALSPAC, N = 5,450; age range = 10.65 / 13.61; Raine Study, N = 1,162, age range: 9.42 / 12.38 years). We identified a novel significant association for GSND (rs9546244, LINC02465, p = 3.43e-08) and replicated associations previously reported in adults including with a HOXB3 gene marker that shows an eQTL effect. Despite a much smaller sample (~3%) compared to the UK Biobank we replicated correlation and polygenic risk score (PRS) analyses previously reported in this much larger adult cohort. Specifically, we observed genetic correlations with coronary artery disease and a PRS association with the risk of overall fracture. Furthermore, we observed a higher SNP-heritability (24-41%) compared to previous studies (4-24%) in adults. Our results suggest that cohorts of children might be better suited for genetic studies of grip strength, possibly due to the shorter exposure to confounding environmental factors compared to adults.


Auditory Cortex Asymmetry Associations with Individual Differences in Language and Cognition

December 2023

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19 Reads

Brain Sciences

A longstanding cerebral lateralization hypothesis predicts that disrupted development of typical leftward structural asymmetry of auditory cortex explains why children have problems learning to read. Small sample sizes and small effects, potential sex-specific effects, and associations that are limited to specific dimensions of language are thought to have contributed inconsistent results. The large ABCD study dataset (baseline visit: N = 11,859) was used to test the hypothesis of significant associations between surface area asymmetry of auditory cortex and receptive vocabulary performance across boys and girls, as well as an oral word reading effect that was specific to boys. The results provide modest support (Cohen’s d effect sizes ≤ 0.10) for the cerebral lateralization hypothesis.


Citations (46)


... Our testing procedure closely mirrored that described in the reference 31 and our recent study 34 . We performed clumping using PLINK (v1.9), setting the physical distance threshold at 10,000 kb and the r 2 threshold at 0.2. ...

Reference:

Genome-wide association study of COVID-19 Breakthrough Infections and genetic overlap with other diseases: A study of the UK Biobank
A genome-wide association study of Chinese and English language phenotypes in Hong Kong Chinese children

npj Science of Learning

... Overall, these genes highlight the role of tubulin in various aspects of brain formation, supporting the idea that handedness is established during the early phases of neurodevelopment and that it is influenced by genes involved in different processes. The observed associations between left-and mixed-handedness and different neurodevelopmental conditions such as schizophrenia, autism spectrum disorder (ASD), and dyslexia are consistent with these observations [7,[68][69][70]. ...

Elevated levels of mixed-hand preference in dyslexia: Meta-analyses of 68 studies
  • Citing Article
  • September 2023

Neuroscience & Biobehavioral Reviews

... Over the past years, the interest in studying laterality has increased considerably, driven by several findings that reveal a higher prevalence of non-right handedness (i.e., left-and mixed-handedness) among individuals with neurodevelopmental disorders. Atypical handedness (i.e., non-right handedness) has been associated with neurodevelopmental disorders such as developmental dyslexia (DD, for metaanalyses see Abbondanza et al., 2023;Eglinton & Annett, 1994;Packheiser et al., 2023), developmental coordination disorder (DCD, see for meta-analysis Darvik et al., 2018), intellectual disability (see for meta-analysis Papadatou-Pastou & Tomprou, 2015), and autism spectrum disorder (see for meta-analysis Markou et al., 2017). Furthermore, there is also evidence of atypical functional and structural lateralization among individuals with DD Bishop, 2013; and DCD (Biotteau et al., 2016;Hodgson & Hudson, 2017), among other disorders. ...

Language and reading impairments are associated with increased prevalence of non-right-handedness

Child Development

... It is very helpful to provide learners with an overall speaking level assessment in computer-assisted language learning systems. There have been many studies in this direction [11][12][13]. In addition to the overall speaking level score of the speaker, providing more detailed and specific feedback on pronunciation errors is more helpful for learners' language learning [14][15]. ...

Non-right handedness is associated with language and reading impairments

Child Development

... Additionally, we observed the presence of non-synonymous SNVs in the DCDC2 and KIAA0319 genes. These genes are recognized for their involvement in neuronal migration and cell adhesion, both of which are crucial processes for brain development and connectivity [43,44]. Variations in these genes could impact the formation of neural circuits and communication between brain regions. ...

Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities

Translational Psychiatry

... We used summary statistics from the most recent large-scale (>10,000 cases) GWAS of neurodevelopmental conditions. These were ADHD (Demontis et al., 2023), autism (Grove et al., 2019), and dyslexia (Doust et al., 2022). The PGS for dyslexia was created using the publicly available summary statistics containing only the top 10,000 SNPs. ...

Discovery of 42 genome-wide significant loci associated with dyslexia

Nature Genetics

... In chicks, light exposure regulates the ontogenesis of brain asymmetries possibly by influencing gene expression. PDGFRB, a gene controlling rearrangement of the actin cytoskeleton, was reported to be differentially expressed through this process [88]. Studies in mice allow the targeted knockout of genes related to microtubules and thus to uncover consequences of missing gene expression. ...

Light-induced asymmetries in embryonic retinal gene expression are mediated by the vascular system and extracellular matrix

... Soprattutto negli ultimi anni, vi è stato anche un considerevole sviluppo degli studi sulle basi genetiche dei disturbi dell'apprendimento e in particolare della dislessia (per una rassegna si veda Paracchini, 2022). Una motivazione forte per lo sviluppo di questi studi deriva dall'osservazione che una quota significativa (sino al 70%) del rischio di avere un disturbo di lettura è riconducibile ad un'origine genetica. ...

The Genetics of Dyslexia: Learning from the Past to Shape the Future
  • Citing Chapter
  • May 2022

... There is a literature about non-right handedness (Abbondanza et al., 2022) and right hemisphere activation (Pugh et al., 2000) for language tasks in dyslexic populations that indicate an aberration in cerebral dominance. Also, a few studies have been published on the issue of structural planum temporale asymmetry as seen in in vivo imaging studies (for a review, see Shapleske et al., 1999). ...

Non-right handedness is associated with language and reading impairments
  • Citing Preprint
  • March 2022

... McManus (2021) suggests that environmental factors could explain, at best, 1%-2% of the variance in handedness, while genetic factors are most likely to be the strongest contributor (McManus, 2009(McManus, , 2021. However, genetic factors are limited in explaining most of the variances in the population, and the heritability of handedness is around 24% (Medland et al., 2009;Schmitz et al., 2022). Therefore, most of the variance in handedness is unaccounted for. ...

Quantitative multidimensional phenotypes improve genetic analysis of laterality traits

Translational Psychiatry