Guest Post: Uncovering the Genetic Mechanisms of Common Language Disabilities, by John Eicher

         May 20, 2014

When many people think of learning disabilities such as dyslexia and language impairment, they typically do not think of a biological or medical condition. Even more rarely do people think of these conditions as being the result of biological and genetic phenomena. However, that is exactly what I have thought of every day during my doctoral training in the Department of Genetics at Yale University.

Here, my colleagues and I work to identify and examine the genes that contribute to common learning disabilities with an emphasis on those concerning language, such as dyslexia and language impairment. Dyslexia is characterized by unexpected difficulties with reading and written language, while language impairment involves deficits in expressive and receptive verbal language. Both dyslexia and language impairment are persistent impairments that affect an individual’s daily life, within or outside a school setting. Interestingly, these disorders commonly co-occur, meaning that children often have both dyslexia and language impairment. This has led my colleagues and I to hypothesize that these conditions may share genetic risk factors.

To test our hypothesis, we recently completed two studies: (1) we first characterized the role of the dyslexia risk locus called DYX2 on chromosome 6p22 with dyslexia and language impairment and (2) we performed a genome-wide association study (GWAS) of children with both dyslexia and language impairment. For both studies, we used data collected as part of the Avon Longitudinal Study of Parents and Children (ALSPAC), which has followed a large number of children from before birth into adulthood. Following these discovery analyses, we replicated associations in several cohorts recruited in the United States and Europe.

What we found was that dyslexia and language impairment do indeed share genetic associations. Within the DYX2 dyslexia risk locus, we found associations between the known dyslexia risk genes DCDC2 and KIAA0319 with both dyslexia and language impairment. We also observed that risk variants in DCDC2 and KIAA0319 interact with each other in a non-additive fashion. That is, the magnitude of the effect of having both risk variants is greater than the sum of their individual effects. We believe that this non-additive effect between with the DCDC2 and KIAA0319 risk variants may reflect a biological, physical interaction between these genes. Additionally, our GWAS analyses revealed that variants in the ZNF385D gene on chromosome 3 are associated specifically in individuals with both dyslexia and language impairment. These risk variants in ZNF385D also influence fiber tract volumes throughout the brain that connect key language processing centers. These differences in fiber tract volumes were correlated with performance on written and verbal language tasks. The identification of these risk genes (DCDC2, KIAA0319, and ZNF385D), and their shared associations with dyslexia and language impairment are important for untangling the underlying genetic mechanisms.

As with all studies, we encountered many hurdles while trying to execute these analyses. One major challenge was incorporating massive amounts of genotype and phenotype data together, from both family-based and population-based cohorts. Fortunately, Golden Helix’s SNP & Variation Suite (SVS) gave us the flexibility to import and export various different data types—including text, SPSS, Illumina Final Reports, ped/map, bed/bim/fam, among with many other different types. This functionality saved our group much time and frustration in trying to make sense of these data. The customer support was also a fantastic resource for all of my questions, which allowed me to take advantage of many of the functionalities of the SVS software.

The overall goal of our work is to identify the underlying genetic and biological mechanisms of common language disabilities. By doing so, we hope to improve the care of affected individuals by both enabling early detection and improving clinical care by pediatricians, teachers, and parents. Improved care will hopefully unlock the potential of all children, even those who integrate language and other aspects of communication in different ways.

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