The genetics of developmental dysexia
There is likely to be significant involvement of genetic factors in predisposing towards dyslexia. However, dyslexia is a complex genetic disorder. It does not appear to be inherited as a single gene disorder, but instead seems to be caused by a number of different genes that combine and interact with environmental factors to produce an overall risk factor for developing dyslexia.
Over the past 15 years or so, there has been remarkable success tracking down genes for single-gene disorders, such as cystic fibrosis, Duchenne muscular dystrophy and Huntington's disease. Unfortunately, such approaches are not usually powerful enough for complex genetic disorders such as dyslexia. Recently, however, novel strategies have been developed that are more appropriate for finding genes influencing complex disorders. We have used these techniques in our research, with the aim to identify the specific genes implicated in dyslexia.
For a more comprehensive account of what we currently know about the genetics of dyslexia see this article, published in the October 2002 issue of Nature Reviews Neuroscience.
A number of genetic studies of dyslexia indicate that there is likely to be a gene influencing reading disability on chromosome 6. Regions on chromosomes 1, 2, 3 and 15 have also been implicated in susceptibility to reading problems. However, prior to our investigation no-one had completed a systematic search of all the chromosomes in large samples of families with developmental dyslexia. This suggested that significant genetic effects influencing this trait might have gone undetected. In our initial study, we therefore carried out a complete genome scan, of all chromosomes of the entire human genome, using the latest methods for genetic analysis of complex traits. We initially used two separate samples of families having a child diagnosed with dyslexia (one sample from the UK, the other from the USA). This was the first time that a complete genome scan had been run on a large sample of dyslexic families.
As in previous analyses, we found clear support for a region on chromosome 6 being linked to dyslexia. However, what was more interesting was that we also detected a strong effect on chromosome 18. We also found evidence for regions of interest in chromosomes 2 and 3. We then replicated our findings using a new set of UK families. The results of our initial study were published in January 2002 (1).
Following on from our initial study, we looked in more detail at the region of interest on chromosome 6. We first identified a risk haplotype for dyslexia spanning three genes in this region. The results of this study were published in 2004 (2). Subsequently, we focused our research on the most promising of these three genes, KIAA0319 (OMIM 609269). The results of this study were published in 2006 (3).
Overall, our initial studies provided us with a comprehensive genome-wide view of the most likely locations of genes influencing dyslexia in our samples. However, this is really just the starting point for the search. As with all analyses of complex genetic disorders, we cannot be certain that we are looking at real effects until we have tracked down the specific genetic variants that are responsible. And even then it might be tough to prove! Having scanned the entire genome and identified regions that might contain genes influencing the measures of reading disability, we and others are trying to replicate the findings in independent sets of families. In addition, we are targeting these regions using more genetic markers and more sensitive statistical methods, to try and pin-point the positions of the risk genes as accurately as possible. The genome screen is therefore just the first step in a long process, referred to as positional cloning, which should eventually enable us to isolate specific gene variants that influence developmental dyslexia.
Our current research focuses on the following three projects:
- Dyslexia / SLI Project: "Gene-gene and gene-environment interactions underlying speech, language and reading development"
- Focus on chromosomes 6 and 18
We are currently investigating in more detail candidate genes from regions of interest on chromosome 6 and chromosome 18.
• Neurodys project
We are currently collaborating with Neurodys, a new European research consortium on dyslexia