1) Strabismus (Squint)

Strabismus (squint) is a misalignment of the eyes so that they are looking in different directions. It is one of the most prevalent neurological abnormalities seen in children; 2% - 4% being affected in white populations. It is associated with reduced ability to combine the images from each eye and often with reduced vision in one or both eyes. Surgery may be required to alleviate double vision, an abnormal compensatory head posture or most frequently for social and interpersonal difficulties.

There are several types of strabismus. ie different strabismus phenotypes, and there is evidence to suggest heritability for most of these. However, only for some of the rare (approx 5% cases) phenotypes involving incomitant strabismus (ie dependent on the direction of gaze) have specific genetic loci been described (Engle et al). These genes also affect other aspects of brain development. Far more prevalent are the comitant convergent or divergent strabismus phenotypes. These differ in prevalence between ethnic groups, are seen with more concordance in monozygotic than dizygotic twins and are seen more often in individuals with a family history of the same condition (Podgor et al).

There are, however, no candidate genes identified so far which map to more than one family. No Genome Wide Association (GWA) studies for strabismus have been reported to date. Understanding the genetic factors which contribute to keeping the eyes straight will help early identification and treatment of the many affected individuals as well as potentially providing important information about ocular and brain development.

ALSPAC is uniquely well placed to support a small but important study in this area because the study has accurate phenotypic data (at age 7 yrs) enabling the types of strabismus and related defects (eg amblyopia) to be clearly identified and GWA data on a subset of participants. We have already published data on risk factors for the two most frequently seen types of strabismus -convergent (211 children, 2.8%) and divergent (45 children, 0.6%), including an adjusted Odds Ratio (OR) of 2.37 for a positive family history as a predictor of convergent strabismus, after accounting for a key known environmental risk factor (prematurity) (Williams et al 2008).

Thus we will use existing 7-yr vision data ("clinically significant convergent strabismus" as in ref 3, plus amblyopia and or binocular vision data as needed), plus the GWA data

2) Stereopsis (binocular vision)

Stereopsis (depth perception) is one benefit of the fact we have two eyes, separated on the head, from which information can usefully be combined. Other manifestations are motor fusion (the ability to move the eyes separately to keep the object of regard in the visual axis for each eye), diplopia and binocular rivalry. The mechanisms for development of binocular vision remain poorly understood but may well be highly conserved as many species have evolved with two eyes in the front of the head.

Evidence from identical twin studies shows precision of stereoscopic depth perception may be heritable (Wilmer et al). That prevalence of primary monofixation syndrome in parents of children with congenital esotropia (Scott et al) is higher than the general population also supports the hypothesis that a hereditary abnormality in disparity sensitivity may be associated with infantile esotropia (convergent squint).

There are no GWA studies in this area. Some metabolic pathways have been linked to the development of stereopsis or binocular vision eg those relating to plasticity in the visual cortex (Cnops et al) and it can be conjectured that those relating to the metabolism of key neural components such as docosahexaenoic acid (DHA) may be implicated as there is evidence (from ALSPAC) that early exposure to DHA affects stereopsis development (ref 5)

ALSPAC data are ideal for an exploratory GWA analysis of the genetic predictors of stereopsis. We have assessed stereopsis at ages 7 and 11 using a well-established clinical test (the "Randot") and at 12 (n = 2000) using a newly designed stereotest which has been designed to avoid some of the flaws in the Randot and other more established tests. In addition ALSPAC has data on related factors such as strabismus, which may need to be included. Identification of genes involved in this important and basic cognitive function could enhance our understanding of brain development in general and of a range of vision problems, with better identification and treatments made possible. Thus we will use the stereo data and related ocular data as needed, plus the GWA data.

References:

1. Engle. Arch Ophthalmol. 2007;125(2):189-195

2. Podgor et al Arch Ophthalmol. 1996 Jun;114(6):739-44.

3. Williams et al Br J Ophthalmol 2008; 92: 959-964

4. Cnops et al Cerebral Cortex 2008 18(5):1221-1231

5. Williams et al Am J Clin Nutr 2001;73:316-22.

6. Wilmer et al Journal of Vision 2007;7:831

7. Scott et al J Pediatr Ophthalmol Strabismus 1994;31:298-301; discussion 302