Aims:

1. To determine whether visual and cognitive phenotypes cluster together within a normal population cohort of children.

2. To determine the underlying genetic associations of visual and cognitive phenotypes on a genome-wide basis in a normal population cohort.

3. To extrapolate datasets from animal models of associated visual and cognitive disorders, e.g. genes expressed in interneuron populations both in the retina and CNS, and investigate these candidate genes (within the datasets obtained as above) for associations with visual and cognitive phenotypes in a normal population cohort (this mouse data is already available from my lab).

Hypotheses:

Eye development in different organisms produces dramatically different structures, like the compound eye of insects and the camera-like eye of vertebrates. Nevertheless, the molecular mechanisms underlying eye specification are highly conserved (1), and the study of eye development in animal models has proven to be highly informative of the regulatory events that control human eye formation. For example, Pax6 was identified as a 'master' regulator, at the top of the hierarchical network of transcription factors (TFs) involved in eye development, since loss-of-function mutations of the eyeless gene (the Pax6 Drosophila homologue) lead to an eyeless phenotype (2) and over-expression can direct the formation of histologically normal ectopic eyes in flies (2) and in some vertebrates. Furthermore, recent work has established that the evolutionary conservation of the visual system extends beyond eye specification (by genes like Pax6) to include the visual system circuitry that connects the eye to the brain (1). Pax6 mutations in mice cause the small eye phenotype, and human PAX6 mutations lead to eye malformations including aniridia and other anomalies, while homozygotes demonstrate malformations of the central nervous system (CNS)(3). More recent work has shown that heterozygote PAX6 mutations are also associated with previously unrecognised and subtle structural brain abnormalities and cognitive deficits in humans (4). Furthermore, distant regulatory enhancer sequences influence transcription of Pax6 in mice, and consequently lead to eye abnormalities without any associated mutations of the Pax6 gene itself (5). While Pax6 is the most well-studied gene influencing eye development, several others are known to regulate interneuron development in the retina and CNS in an increasing number of animal models. Based on these data, we would predict that children carrying genetic polymorphisms and/or mutations in genomic regions encompassing so-called retinal and CNS "interneuron genes" would manifest deficits in vision and/or cognition.