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

Abstract

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s11689-009-9031-x) contains supplementary material, which is available to authorized users.

Genetic Variants ofFOXP2andKIAA0319/TTRAP/THEM2Locus Are Associated with Altered Brain Activation in Distinct Language-Related Regions

“…SPM5 analyses were performed for imputed polymorphisms comprising the Illumina BeadChips' SNPs and variants from the 1000 Genomes Project (Durbin et al, 2010). At the temporal peak, associations were found with rs3181244, rs2143340, rs3756819, rs1061925 and rs17243157, which were previously associated with reading skills (Francks et al, 2004;Cope et al, 2005;Luciano et al, 2007;Paracchini et al, 2008;Dennis et al, 2009;Rice et al, 2009). The peak of association (Ϫlog 10 (p) ϭ 5.11) was found at position 24777721 (labeled chr6:24777721 in the 1000 Genomes Project).…”

“…Additionally, rs6980093 is in high LD with one of the most reliable FOXP2 SNP, rs17137124, associated with phonological fluency and severity of degeneration of the inferior and dorsolateral frontal areas in elderly patients (Pado- Figure 4. Convergence of the DYX2 genetic variants for lower asymmetry in the pSTS with the risk haplotype for dyslexia identified in previous studies (Francks et al, 2004;Cope et al, 2005;Harold et al, 2006;Luciano et al, 2007;Paracchini et al, 2008;Dennis et al, 2009;Rice et al, 2009;Newbury et al, 2011). On the left is displayed a zoomed view within the KIAA0319/TTRAP/THEM2 region of the observed genetic association with functional pSTS asymmetry.…”

“…Recently, rs923875 was also reported in association with behavioral word reading efficiency and finger motor sequencing tests (Peter et al, 2011) while rs2396722 was associated with speech sound disorders in a cohort of 150 patients (Zhao et al, 2010). The SNP rs17137124 has been associated with Specific Language Impairment (Rice et al, 2009) and with modulation of frontal degeneration in elderly subjects (Padovani et al, 2010). The other published SNP associations were located in the same range of positions.…”

“…The first region covers partially KIAA0319 gene and the KIAA0319/TTRAP intergenic region where strong associations with a reading score were reported, among others, for rs2235676 and rs9467247 within a dense cluster of associations (Francks et al, 2004), rs3212236 (Harold et al, 2006;Dennis et al, 2009;Newbury et al, 2011) and rs9461045 (Dennis et al, 2009). The second region covers the TTRAP and a part of THEM2 gene where associations were reported for rs2143340 (Francks et al, 2004;Cope et al, 2005;Luciano et al, 2007;Dennis et al, 2009), rs3756819 (Paracchini et al, 2008;Rice et al, 2009), and rs1061925 (Francks et al, 2004). Finally, recent significant associations with normal variation in reading and spelling ability have been found with a haplotype spanning KIAA0319 and TTRAP (Luciano et al, 2007;Paracchini et al, 2008).…”

Motor Issues in Specific Language Impairment: a Window into the Underlying Impairment

“…An endophenotype is Bany hereditary characteristic that is normally associated with some condition but is not a direct symptom of that condition [71, p. 10].^If, via the search for endophenotypes, one or more common genetic sources could be found for SLI and other syndromes such as dyslexia where sequencing suffers in both the language and motor domains [72,73], that outcome would further support Ullman and Pierpont's proposal. Preliminary work that has been done in this connection has suggested genetic contributions to SLI [74], though identification of candidate genes [75] has been slowed by the varied diagnostic categories for SLI [76], and more recently the suggestion of complex interactions between genetic and environmental factors [77]. It is too early to tell whether the genetic data bear critically on the sequencing view or the other views that were reviewed here.…”