Genome-wide analysis of genetic susceptibility to language impairment in an isolated Chilean population

Abstract

Specific language impairment (SLI) is an unexpected deficit in the acquisition of language skills and affects between 5 and 8% of pre-school children. Despite its prevalence and high heritability, our understanding of the aetiology of this disorder is only emerging. In this paper, we apply genome-wide techniques to investigate an isolated Chilean population who exhibit an increased frequency of SLI. Loss of heterozygosity (LOH) mapping and parametric and non-parametric linkage analyses indicate that complex genetic factors are likely to underlie susceptibility to SLI in this population. Across all analyses performed, the most consistently implicated locus was on chromosome 7q. This locus achieved highly significant linkage under all three non-parametric models (max NPL=6.73, P=4.0 × 10−11). In addition, it yielded a HLOD of 1.24 in the recessive parametric linkage analyses and contained a segment that was homozygous in two affected individuals. Further, investigation of this region identified a two-SNP haplotype that occurs at an increased frequency in language-impaired individuals (P=0.008). We hypothesise that the linkage regions identified here, in particular that on chromosome 7, may contain variants that underlie the high prevalence of SLI observed in this isolated population and may be of relevance to other populations affected by language impairments.

Genome-Wide Association and Exome Sequencing Study of Language Disorder in an Isolated Population

“…19 A whole exome sequencing (WES) study of DLD in an admixed Chilean founder population suggested the involvement of a nonsynonymous single nucleotide variant (SNV) in NFXL1 22 ; however, its location is not in the previously identified linkage regions in this population. 23 This pattern of findings highlights the complexity of DLD's etiology, driven by the exclusionary nature of the diagnosis, the multicomponential nature of the phenotype, and the heterogeneity of the samples studied. The main objective of the present study was to identify genetic bases of DLD in a unique population (small, geographically secluded, and with an elevated prevalence of DLD [hereafter, the AZ population]) in which genetic and environmental variability is constrained.…”

Dental Morphological Markers as a Proxy for Ethnicity in Robinson Crusoe Islanders

“…In the population of Robinson Crusoe, a marker has been identified, along with five zones highly associated with the pathology on other chromosomes (Villanueva et al, 2010(Villanueva et al, , 2011. Among these, a zone in chromosome 7 coincides with the location of genes identified as an area of susceptibility for SLI, autism, and vocabulary and grammar disorders.…”

“…This language disorder has been described as highly heritable, complex, and multifactorial (Newbury et al, 2010;Villanueva et al, 2011). Therefore, identifying the genetic components of this interesting population (gene pool) allows for a more detailed evaluation of the role of genetic and environmental contributions in this developmental disorder.…”

“…As this language pathology has a genetic basis, it may be associated with a founder effect, that is, the genetic homogeneity that develops in isolated locations with low population variance (Cavalli-Sforza & Bodmer; Villanueva et al, 2010Villanueva et al, , 2011.…”

Insights into the Genetic Foundations of Human Communication

“…First, some DNA variants occur at different frequencies in different populations, which may affect the prevalence of language disorders. For instance, unusually high rates of SLI have been observed on Robinson Crusoe island, which might be explained by a founder effect in this isolated Chilean population (Villanueva et al 2011). Non-European populations carry a number of unique genetic variants not found in Europeans, some of which might contribute to risk of language-related problems.…”