Testing genetic causes of dyslexia

Although at least four genes have been identified as possible markers for dyslexia, scientists have encountered considerable difficulty in coming to consensus about identifying a culprit as a contributing cause for the perplexing reading disorder. As noted previously here on LD Blog, DCDC2 (1 November 2005) and DYX1C1 (1 August 2008; 19 November 2009), among others, have been cited as possible loci for disruptions. But problems emerge when seeking to connect studies that point toward these candidate genes and studies showing the individuals with the problems. The associations between genes and problems appear in some language populations, but perhaps not in others, making one wonder about the clarity of the relationships.

Seeking a means of examining the relationships at a more abstract level, a group of European researchers collected data from a sample of individuals with dyslexia that represented people from eight different countries (Austria, France, Germany, The Netherlands, Switzerland, Finland, Hungary, and the United Kingdom). Using this diverse language sample, they reasoned, would allow them to search the the connections between genes and dyslexia at a more abstract level than when testing with a sample of people speaking just one or two languages.

To identify their sample of individuals with dyslexia, the researchers used a discrepancy definition of reading disability. To be counted as an individual with reading problems (n=958), the participants had to score 1.25 standard deviations below grade level on a standardized test of word reading skill (in their native language, of course); the researchers excluded individuals for a host of others reasons including sensory deficits, native language background, medications for seizure of behavioral issues, ADHD, and so forth. To be included in the control group (n=1150), students had to score no more than 0.85 standard deviations below grade level on the reading test.

In addition to testing all 2000+ students for reading and spelling, the researchers used genetic data from the participants to search for single nucleotide polymorphisms (SNPs) between groups at the various sites. For example, at the location rs793862 on Chromosome 6, they were looking for differences between the groups in the gene DCDC2. They examined a total of 19 such locations. They also examined four haplotypes or clusters of genes that are inherited together.

Without delving deeply into the data analysis, the main findings were that the researchers found only a few (5 of 54 in one set; 3 of ~139 in another) significant connections and these were scattered and inconsistent. It’s worth noting that the researchers were careful and conservative, so they won’t be accused of overstating their findings. They did not find the consistent result that would resolve matters, that would point to a specific marker and allow scientists to say, “See, that gene affects metabolism in dyslexia. Now we need to determine how the metabolism affects performance” (or something comparable).

Still, we are left with the tantalizing recurrences of the previous work on these genes and the bits of replication found in this study….

Abstract

Becker, J., Czamara, D., Scerri, T. S., Ramus, F., Csépe, V., Talcott, J. B., & Schumacher, J. (2013). Genetic analysis of dyslexia candidate genes in the European cross-linguistic NeuroDys cohort. European Journal of Human Genetics, 1–6. Advance online publication, 11 September 2013; doi:10.1038/ejhg.2013.199

Dyslexia is one of the most common childhood disorders with a prevalence of around 5–10% in school-age children. Although an important genetic component is known to have a role in the aetiology of dyslexia, we are far from understanding the molecular mechanisms leading to the disorder. Several candidate genes have been implicated in dyslexia, including DYX1C1, DCDC2, KIAA0319, and the MRPL19/C2ORF3 locus, each with reports of both positive and no replications. We generated a European cross-linguistic sample of school-age children – the NeuroDys cohort – that includes more than 900 individuals with dyslexia, sampled with homogenous inclusion criteria across eight European countries, and a comparable number of controls. Here, we describe association analysis of the dyslexia candidate genes/locus in the NeuroDys cohort. We performed both case–control and quantitative association analyses of single markers and haplotypes previously reported to be dyslexia-associated. Although we observed association signals in samples from single countries, we did not find any marker or haplotype that was significantly associated with either case–control status or quantitative measurements of word-reading or spelling in the meta-analysis of all eight countries combined. Like in other neurocognitive disorders, our findings underline the need for larger sample sizes to validate possibly weak genetic effects.

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