Dissection of genetic associations with language-related traits in population-based cohorts

Recent advances in the field of language-related disorders have led to the identification of candidate genes for specific language impairment (SLI) and dyslexia. Replication studies have been conducted in independent samples including population-based cohorts, which can be characterised for a large number of relevant cognitive measures. The availability of a wide range of phenotypes allows us to not only identify the most suitable traits for replication of genetic association but also to refine the associated cognitive trait. In addition, it is possible to test for pleiotropic effects across multiple phenotypes which could explain the extensive comorbidity observed across SLI, dyslexia and other neurodevelopmental disorders. The availability of genome-wide genotype data for such cohorts will facilitate this kind of analysis but important issues, such as multiple test corrections, have to be taken into account considering that small effect sizes are expected to underlie such associations

Role of simian virus 40 in cancer incidence in solid organ transplant patients

Transplant recipients have an increased risk of developing cancer in comparison with the general population. We present here data on cancer development in transplanted subjects who received organs from donors whose DNA was previously examined for the genomic insertion of Simian Virus 40 (SV40). Active follow-up of 387 recipients of solid organs donated by 134 donors, not clinically affected by cancer, was performed through the National Transplant Center (NTC). The average length of follow-up after transplant was 671±219 days (range 0–1085 days). Out of 134 proposed donors, 120 were utilised for organ donation. Of these, 12 (10%) were classified as positive for SV40 genomic insertion. None of the 41 recipients of organs from SV40 positive donors developed a tumour during the follow-up. In all, 11 recipients of organs given by SV40 negative donors developed a tumour (cancer incidence: 0.015 per year). In conclusion, cancer rates observed in our study are comparable to what reported by the literature in transplanted patients. Recipients of solid organs from SV40 positive donors do not have an increased risk of cancer after transplant. The role of SV40 in carcinogenesis in transplanted patients may be minimal

Convergent genetic linkage and associations to language, speech and reading measures in families of probands with Specific Language Impairment

We analyzed genetic linkage and association of measures of language, speech and reading phenotypes to candidate regions in a single set of families ascertained for SLI. Sib-pair and family-based analyses were carried out for candidate gene loci for Reading Disability (RD) on chromosomes 1p36, 3p12-q13, 6p22, and 15q21, and the speech-language candidate region on 7q31 in a sample of 322 participants ascertained for Specific Language Impairment (SLI). Replication or suggestive replication of linkage was obtained in all of these regions, but the evidence suggests that the genetic influences may not be identical for the three domains. In particular, linkage analysis replicated the influence of genes on chromosome 6p for all three domains, but association analysis indicated that only one of the candidate genes for reading disability, KIAA0319, had a strong effect on language phenotypes. The findings are consistent with a multiple gene model of the comorbidity between language impairments and reading disability and have implications for neurocognitive developmental models and maturational processes

Investigation of Dyslexia and SLI Risk Variants in Reading- and Language-Impaired Subjects

Dyslexia (or reading disability) and specific language impairment (or SLI) are common childhood disorders that show considerable co-morbidity and diagnostic overlaps and have been suggested to share some genetic aetiology. Recently, genetic risk variants have been identified for SLI and dyslexia enabling the direct evaluation of possible shared genetic influences between these disorders. In this study we investigate the role of variants in these genes (namely MRPL19/C20RF3,ROBO1,DCDC2, KIAA0319, DYX1C1, CNTNAP2, ATP2C2 and CMIP) in the aetiology of SLI and dyslexia. We perform case–control and quantitative association analyses using measures of oral and written language skills in samples of SLI and dyslexic families and cases. We replicate association between KIAA0319 and DCDC2 and dyslexia and provide evidence to support a role for KIAA0319 in oral language ability. In addition, we find association between reading-related measures and variants in CNTNAP2 and CMIP in the SLI families

Approach to epigenetic analysis in language disorders

Language and learning disorders such as reading disability and language impairment are recognized to be subject to substantial genetic influences, but few causal mutations have been identified in the coding regions of candidate genes. Association analyses of single nucleotide polymorphisms have suggested the involvement of regulatory regions of these genes, and a few mutations affecting gene expression levels have been identified, indicating that the quantity rather than the quality of the gene product may be most relevant for these disorders. In addition, several of the candidate genes appear to be involved in neuronal migration, confirming the importance of early developmental processes. Accordingly, alterations in epigenetic processes such as DNA methylation and histone modification are likely to be important in the causes of language and learning disorders based on their functions in gene regulation. Epigenetic processes direct the differentiation of cells in early development when neurological pathways are set down, and mutations in genes involved in epigenetic regulation are known to cause cognitive disorders in humans. Epigenetic processes also regulate the changes in gene expression in response to learning, and alterations in histone modification are associated with learning and memory deficits in animals. Genetic defects in histone modification have been reversed in animals through therapeutic interventions resulting in rescue of these deficits, making it particularly important to investigate their potential contribution to learning disorders in humans

Further evidence for a parent-of-origin effect at the NOP9 locus on language-related phenotypes

Background - Specific language impairment (SLI) is a common neurodevelopmental disorder, observed in 5–10 % of children. Family and twin studies suggest a strong genetic component, but relatively few candidate genes have been reported to date. A recent genome-wide association study (GWAS) described the first statistically significant association specifically for a SLI cohort between a missense variant (rs4280164) in the NOP9 gene and language-related phenotypes under a parent-of-origin model. Replications of these findings are particularly challenging because the availability of parental DNA is required. Methods - We used two independent family-based cohorts characterised with reading- and language-related traits: a longitudinal cohort (n = 106 informative families) including children with language and reading difficulties and a nuclear family cohort (n = 264 families) selected for dyslexia. Results - We observed association with language-related measures when modelling for parent-of-origin effects at the NOP9 locus in both cohorts: minimum P = 0.001 for phonological awareness with a paternal effect in the first cohort and minimum P = 0.0004 for irregular word reading with a maternal effect in the second cohort. Allelic and parental trends were not consistent when compared to the original study. Conclusions - A parent-of-origin effect at this locus was detected in both cohorts, albeit with different trends. These findings contribute in interpreting the original GWAS report and support further investigations of the NOP9 locus and its role in language-related traits. A systematic evaluation of parent-of-origin effects in genetic association studies has the potential to reveal novel mechanisms underlying complex traits