The present proposal is a a follow up of our current B598 project, which aims to investigate the gene x gene and gene x environment interactions at the basis of dyslexia and related disorders. Preliminary data from the analysis conducted so far are encouraging. We were able to replicate in the ALSPAC sample some associations of genetic markers we have idetified in our selected samples for dyslexia and SLI (Paracchini et al, 2008 , Newbury et al, submitted). The B598 has been designed as a short 2-years pilot study and we would now like to take forward and extend its format while the aims remain the same.

Aims of the project are:

1) To replicate in the ALSPAC sample previously reported genetic association at the basis of dyslexia and SLI

2) To investigate whether the effect of dyslexia and SLI susceptibility variants can be modulated by different genetic factors (gene x gene interactions).

3) To investigate the role of environmental factors in modulating the effect of genes that contribute to measures of reading, speech and language (gene x environment interactions).

4) To test whether shared genetic or environmental factors can explain co-morbidity between dyslexia and SLI and whether it is possible to identify a correlation between genetic/environment background and specific sub-groups of phenotypes.

We would like to expand the current analysis by genotyping additional SNP, genotyping the mother cohort and possibly the fathers. We will also expand, consequentially, the statistical analysis.

We would like to include in the analysis additional genes that have been implicated in SLI, dyslexia and ADHD as well as interesting gene implicated in regulating cognitive function. We are also cunducting an extensice functional characterisation of the KIAA0319, focusing in particular on the identification of interacting proteins. We have identify and verified several protein interacting with KIAA0319 and we would like to include these in our analysis. We are in the process of testing for association SNPs within these genes and we planning to include in ALSPAC only significantly associated SNPs. Therefore at this stage we cannot speficy any rs number for these genes.

For some genes we are planning to investigate parent-of-origin effect. Therefore we would like to include in this proposal the genotypic analysis of the available parents.

Details of resources requested:

- Biological materials

We have enough DNA for the children cohort to carry out this project. we will perform the genetic analysis here at the Wellcome trust Centre for Human genetics using the I-plex sequenom system. We are planning to analyse in the parents only specific SNPs and, if possible, we would like to genotype these through the K-Biosciences service.

-Existing data

We would like to include in this project the analysis of genes already genotyped in the ALSPAC sample by different research groups. In some case we would like to use the existing genotypic data (providing the quality is good) and in other cases we would to genotype additional markers.

- Phenotypic measures

We would like to include in this project all the outcomes that we have already accessed through the our previous project DTA (B566) and the ones we will finalise for the B598 project. I anticipate that we might add some specific extra measures but the the basic "concepts" will be the same.

- Data linking

We would like the genotypic data to be linked to the database including the genotypes generated in our previous projects. If possible we would like to use the same old codes otherwise we are happy to get a new code as long as all the genotypes will be included.

-Statistical analysis

We would like to choose the option of performing the staitical analysis in our laboratory.

Details of funding

This project will be part of my next fellowship applications. I am planning to apply to the Wellcome Trust, MRC, Royal Society and European Council aiming to a project starting date in Oct 2010. I will submit to ALSPAC copies of my application for your approval before submitting to funding bodies.