To determine whether exposure to specific dietary factors in utero and infancy influences cognition.

Specific Hypotheses:

1) Suboptimum levels of specific nutrients such as folate and omega-3 fatty acids in utero lead to impaired neurodevelopment and low cognitive ability.

2) Polymorphisms in genes which metabolise nutrients are associated with neurodevelopment in infancy and can be used to infer causal relationships between specific nutrients and cognition.

3) Maternal genotype and corresponding offspring genotype, jointly determine neurodevelopment in infancy and childhood. Associations with maternal genotype, independent of offspring genotype, will support the role of the prenatal environment.

Neuroanatomical and neurophysiological studies show that brain development occurs most rapidly during fetal development and in infancy. Nutrition is probably the single greatest environmental influence both on the fetus and neonate, and plays a necessary role in the maturation and functional development of the central nervous system. Therefore a lack of any nutrient required for brain development may be related to neurodevelopmental diseases such as autism as well as influencing general cognition. Nutrients found to be lacking in the mothers' diet could, if shown to be related to brain development, be modified to prevent disease and ensure that the childs' cognitive ability is not impaired.

We plan to:

1) Genotype mothers and their offspring with respect to candidate polymorphisms which influence nutrient intake, metabolism, transport or cellular uptake.

2) Determine associations between the above maternal and infant polymorphisms and childhood cognition.

3) Stratifying by offspring genotype, determine associations between maternal genotype and offspring cognition.

4) Investigate whether the above polymorphisms are associated with cigarette smoking, socioeconomic status, reproductive factors and other potential confounders in the mothers, to confirm that developmental outcome associations with genotypes are not confounded.

Genotype analysis

Variation in genes which alter the availability of specific nutrients will be exploited in this project. Suitable candidate genes include those which are; a) associated with nutrient intake, such as the lactase gene, polymorphisms of which determine lactose intolerance and therefore intake of lactose b) involved in nutrient metabolism, for example there are several enzymes involved in the biosynthesis of the omega-3 fatty acid DHA from its' precursors in the diet including cycloxygenase (COX), lipoxygenase (LOX) and delta-5 desaturase, c) important in the transport and internalization of nutrients into target cells, such as the choline transporter (CHT1) gene. Genotyping of SNPs will be carried by K-Biosciences (http://www.kbioscience.co.uk).

Outcome measurements

The primary outcome will be the Wechsler Intelligence Scale for Children (WISC)-III, which is a UK measure of cognitive ability (IQ) measured at the focus clinic at age 8 1/2 (score available for 7188 children). Education is strongly influenced by political and social factors and is therefore less likely to be due to mothers' diet, however, educational scores will be secondary outcomes in this study as education is likely to be important in the pathway between cognition and later health. Additional outcome measures will be included in this project as they may provide insights into specific aspects of neurodevelopment that may be particularly sensitive to maternal dietary influences in-utero. The secondary outcomes are:

* Wechsler Objective Reading Dimensions (WORD) test and the Wechsler Objective Language Dimension (WOLD) Test - which measure reading and language respectively,

* Social Communication Disorders Checklist (SCDC), - measures social interaction and communication skills.

* Development and Well-Being Assessment (DAWBA) and the Strengths and Difficulties Questionaire (SDQ) - both designed to measure conduct problems, emotional behaviour and hyperactivity,

* School and hospital diagnosed learning difficulties - will pick up individuals with clinically diagnosed conditions.

* SATS test scores and GCSE results are included in the list of outcomes to determine whether dietary effects on cognition, are translated into school performance. We would only explore associations with this outcome where there was a positive association of a maternal dietary factor with cognitive ability. Thus, this would extend the primary analysis to provide an indication of whether the effect of maternal diet on cognition had an important effect on performance.

* Head circumference- this is a more crude measure of brain development than the other outcome measures proposed in this grant. However, it was measured at birth for all children in the ALSPAC study and as this is an indicator which relates specifically to in-utero development.

The large number of tests generated by having several outcomes will increase the possibility of false positive results. In order to guard against this we will:

* Undertake secondary analyses only when there is an indication to do so from the primary analyses (e.g. with school performance)

* Seek to replicate any positive results (with primary or secondary outcomes) in other cohort studies as described in the proposal.