Molecular genetic analyses in developmental dyslexia & related endophenotypes

Abstract

Developmental dyslexia is one of the most common neurodevelopmental disorders, with a prevalence of 5% to 12% among school-aged children. It is a severe and specific impairment in the acquisition of reading and spelling skills, which is unexpected in relation to other cognitive abilities. It is widely accepted that genetic factors play an essential role in dyslexia susceptibility. In this thesis, genetic analyses have been conducted (i) to investigate known susceptibility variants and (ii) to identify new genetic variants that would explain the heritability observed for both, dyslexia as qualitative trait and dyslexia-related quantitative endophenotypes. <br /> Causal susceptibility variants have been reported for two genes on chromosome 6p22, namely DCDC2 and KIAA0319. In our German dyslexia (DYS-) sample, we were not able to replicate prior findings on an intronic deletion or a compound STR marker in intron 2 of DCDC2 to be causative for dyslexia. Also, the analysis of further common variants in KIAA0319 did not provide evidence for a genetic effect in the German DYS-sample. However, we were able to confirm previous findings on epistatic gene-gene interactions between an intronic DCDC2 two-marker risk haplotype and SNPs within KIAA0319. This suggests that genetic variation within KIAA0319 might confer small modifying effects on dyslexia susceptibility in the presence of the DCDC2 risk haplotype. <br /> We next analyzed quantitative measures using candidate-gene approaches. Dyslexic children often perform poorly in verbal short-term memory tasks, and GRIN2B has been reported to play an important role in human memory and cognition. Our genetic results provide evidence that variation within intron 3 of GRIN2B contributes to the weakness of dyslexic children in short-term memory. A non-synonymous variant within a second gene, LRRTM1, was found to be associated with the measure of relative hand skill, which represents a correlate for asymmetrical brain function, and has been suggested to partly underlie the neural signature of dyslexia.<br /> We also attempted to identify new variants contributing to the development of dyslexia using a genome-wide association approach. To increase power, we combined individual genotyping with large pooling efforts. Our study revealed four new susceptibility loci on chr. 5p13, 9q21, 21q21 and 22q13. Promising candidate genes within these regions include GRIK1, TMC1 and FBLN1. As each of the identified variants only confers a small effect size, replication in large, independent samples will be required to confirm our findings.<br /> The application of the genome-wide approach on quantitative dimensions of dyslexia led to the identification of new susceptibility variants for two dyslexia-related endophenotypes. First, an intergenic marker on chromosome 4q32.1 was found to be highly associated with mismatch negativity, a neural correlate of speech perception. Our data indicate that the locus mediates its function via trans-regulational effects on the expression level of SLC2A3, a facilitative glucose transporter expressed in brain. It can be suggested that the effect is functionally relevant during childhood, when an increased amount of glucose substrate is required for the formation of synaptic connections in the human brain. In a second approach, we found that arithmetical skills are associated with alleles of rs133885, a non-synonymous marker in the long isoform of MYO18B. Structural MRI data provided evidence that in contrast to the non-risk group, carriers of the risk allele show a lower depth and volume of the right intraparietal sulcus, a structural entity involved in numerical processing. The new findings presented within this thesis might contribute to a better understanding of dyslexia susceptibility, genetic effects on related endophenotypes and the functional mechanisms that underlie human reading and writing skills.